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Biomedical subjects

H Leung

Publications and source records attributed to H Leung.

At least 37 records · Page 2Linked to original sources
PubMed2000

Genetic diversity and disease control in rice.

Crop heterogeneity is a possible solution to the vulnerability of monocultured crops to disease. Both theory and observation indicate that genetic heterogeneity provides greater disease suppression when used over large areas, though experimental data are lacking. Here we report a unique cooperation among farmers, researchers and extension personnel in Yunnan Province, China--genetically diversified rice crops were planted in all the rice fields in five townships in 1998 and ten townships in 1999. Control plots of monocultured crops allowed us to calculate the effect of diversity on the severity of rice blast, the major disease of rice. Disease-susceptible rice varieties planted in mixtures with resistant varieties had 89% greater yield and blast was 94% less severe than when they were grown in monoculture. The experiment was so successful that fungicidal sprays were no longer applied by the end of the two-year programme. Our results support the view that intraspecific crop diversification provides an ecological approach to disease control that can be highly effective over a large area and contribute to the sustainability of crop production.

Agriculture↗
PubMed2000

Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group.

OBJECTIVE: To determine whether treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) for 6-12 months retards progression of radiographic damage and to identify clinical variables that correlate with radiographic progression. METHODS: Radiographs of the hands and feet were performed at baseline and at the end of study or early exit in 3 randomized controlled trials. Protocol US301 was a 12-month controlled trial of LEF or MTX treatment compared with placebo in 482 patients randomized in a 3:3:2 ratio. Protocol MN301 compared 6 months of LEF or SSZ treatment with placebo in 358 patients, randomized in a 3:3:2 ratio, with continued blinded treatment in the active control arms for 12 months. Protocol MN302 compared 12 months of LEF treatment with MTX in 999 patients. Radiographs were blinded for sequence and treatment and were scored for erosions and joint space narrowing. All analyses were by intent-to-treat. Sensitivity analyses were performed to account for missing data. RESULTS: LEF, MTX, and SSZ treatment resulted in statistically significantly less radiographic progression compared with placebo at 6 and 12 months: for protocol US301, LEF versus placebo P = 0.0007 and MTX versus placebo P = 0.0196; for protocol MN301, LEF versus placebo P = 0.0004 and SSZ versus placebo P = 0.0484. The effect of LEF treatment was similar to that of MTX and SSZ. CONCLUSION: These are the first 6- and 12-month randomized placebo- and active drug-controlled trials to demonstrate retardation of radiographic progression by a new disease-modifying antirheumatic drug (DMARD), LEF, as well as 2 commonly used DMARDs, MTX and SSZ.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Xanthomonas oryzae pv. oryzae avirulence genes contribute differently and specifically to pathogen aggressiveness.

Genomic copies of three Xanthomonas oryzae pv. oryzae avirulence (avr) genes, avrXa7, avrXal0, and avrxa5, and four homologous genes, aB3.5, aB3.6, aB4.3, and aB4.5, were mutagenized individually or in combination to study the roles of avr genes in one component of pathogen fitness, i.e., aggressiveness or the amount of disease X. oryzae pv. oryzae causes in susceptible rice lines. These X. oryzae pv. oryzae genes are members of the highly related Xanthomonas avrBs3 gene family. Compared to the wild-type strain, X. oryzae pv. oryzae strains with mutations in avrXa7, avrxa5, and the four homologous genes caused shorter lesions on rice line IR24, which contains no resistance genes relevant to the wild-type strain. The contribution of each gene to lesion length varied, with avrXa7 contributing the most and avrXal0 showing no measurable effect on aggressiveness. The functional, plasmidborne copies of avrXa7, aB4.5, and avrxa5 restored aggressiveness only to strains with mutations in avrXa7, aB4.5, and avrxa5, respectively. Mutations in avrXa7 were not complemented by plasmids carrying any other avr gene family members. These data indicate that some, but not all, avr family members contribute to pathogen aggressiveness and that the contributions are quantitatively different. Furthermore, despite their sequence similarity, the aggressiveness functions of these gene family members are not interchangeable. The results suggest that selection and pyramiding resistance genes can be guided by the degree of fitness penalty that is empirically determined in avr gene mutations.

Bacterial Proteins↗
PubMed2000

Characterizing rice lesion mimic mutants and identifying a mutant with broad-spectrum resistance to rice blast and bacterial blight.

Many plant mutants develop spontaneous lesions that resemble disease symptoms in the absence of pathogen attack. In several pathosystems, lesion mimic mutations have been shown to be involved in programmed cell death, which in some instances leads to enhanced disease resistance to multiple pathogens. We investigated the relationship between spontaneous cell death and disease resistance in rice with nine mutants with a range of lesion mimic phenotypes. All nine mutations are controlled by recessive genes and some of these mutants have stunted growth and other abnormal characteristics. The lesion mimics that appeared on the leaves of these mutants were caused by cell death as measured by trypan blue staining. Activation of six defense-related genes was observed in most of the mutants when the mimic lesions developed. Four mutants exhibited significant enhanced resistance to rice blast. One of the mutants, spl11, confers non-race-specific resistance not only to blast but also to bacterial blight. The level of resistance in the spl11 mutant to the two pathogens correlates with the defense-related gene expression and lesion development on the leaves. The results suggest that some lesion mimic mutations in rice may be involved in disease resistance, and cloning of these genes may provide a clue to developing broad-spectrum resistance to diverse pathogens.

