Biomedical subjects

Henry Huang

Publications and source records attributed to Henry Huang.

8 recordsLinked to original sources

PubMed2006

A positive feedback loop promotes transcription surge that jump-starts Salmonella virulence circuit.

The PhoP/PhoQ two-component system is a master regulator of Salmonella pathogenicity. Here we report that induction of the PhoP/PhoQ system results in an initial surge of PhoP phosphorylation; the occupancy of target promoters by the PhoP protein; and the transcription of PhoP-activated genes, which then subsides to reach new steady-state levels. This surge in PhoP activity is due to PhoP positively activating its own transcription, because a strain constitutively expressing the PhoP protein attained steady-state levels of activation asymptotically, without the surge. The strain constitutively expressing the PhoP protein was attenuated for virulence in mice, demonstrating that the surge conferred by PhoP's positive feedback loop is necessary to jump-start Salmonella's virulence program.

Animals↗

PubMed2006

Manifold learning for robot navigation.

In this paper we introduce methods to build a SOM that can be used as an isometric map for mobile robots. That is, given a dataset of sensor readings collected at points uniformly distributed with respect to the ground, we wish to build a SOM whose neurons (prototype vectors in sensor space) correspond to points uniformly distributed on the ground. Manifold learning techniques have already been used for dimensionality reduction of sensor space in navigation systems. Our focus is on the isometric property of the SOM. For reliable path-planning and information sharing between several robots, it is desirable that the robots build an internal representation of the sensor manifold, a map, that is isometric with the environment. We show experimentally that standard Non-Linear Dimensionality Reduction (NLDR) algorithms do not provide isometric maps for range data and bearing data. However, the auxiliary low dimensional manifolds created can be used to improve the distribution of the neurons of a SOM (that is, make the neurons more evenly distributed with respect to the ground). We also describe a method to create an isometric map from a sensor readings collected along a polygonal line random walk.

Artificial Intelligence↗

PubMed2005

Analysis of differentially-regulated genes within a regulatory network by GPS genome navigation.

MOTIVATION: A critical challenge of the post-genomic era is to understand how genes are differentially regulated even when they belong to a given network. Because the fundamental mechanism controlling gene expression operates at the level of transcription initiation, computational techniques have been developed that identify cis regulatory features and map such features into expression patterns to classify genes into distinct networks. However, these methods are not focused on distinguishing between differentially regulated genes within a given network. Here we describe an unsupervised machine learning method, termed GPS for gene promoter scan, that discriminates among co-regulated promoters by simultaneously considering both cis-acting regulatory features and gene expression. GPS is particularly useful for knowledge discovery in environments with reduced datasets and high levels of uncertainty. RESULTS: Application of this method to the enteric bacteria Escherichia coli and Salmonella enterica uncovered novel members, as well as regulatory interactions in the regulon controlled by the PhoP protein that were not discovered using previous approaches. The predictions made by GPS were experimentally validated to establish that the PhoP protein uses multiple mechanisms to control gene transcription, and is a central element in a highly connected network. AVAILABILITY: The scripts and programs used in this work are accessible from the gps-tools.wustl.edu website. Data and predictions are available by request.

Algorithms↗

PubMed2005

Dissecting the PhoP regulatory network of Escherichia coli and Salmonella enterica.

Genetic and genomic approaches have been successfully used to assign genes to distinct regulatory networks. However, the present challenge of distinguishing differentially regulated genes within a network is particularly hard because members of a given network tend to have similar regulatory features. We have addressed this challenge by developing a method, termed Gene Promoter Scan, that discriminates coregulated promoters by simultaneously considering both multiple cis promoter features and gene expression. Here, we apply this method to probe the regulatory networks governed by the PhoP/PhoQ two-component system in the enteric bacteria Escherichia coli and Salmonella enterica. Our analysis uncovered members of the PhoP regulon and interactions with other regulatory systems that were not discovered in previous approaches. The predictions made by Gene Promoter Scan were experimentally validated to establish that the PhoP protein uses multiple mechanisms to control gene transcription, regulates acid resistance determinants, and is a central element in a highly connected network.

Bacterial Proteins↗

PubMed2003

Pharmacological and genetic characterization of two selective serotonin transporter ligands: 2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine (AFM) and 3-amino-4-[2-(dimethylaminomethyl-phenylthio)]benzonitrile (DASB).

