Mining gene expression profiles: an integrated implementation of kernel principal component analysis and singular value decomposition

The detection of genes that show similar profiles under different experimental conditions is often an initial step in inferring the biological significance of such genes. Visualization tools are used to identify genes with similar profiles in microarray studies. Given the large number of genes recorded in microarray experiments, gene expression data are generally displayed on a low dimensional plot, based on linear methods. However, microarray data show nonlinearity, due to high-order terms of interaction between genes, so alternative approaches, such as kernel methods, may be more appropriate. We introduce a technique that combines kernel principal component analysis (KPCA) and Biplot to visualize gene expression profiles. Our approach relies on the singular value decomposition of the input matrix and incorporates an additional step that involves KPCA. The main properties of our method are the extraction of nonlinear features and the preservation of the input variables (genes) in the output display. We apply this algorithm to colon tumor, leukemia and lymphoma datasets. Our approach reveals the underlying structure of the gene expression profiles and provides a more intuitive understanding of the gene and sample association.     

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

Background

Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study.

Methods

From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors.

Results

Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of ≥66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk.

Conclusions

We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.     

First record of Hesperolabops nigriceps Reuter (Hemiptera: Miridae) on Opuntia ficus-indica in Milpa Alta, Mexico City

In recent years a species of Hesperolabops has become a problem as a pest of nopalitos, Opuntia ficus-indica, in Milpa Alta, in the south of Mexico City, which is the most important production region of this vegetable in the country. A survey of Hesperolabops in Milpa Alta has resulted in the first report of Hesperolabops nigriceps Reuter. This occurrence should be monitored and considered in future studies in order to avoid misidentification of Hesperolabops spp. Kirkaldy native populations there, and to avoid the confusion of the damage that may be caused on O. ficus-indica.     

The Role of <Emphasis Type="SmallCaps">l</Emphasis>-arginine in Inclusion Complexes of Omeprazole with Cyclodextrins

In this study, we investigate how the effect of l-arginine (ARG) and cyclodextrins upon omeprazole (OME) stability and solubility. The effect of the presence of ARG on the apparent stability constants (K_1:1) of the inclusion complexes formed between OME and each cyclodextrin, β-cyclodextrin (βCD), and methyl-β-cyclodextrin (MβCD) is studied by phase solubility diagrams and nuclear magnetic resonance (NMR) spectroscopy. The interaction of OME with those cyclodextrins, in the presence of ARG, is characterized using NMR spectroscopy and molecular dynamics simulations. ARG significantly increases the drug solubility and complex stability, in comparison to inclusion complexes formed in its absence. The effect is more pronounced for the OME:βCD complex. ARG also contributes to a larger stability of OME when free in aqueous solution. The combination of ARG with cyclodextrins can represent an important tool to develop stable drug formulations.     

Development of novel plasmid vectors and a promoter trap system in Francisella tularensis compatible with the pFLN10 based plasmids

Francisella tularensis is a category A bioterror pathogen which in some cases can cause a severe and fatal human infection. Very few virulence factors are known in this species due to the difficulty in working with it as well as the lack of tools for genetic manipulation. This work describes the construction of a shuttle vector that can replicate in Escherichia coli and F. tularensis as well as two distinct promoter trap constructs based on the shuttle vector backbone. Replication in F. tularensis is based on the promiscuous origin of replication from the Staphylococcus aureus plasmid pC194. We demonstrate the novel plasmids can coexist with established F. tularensis vectors based on the pFNL10 plasmid, the current workhorse of F. tularensis genetics. Our promoter trap can identify promoters that are activated during intracellular growth and survival. These new vectors provide additional tools for the genetic manipulation of F. tularensis.     

Interactions of the RNA polymerase with the viral genome at the 5'- and 3'-ends contribute to 20S RNA narnavirus persistence in yeast

20S RNA narnavirus is a positive strand RNA virus found in the yeast Saccharomyces cerevisiae. The viral genome (2514 nucleotides) only encodes a single protein (p91), the RNA-dependent RNA polymerase and does not have capsid proteins to form intracellular virions. The genomic RNA has no 3' poly(A) tail and perhaps no cap structure at the 5'-end; thus resembling an intermediate of mRNA degradation. The virus, however, escapes the host surveillance and replicates in the yeast cytoplasm persistently. The viral genome is not naked but exists in the form of a ribonucleoprotein complex with p91 in a 1:1 stoichiometry. Here we investigated interactions between p91 and the viral genome. Our results indicate that p91 directly or indirectly interacts with the RNA at the 5'- and 3'-end regions and to a lesser extent at a central part. The 3'-end site is identical to or overlaps with the 3' cis signal for replication identified previously. The 5'-site is at the second stem loop structure from the 5'-end (nucleotides 72-104), and this structure also contains a cis signal for replication. Analysis of mutants in the structure revealed a tight correlation between replication and formation of complexes. These results highlight the importance of ribonucleoprotein complexes for the viral life cycle. We will discuss implications of these findings especially on how the virus escapes from mRNA degradation pathways and resides in the cytoplasm persistently despite the lack of a protective capsid.     

