A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Background

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929–1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.

Results

Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.

Conclusion

The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.

Unconditional constants and polynomial inequalities

If P is a polynomial on Rm of degree at most n then we define the polynomial |P|. Now if B is a convex compact set in Rm, we define the norm ||P||B of P as the maximum of P on B, and then we investigate the inequality || |P| ||B

Mixed-dimensional coupling in finite element models

In many finite element analysis models it would be desirable to combine reduced- or lower-dimensional element types with higher-dimensional element types in a single model. In order to achieve compatibility of displacements and stress equilibrium at the junction or interface between the differing element types, it is important in such cases to integrate into the analysis some scheme for coupling the element types. A novel and effective scheme for establishing compatibility and equilibrium at the dimensional interface is described and its merits and capabilities are demonstrated. Copyright (C) 2000 John Wiley & Sons, Ltd.

An experimental investigation into the influence of user state and environment on fading characteristics in wireless body area networks at 2.45 GHz

Using seven strategically placed, time-synchronized bodyworn receivers covering the head, upper front and back torso, and the limbs, we have investigated the effect of user state: stationary or mobile and local environment: anechoic chamber, open office area and hallway upon first and second order statistics for on-body fading channels. Three candidate models were considered: Nakagami, Rice and lognormal. Using maximum likelihood estimation and the Akaike information criterion it was established that the Nakagami-m distribution best described small-scale fading for the majority of on-body channels over all the measurement scenarios. When the user was stationary, Nakagami-m parameters were found to be much greater than 1, irrespective of local surroundings. For mobile channels, Nakagami-m parameters significantly decreased, with channels in the open office area and hallway experiencing the worst fading conditions.

Characterization and modeling of on-body spatial diversity within indoor environments at 868 MHz

For the first time in the open literature we present a full characterization of the performance of receiver diversity for the on-body channels found in body area networks. The study involved three commonly encountered diversity combining schemes: selection combination (SC), maximal ratio combining (MRC) and equal gain combining (EGC). Measurements were conducted for both stationary and mobile user scenarios in an anechoic chamber and open office area environment. Achievable diversity gain for various on-body dual branch diversity receivers, consisting of horizontal and vertical spatially separated antennas, was found to be dependent upon transmitter-receive array separation, user state and level of multipath contribution from the local environment. The maximum diversity gain (6.4 dB) was observed for a horizontal two branch MRC combiner while the transmitter and receiver were on opposite sides of the body, and the user was mobile in the open office area. A novel statistical characterization of the fading experienced in on-body diversity channels is also performed using purposely derived first and second order diversity statistics for combiners operating in Nakagami fading.

Multidimensional operator multipliers

We introduce multidimensional Schur multipliers and characterise them, generalising well-known results by Grothendieck and Peller. We define a multidimensional version of the two-dimensional operator multipliers studied recently by Kissin and Shulman. The multidimensional operator multipliers are defined as elements of the minimal tensor product of several C *-algebras satisfying certain boundedness conditions. In the case of commutative C*-algebras, the multidimensional operator multipliersreduce to continuousmul-tidimensional Schur multipliers. We show that the multiplierswith respect to some given representations of the corresponding C*-algebrasdo not change if the representations are replaced by approximately equivalent ones. We establish a non-commutative and multidimensional version of the characterisations by Grothendieck and Peller which shows that universal operator multipliers can be obtained ascertain weak limits of elements of the algebraic tensor product of the corresponding C *-algebras.

Bimodules over nest algebras and Deddens'

We generalise Dedden's Theorem for nest algebras to nest algebra bimodules. We define an object which extends the Jacobson radical of a nest algebra, and characterose it generalising a theorem of Erdos.

A Cyclotomic Lattice Based Quasi-Orthogonal STBC for Eight Transmit Antennas

In this letter, we propose a lattice-based full diversity design for rate-one quasi-orthogonal space time block codes (QSTBC) to obtain an improved diversity product for eight transmit antennas where the information bits are mapped into 4-D lattice points instead of the common modulation constellations. Particularly, the diversity product of the proposed code is directly determined by the minimum Euclidean distance of the used lattice and can be improved by using the lattice packing. We show analytically and by using simulation results that the proposed code achieves a larger diversity product than the rate-one QSTBCs reported previously.

Analysis of Receiver Algorithms for LTE SC-FDMA Based Uplink MIMO Systems

This letter derives mathematical expressions for the received signal-to-interference-plus-noise ratio (SINR) of uplink Single Carrier (SC) Frequency Division Multiple Access (FDMA) multiuser MIMO systems. An improved frequency domain receiver algorithm is derived for the studied systems, and is shown to be significantly superior to the conventional linear MMSE based receiver in terms of SINR and bit error rate (BER) performance.

Iterative Multiuser Detection and Decoding for DS-CDMA System With Space-Time Linear Dispersion

This paper considers a Q-ary orthogonal direct-sequence code-division multiple-access (DS-CDMA) system with high-rate space-time linear dispersion codes (LDCs) in time-varying Rayleigh fading multiple-input-multiple-output (MIMO) channels. We propose a joint multiuser detection, LDC decoding, Q-ary demodulation, and channel-decoding algorithm and apply the turbo processing principle to improve system performance in an iterative fashion. The proposed iterative scheme demonstrates faster convergence and superior performance compared with the V-BLAST-based DS-CDMA system and is shown to approach the single-user performance bound. We also show that the CDMA system is able to exploit the time diversity offered by the LDCS in rapid-fading channels.

A New Restricted Full-Rank Single-Symbol Decodable Design for Four Transmit Antennas

Recently, a single-symbol decodable transmit strategy based on preprocessing at the transmitter has been introduced to decouple the quasi-orthogonal space-time block codes (QOSTBC) with reduced complexity at the receiver [9]. Unfortunately, it does not achieve full diversity, thus suffering from significant performance loss. To tackle this problem, we propose a full diversity scheme with four transmit antennas in this letter. The proposed code is based on a class of restricted full-rank single-symbol decodable design (RFSDD) and has many similar characteristics as the coordinate interleaved orthogonal designs (CIODs), but with a lower peak-to-average ratio (PAR).

On the Uncoded BER Performance Bound of the IEEE 802.16d Channel

In this letter, the performance bound of the IEEE 802.16d channel is examined analytically in order to gain an insight into its theoretical potential. Different design strategies, such as orthogonal frequency division multiplexing (OFDM) and single-carrier frequency-domain equalization (SC-FDE), time-domain decision feedback equalization (DFE), and sphere decoder (SD) techniques are discussed and compared to the theoretical bound.

Hierarchical coordination of periodic genes in the cell cycle of Saccharomyces cerevisiae

Background: Gene networks are a representation of molecular interactions among genes or products thereof and, hence, are forming causal networks. Despite intense studies during the last years most investigations focus so far on inferential methods to reconstruct gene networks from experimental data or on their structural properties, e.g., degree distributions. Their structural analysis to gain functional insights into organizational principles of, e.g., pathways remains so far under appreciated.

Information processing in the transcriptional regulatory network of yeast: Functional robustness

Background: Gene networks are considered to represent various aspects of molecular biological systems meaningfully because they naturally provide a systems perspective of molecular interactions. In this respect, the functional understanding of the transcriptional regulatory network is considered as key to elucidate the functional organization of an organism.