794 research outputs found
Adaptive whitening in neural populations with gain-modulating interneurons
Statistical whitening transformations play a fundamental role in many
computational systems, and may also play an important role in biological
sensory systems. Existing neural circuit models of adaptive whitening operate
by modifying synaptic interactions; however, such modifications would seem both
too slow and insufficiently reversible. Motivated by the extensive neuroscience
literature on gain modulation, we propose an alternative model that adaptively
whitens its responses by modulating the gains of individual neurons. Starting
from a novel whitening objective, we derive an online algorithm that whitens
its outputs by adjusting the marginal variances of an overcomplete set of
projections. We map the algorithm onto a recurrent neural network with fixed
synaptic weights and gain-modulating interneurons. We demonstrate numerically
that sign-constraining the gains improves robustness of the network to
ill-conditioned inputs, and a generalization of the circuit achieves a form of
local whitening in convolutional populations, such as those found throughout
the visual or auditory systems.Comment: 20 pages, 10 figures (incl. appendix). To appear in the Proceedings
of the 40th International Conference on Machine Learnin
Effective affinities in microarray data
In the past couple of years several studies have shown that hybridization in
Affymetrix DNA microarrays can be rather well understood on the basis of simple
models of physical chemistry. In the majority of the cases a Langmuir isotherm
was used to fit experimental data. Although there is a general consensus about
this approach, some discrepancies between different studies are evident. For
instance, some authors have fitted the hybridization affinities from the
microarray fluorescent intensities, while others used affinities obtained from
melting experiments in solution. The former approach yields fitted affinities
that at first sight are only partially consistent with solution values. In this
paper we show that this discrepancy exists only superficially: a sufficiently
complete model provides effective affinities which are fully consistent with
those fitted to experimental data. This link provides new insight on the
relevant processes underlying the functioning of DNA microarrays.Comment: 8 pages, 6 figure
The Structure of the Big Bang from Higher-Dimensional Embeddings
We give relations for the embedding of spatially-flat
Friedmann-Robertson-Walker cosmological models of Einstein's theory in flat
manifolds of the type used in Kaluza-Klein theory. We present embedding
diagrams that depict different 4D universes as hypersurfaces in a higher
dimensional flat manifold. The morphology of the hypersurfaces is found to
depend on the equation of state of the matter. The hypersurfaces possess a
line-like curvature singularity infinitesimally close to the
3-surface, where is the time expired since the big bang. The family of
timelike comoving geodesics on any given hypersurface is found to have a
caustic on the singular line, which we conclude is the 5D position of the
point-like big bang.Comment: 11 pages, 5 figures, revtex4, accepted in Class. Quant. Gra
Preparation of anti-vicinal amino alcohols: asymmetric synthesis of D-erythro-Sphinganine, (+)-spisulosine and D-ribo-phytosphingosine
Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM-ether directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D-erythro-sphinganine and the antitumor agent (+)-spisulosine, while the Overman rearrangement of chiral allylic trichloroacetimidates generated by asymmetric reduction of an alpha,beta-unsaturated methyl ketone allowed rapid access to both D-ribo-phytosphingosine and L-arabino-phytosphingosine
Highly Diastereo- and Enantioselective CuH-Catalyzed Synthesis of 2,3-Disubstituted Indolines
A diastereo- and enantioselective CuH-catalyzed method for the preparation of highly functionalized indolines is reported. The mild reaction conditions and high degree of functional group compatibility as demonstrated with substrates bearing heterocycles, olefins, and substituted aromatic groups, renders this technique highly valuable for the synthesis of a variety of cis-2,3-disubstituted indolines in high yield and enantioeselectivity.National Institutes of Health (U.S.) (Award GM46059)Danish Council for Independent Research (Postdoctoral Fellowship
Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer
Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven-step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2'-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product.P50 GM067041 - NIGMS NIH HHS; R01 GM099920 - NIGMS NIH HHS; GM-067041 - NIGMS NIH HHS; GM-099920 - NIGMS NIH HH
Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols
The chirality, or ‘handedness’, of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge3. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.National Institutes of Health (U.S.) (Grant GM-58160
Washing scaling of GeneChip microarray expression
BACKGROUND Post-hybridization washing is an essential part of microarray experiments. Both the quality of the experimental washing protocol and adequate consideration of washing in intensity calibration ultimately affect the quality of the expression estimates extracted from the microarray intensities. RESULTS We conducted experiments on GeneChip microarrays with altered protocols for washing, scanning and staining to study the probe-level intensity changes as a function of the number of washing cycles. For calibration and analysis of the intensity data we make use of the 'hook' method which allows intensity contributions due to non-specific and specific hybridization of perfect match (PM) and mismatch (MM) probes to be disentangled in a sequence specific manner. On average, washing according to the standard protocol removes about 90% of the non-specific background and about 30-50% and less than 10% of the specific targets from the MM and PM, respectively. Analysis of the washing kinetics shows that the signal-to-noise ratio doubles roughly every ten stringent washing cycles. Washing can be characterized by time-dependent rate constants which reflect the heterogeneous character of target binding to microarray probes. We propose an empirical washing function which estimates the survival of probe bound targets. It depends on the intensity contribution due to specific and non-specific hybridization per probe which can be estimated for each probe using existing methods. The washing function allows probe intensities to be calibrated for the effect of washing. On a relative scale, proper calibration for washing markedly increases expression measures, especially in the limit of small and large values. CONCLUSIONS Washing is among the factors which potentially distort expression measures. The proposed first-order correction method allows direct implementation in existing calibration algorithms for microarray data. We provide an experimental 'washing data set' which might be used by the community for developing amendments of the washing correction.This publication is supported by the Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universität Leipzig) and an Australian Academy of Science Visits to Europe grant. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERFD) and by means of the Free State of Saxony within the framework of the excellence initiative
Copper-catalysed selective hydroamination reactions of alkynes
The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.National Institutes of Health (U.S.) (GM58160
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