Indirect mechanism of histamine-induced nociception in temporomandibular joint of rats

A considerable amount of evidence suggests that temporomandibular joint (TMJ) pain associated with temporomandibular disorder results, at least in part, from an inflammatory episode. Although histamine can cause pain, it is not clear whether this mediator induces nociception in the TMJ. In this study, we investigated the contribution of endogenous histamine to formalin-induced nociception in the TMJ of rats. We also investigated whether the administration of histamine induces nociception in the TMJ and, if so, whether this effect is mediated by an indirect action on primary afferent nociceptors. Local administration of the H1-receptor antagonist pyrilamine prevented formalin-induced nociception in the TMJ in a dose-dependent manner. Local administration of histamine (250 microg) in the TMJ induced nociceptive behavior that was inhibited by co-administration of the lidocaine N-ethyl bromide quaternary salt QX-314 (2%) or the selective H1-receptor antagonist pyrilamine (400 microg). Nociception induced by histamine was also inhibited by pre-treatment with sodium cromoglycate (800 microg) and by co-administration of the 5-HT(3) receptor antagonist tropisetron (400 mug), while pyrilamine (400 mug) did not inhibit nociception induced by 5-hydroxytryptamine (5-HT, 250 microg) in the TMJ. Furthermore, histamine, in a dose that did not induce nociception by itself, strongly enhanced 5-HT-induced nociception. Finally, the administration of a sub-threshold dose of 5-HT (100 microg), but not of histamine (100 microg), elicited nociception in the TMJ previously challenged with the inflammatory agent carrageenan (100 microg). In conclusion, these data suggest that histamine induces TMJ nociception by an indirect mechanism involving endogenous release of 5-HT and activation of 5-HT(3) receptors on sensory afferents. It is proposed that histamine activates the H1 receptor to induce the release of 5-HT which depolarizes the nociceptor by activating 5-HT(3) receptor.     

A genomewide admixture mapping panel for Hispanic/Latino populations

Admixture mapping (AM) is a promising method for the identification of genetic risk factors for complex traits and diseases showing prevalence differences among populations. Efficient application of this method requires the use of a genomewide panel of ancestry-informative markers (AIMs) to infer the population of origin of chromosomal regions in admixed individuals. Genomewide AM panels with markers showing high frequency differences between West African and European populations are already available for disease-gene discovery in African Americans. However, no such a map is yet available for Hispanic/Latino populations, which are the result of two-way admixture between Native American and European populations or of three-way admixture of Native American, European, and West African populations. Here, we report a genomewide AM panel with 2,120 AIMs showing high frequency differences between Native American and European populations. The average intermarker genetic distance is ~1.7 cM. The panel was identified by genotyping, with the Affymetrix GeneChip Human Mapping 500K array, a population sample with European ancestry, a Mesoamerican sample comprising Maya and Nahua from Mexico, and a South American sample comprising Aymara/Quechua from Bolivia and Quechua from Peru. The main criteria for marker selection were both high information content for Native American/European ancestry (measured as the standardized variance of the allele frequencies, also known as "f value") and small frequency differences between the Mesoamerican and South American samples. This genomewide AM panel will make it possible to apply AM approaches in many admixed populations throughout the Americas.     

Recent genetic selection in the ancestral admixture of Puerto Ricans

Recent studies have used dense markers to examine the human genome in ancestrally homogeneous populations for hallmarks of selection. No genomewide studies have focused on recently admixed groups--populations that have experienced admixing among continentally divided ancestral populations within the past 200-500 years. New World admixed populations are unique in that they represent the sudden confluence of geographically diverged genomes with novel environmental challenges. Here, we present a novel approach for studying selection by examining the genomewide distribution of ancestry in the genetically admixed Puerto Ricans. We find strong statistical evidence of recent selection in three chromosomal regions, including the human leukocyte antigen region on chromosome 6p, chromosome 8q, and chromosome 11q. Two of these regions harbor genes for olfactory receptors. Interestingly, all three regions exhibit deficiencies in the European-ancestry proportion.