Transposon inactivation of Arabidopsis MAP kinase 4 produced the mpk4 mutant exhibiting constitutive systemic acquired resistance (SAR) including elevated salicylic acid (SA) levels, increased resistance to virulent pathogens, and constitutive pathogenesis-related gene expression shown by Northern and microarray hybridizations. MPK4 kinase activity is required to repress SAR, as an inactive MPK4 form failed to complement mpk4. Analysis of mpk4 expressing the SA hydroxylase NahG and of mpk4/npr1 double mutants indicated that SAR expression in mpk4 is dependent upon elevated SA levels but is independent of NPR1. PDF1.2 and THI2.1 gene induction by jasmonate was blocked in mpk4 expressing NahG, suggesting that MPK4 is required for jasmonic acid-responsive gene expression.

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European-ancestry we identified 244 independent multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases that is genetically identical to another disease, possibly due to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

A key prerequisite for precision medicine is the estimation of disease progression from the current patient state. Disease correlations and temporal disease progression (trajectories) have mainly been analysed with focus on a small number of diseases or using large-scale approaches without time consideration, exceeding a few years. So far, no large-scale studies have focused on defining a comprehensive set of disease trajectories. Here we present a discovery-driven analysis of temporal disease progression patterns using data from an electronic health registry covering the whole population of Denmark. We use the entire spectrum of diseases and convert 14.9 years of registry data on 6.2 million patients into 1,171 significant trajectories. We group these into patterns centred on a small number of key diagnoses such as chronic obstructive pulmonary disease (COPD) and gout, which are central to disease progression and hence important to diagnose early to mitigate the risk of adverse outcomes. We suggest such trajectory analyses may be useful for predicting and preventing future diseases of individual patients.

Glucosinolates are natural plant products that function in the defense toward herbivores and pathogens. Plant defense is regulated by multiple signal transduction pathways in which salicylic acid (SA), jasmonic acid, and ethylene function as signaling molecules. Glucosinolate content was analyzed in Arabidopsis wild-type plants in response to single or combinatorial treatments with methyljasmonate (MeJA), 2,6-dichloro-isonicotinic acid, ethylene, and 2,4-dichloro-phenoxyacetic acid, or by wounding. In addition, several signal transduction mutants and the SA-depleted transgenic NahG line were analyzed. In parallel, expression of glucosinolate biosynthetic genes of the CYP79 gene family and the UDPG:thiohydroximate glucosyltransferase was monitored. After MeJA treatment, the amount of indole glucosinolates increased 3-to 4-fold, and the corresponding Trp-metabolizing genes CYP79B2 and CYP79B3 were both highly induced. Specifically, the indole glucosinolate N-methoxy-indol-3-ylmethylglucosinolate accumulated 10-fold in response to MeJA treatment, whereas 4-methoxy-indol-3-ylmethylglucosinolate accumulated 1.5-fold in response to 2,6-dichloro-isonicotinic acid. In general, few changes were seen for the levels of aliphatic glucosinolates, although increases in the levels of 8-methylthiooctyl glucosinolate and 8-methylsulfinyloctyl glucosinolate were observed, particularly after MeJA treatments. The findings were supported by the composition of glucosinolates in the coronatine-insensitive mutant coi1, the ctr1 mutant displaying constitutive triple response, and the SA-overproducing mpk4 and cpr1 mutants. The present data indicate that different indole glucosinolate methoxylating enzymes are induced by the jasmonate and the SA signal transduction pathways, whereas the aliphatic glucosinolates appear to be primarily genetically and not environmentally controlled. Thus, different defense pathways activate subsets of biosynthetic enzymes, leading to the accumulation of specific glucosinolates.Glucosinolates are amino acid-derived natural plant products that function in the defense against herbivores and microorganisms. Upon tissue disruption, e.g. caused by insect feeding, glucosinolates are hydrolyzed by specific thioglucosidases called myrosinases to produce an array of biologically active compounds, typically isothiocyanates, nitriles, and thiocyanates (for review, see Halkier, 1999;Rask et al., 2000). These compounds function as inhibitors of microbial growth (Mari et al., 1993;Manici et al., 1997), as attractants for specialist insects, and as deterrents of generalist herbivores. For humans, glucosinolates are important as flavor compounds, as cancer-preventive agents, and as biopesticides in agriculture.Glucosinolate biosynthesis is considered a threestep process: First, the amino acid may enter the chain elongation pathway, in which the condensing enzymes MAM1 and MAM-L have recently been identified (de Quiros et al., 2000;Kroymann et al., 2001). Second, the core glucosinolate structure is formed (see below); and t...