The expression and function of the serotonin transporter (SERT) is important in the regulation of mood and emotion. Determination of SERT alterations in physiological and pathological states is essential for understanding the role of SERT in mood regulation, and in the etiology and therapy of psychiatric disorders. Two SERT ligands, AFM ([(3)H]2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine) and DASB ([(3)H]3-amino-4-[2-(dimethylaminomethylphenylthio)]benzonitrile), have recently been developed for positron emission tomography (PET) imaging. The aim of the present study was to determine the selectivity of these compounds for SERT. Autoradiography of AFM or DASB binding was compared in the brains of mice with genetically normal, diminished, or absent SERT. In addition, the pharmacodynamic profile of [(3)H]AFM was examined in the mouse brain. The distribution of [(3)H]AFM and [(3)H]DASB binding in the normal brains was consistent with that of previously studied serotonin reuptake inhibitors. Both ligands had negligible binding in the brain of SERT knockout mice, and binding was reduced approximately 50% in heterozygote SERT mice. The K(d) of [(3)H]AFM binding in the cortex and midbrain was 1.6 and 1.0 nM, respectively. Competition studies showed that [(3)H]AFM has very low affinity for norepinephrine and dopamine transporters as well as 5-HT receptors, including 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(2C) receptors. In addition, fenfluramine showed a low capability to compete with [(3)H]AFM. The present results suggest that both AFM and DASB are highly selective SERT ligands potentially suitable for use in human PET studies of SERT.

Aniline Compounds↗

PubMed2003

Wavelength-tunable semiconductor pump diode for reconfigurable Raman amplification.

We demonstrate a wavelength-tunable semiconductor pump diode for Raman amplification. Thediode is stabilized by a fiber Bragg grating (FBG) that can be continuously tuned over more than 20 nm. Tuning of the diode output wavelength is achieved by varying the center wavelength of the FBG, since the diode preferentially lases within the FBG bandwidth. We investigate the effects of wavelength tuning on the diode spectrum on its corresponding Raman gain, and on pump-pump four-wave mixing in fiber having zero-dispersion wavelength coincident with the Raman pumps.

Journal Article↗

PubMed2002

The effect of different tumor groupings on findings of anticarcinogenic responses in long-term rodent bioassays.

Many investigators have found that there is a decrease in tumor rates at some sites when rodents are exposed to some chemicals. The generality of this finding of anticarcinogenicity has been questioned. In this study, we evaluate the effect of several alternative ways of grouping the 3000 tumor types in the Cancer Bioassay Data System (CBDS) database of carcinogenesis test results into a limited number of classes on findings of anticarcinogenicity. We also study the influence of random variation of tumor rate on the apparent anticarcinogenic effects of specific chemicals. We compare the numbers of chemicals classified as anticarcinogenic in (1) our "standard" classification system, (2) a modification of that system to correct some deficiencies in the CBDS database pointed out by Dr. J. Haseman, (3) an alternative classification system developed by Dr. K. S. Crump and colleagues, (4) the number of animals displaying at least one tumor, or (5) the total number of tumors appearing in all animals in control and dosed groups. Although there is a difference in the number of chemicals classified as anticarcinogens by these alternative classification schemes, all of them show a statistically significant increase in the number of anticarcinogenic responses above the random rate predicted by a Monte Carlo simulation of the rodent bioassay. The number of anticarcinogenic responses is similar in our standard classification, our modified classification, and a classification scheme developed by Crump, though specific site/organs may differ. This arises because these schemes use approximately the same number of tumor groups (about 100). If the number of tumor groups decreases (for example, in the total tumors or tumor-bearing animal schemes), the number of anticarcinogenic responses decreases because of the decrease in overall sensitivity of the test. A scheme which combines tumor types can be useful by integrating carcinogenic and anticarcinogenic responses to exposure. At the same time, combination may hide important biological information. We urge consideration of both increases and decreases when evaluating the likely human effects of exposure.

Animals↗

PubMed2002

Conflicting needs for a Salmonella hypervirulence gene in host and non-host environments.

The Gram-negative pathogen Salmonella enterica harbours a periplasmic D-Ala-D-Ala dipeptidase (termed PcgL), which confers the ability to grow on D-Ala-D-Ala as sole carbon source. We now demonstrate that inactivation of the pcgL gene renders Salmonella hypervirulent. This phenotype results from the accumulation of peptidoglycan-derived D-Ala-D-Ala in the pcgL mutant and not from an intrinsically faster growth rate. Synthetic D-Ala-D-Ala (but not L-Ala-L-Ala or D-Ala) increased the number of wild-type Salmonella in the liver and spleen of mice within 24 h of injection, suggesting that D-Ala-D-Ala interferes with some aspect of innate immunity. However, the pcgL mutant was unable to grow on D-Ala-D-Ala as sole carbon source and was defective for survival in nutrient-poor conditions. We identified clinical isolates lacking D-Ala-D-Ala dipeptidase activity and unable to grow on D-Ala-D-Ala because of inactivation of the pcgL gene. Our data suggest that genes (such as pcgL) that, when mutated make pathogens more virulent, may be retained because their contribution to pathogen fitness in non-host environments outweighs potential advantages of the hypervirulent vari-ant in the infected host.

Amino Acid Transport Systems↗