Summary Whereas countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. Here, we examine the extent to which Mendelian variation contributes to complex disease risk by mining the medical records of over 110 million patients. We detect thousands of associations between Mendelian and complex diseases, revealing a non-degenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this “Mendelian code.” Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute non-additively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

The maize abscisic acid (ABA)-responsive rabl7 mRNA and Rabl7 protein distribution in maize embryo tissues was investigated by in situ hybridization and immunocytochemistry. rabl7 mRNA and Rabl7 protein were found in all cells of embryo tissues. Synthesis of rabl7 mRNA occurred initially in the embryo axis. As maturation progressed, rabl7 mRNA was detectable in the scutellum and accumulated in axis cells and provascular tissues. However, the response to exogenous ABA differed in various embryo cell types. The Rabl7 protein was located in the nucleus and in the cytoplasm, and qualitative differences in the phosphorylation states of the protein were found between the two subcellular compartments. Based on the similar domain arrangements of Rabl7 and a nuclear localization signal (NLS) binding phosphoprotein, Noppl40, interaction of Rabl7 with NLS peptides was studied. We found specific binding of Rabl7 to the wild-type NLS of the SV40 T antigen but not to an import incompetent mutant peptide. Moreover, binding of the NLS peptide to Rabl7 was found to be dependent upon phosphorylation. These results suggest that Rabl7 may play a role in nuclear protein transport.

The rab17 gene from maize is transcribed in late embryonic development and is responsive to abscisic acid and water stress in embryo and vegetative tissues. In vivo footprinting and transient transformation of rab17 were performed in embryos and vegetative tissues to characterize the cis-elements involved in regulation of the gene. By in vivo footprinting, protein binding was observed to nine elements in the promoter, which correspond to five putative ABREs (abscisic acid responsive elements) and four other sequences. The footprints indicated that distinct proteins interact with these elements in the two developmental stages. In transient transformation, six of the elements were important for high level expression of the rab17 promoter in embryos, whereas only three elements were important in leaves. The cis-acting sequences can be divided in embryo-specific, ABA-specific and leaf-specific elements on the basis of protein binding and the ability to confer expression of rab17. We found one positive, new element, called GRA, with the sequence CACTGGCCGCCC. This element was important for transcription in leaves but not in embryos. Two other non-ABRE elements that stimulated transcription from the rab17 promoter resemble previously described abscisic acid and drought-inducible elements. There were differences in protein binding and function of the five ABREs in the rab17 promoter. The possible reasons for these differences are discussed. The in vivo data obtained suggest that an embryo-specific pathway regulates transcription of the rab genes during development, whereas another pathway is responsible for induction in response to ABA and drought in vegetative tissues.

This study was aimed at screening solvent systems of varying polarities to identify suitable solvents for efficient and practical enzymatic glycerolysis. Several pure solvents and solvent mixtures were screened in a batch reaction system consisting of glycerol, sunflower oil, and Novozym ® 435 lipase. Out of 13 solvents tested, tert-butanol and tert-pentanol were the only pure solvents suitable for a fast glycerolysis reaction with an acceptably high formation of MAG. In these systems, MAG contents of 68-82% were achieved within a few hours. Mixtures of tertbutanol/hexane, tert-pentanol/hexane, and tert-butanol/tert-pentanol in varying ratios also gave high MAG contents (58-78%). The tertiary alcohols tert-butanol and tert-pentanol, or mixtures of one of them with hexane, seemed to be the best choice among the solvents tested with respect to reaction efficiency, practical industrial applications, and steric hydroxyl group hindrance, which suppresses the ester formation with FA.Paper no. J11089 in JAOCS 82, 559-564 (August 2005).