Bacteria↗
PubMed2000

Issues involved in a metaanalysis of rheumatoid arthritis radiographic progression. Analysis issues.

Missing data in controlled clinical trials may create uncertainty in the results of a study based on non-missing data. We used 4 approaches of sensitivity analysis to address this problem. Radiographic progression data were used from a randomized controlled trial of patients with rheumatoid arthritis treated with leflunomide, methotrexate, or placebo for 12 months as an example. The mean change from baseline of the Sharp total radiographic score was the primary efficacy variable for the evaluation of leflunomide in comparison with placebo in the retardation of radiographic progression. Computer simulations were used in some of these approaches. The proportion of missing radiographic data was 26.4%. Result from the non-missing data showed that leflunomide was highly statistically significantly better than placebo in the retardation of radiographic progression. Results from the sensitivity analysis showed that radiographic data are sufficiently robust that it is unlikely that the missing data would have changed the conclusions from the analysis based on non-missing data. The potential effect of missing data in the results of a clinical trial may be addressed by various methods of sensitivity analysis. Computer simulation can be a useful tool in some of these approaches.

Arthritis, Rheumatoid↗
PubMed1999

Metalloproteinases are involved in lipopolysaccharide- and tumor necrosis factor-alpha-mediated regulation of CXCR1 and CXCR2 chemokine receptor expression.

The neutrophil-specific G-protein-coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-alpha-induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF-alpha was most dramatically inhibited by metalloproteinase inhibitors; 1, 10-phenanthroline and EDTA significantly attenuated LPS- and TNF-alpha-induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-alpha-stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF-alpha inhibited IL-8 receptor-mediated calcium mobilization and IL-8-directed neutrophil chemotaxis, both 1, 10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8-mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.

Antigens, CD↗
PubMed1998

Interactions between spore morphogenetic mutations affect cell types, sporulation, and pathogenesis in Magnaporthe grisea.

We have previously defined four single-gene mutations, con1, con2, con4, and con7, that control various stages of spore morphogenesis in the rice blast fungus. To delineate the developmental pathway of spore morphogenesis, we investigated the interactions among these morphogenetic genes by generating strains with double mutations via transformation-mediated gene disruption. Plasmids containing portions of the inactivated CON4 and CON7 genes were introduced into strains harboring single mutation to produce double mutants. Interaction between con1 and con4 resulted in reduced vegetative growth and suppression of sporulation. Interaction between con1 and con7 suppressed spore production but not vegetative growth. The con2/con4 and con4/con7 double mutants produced hybrid spore types with characteristic features of both parental mutants. The con2/con7 mutant produced con2 type spores, indicating that con2 is epistatic to con7 in spore morphogenesis. The epistatic relationship, however, reversed when traits related to pathogenesis were considered. Double mutants harboring the con7 mutation could not form appressoria or colonize plant tissue, indicating that con7 is epistatic to con2 and con4 in appressorium formation and pathogenesis. Thus, morphogenetic genes interact at multiple levels leading to different epistatic relationships in the pathways of spore morphogenesis, appressorium formation, and pathogenesis.

Ascomycota↗
PubMed1996

Peptide growth factors in the prostate as mediators of stromal epithelial interaction.

Peptide growth factors play a role in the maintenance of normal prostatic growth and differentiation (Fig. 2). It seems likely that the androgen sensitivity of human prostate is mediated by the production of peptide growth factors from stromal cells which act as the direct intermediate of androgen action on epithelial cells. TGF-beta 1 inhibition of epithelial cells is opposed by the stimulatory action of EGF, IGF and FGFs to maintain an equilibrium of epithelial cell numbers. The indirect mitogenic action of androgens appear to act by down-regulation of TGF-beta 1 and possibly EGF receptors. There is also interaction with the effects of IGF-II, produced by prostatic stromal cells and acting on epithelial cells to increase proliferation. The growth of normal prostatic fibroblasts is under the control of bFGF and TGF-beta 1. However, although our understanding of the actions of these growth factors in the normal prostate has improved over the last decade, their role in the development and maintenance of prostate cancer is less clearly defined. TGF-beta 1, classically considered to be inhibitory for epithelial cells, may be up-regulated in prostatic tumours, stimulating growth. Alternatively, autocrine production of such growth factors by tumour cells may lead to loss of inhibitory effects from exogenous TGF-beta 1, a mechanism also witnessed with TGF-alpha and bFGF. The role of EGF in the development of prostate cancer is confusing because results from the use of different cell types and experimental conditions is contradictory. It may be that a switch in the production of the predominant EGFr ligand from EGF to TGF-alpha is an important feature in the development and maintenance of the malignant phenotype. The presence of TGF-alpha autocrine loops has been shown clearly in some tumour cell lines. This switch in the production of a particular ligand may also be a feature of IGFs in prostate cancer. IGF-II may be replaced by IGF-I during malignant progression, both of which are able to act via the type 1 receptor. This change in IGF expression appears to be accompanied by altered expression of the IGF-BP2, with less detectable within prostatic tissues but elevated serum levels [58]. Basic FGF is normally produced by prostatic fibroblasts but is also produced by some prostatic cancer cell lines [64]. However, as with all growth factors, the expression of the bFGF protein and its receptor is dependent on the cell line examined. The autocrine and paracrine control of normal and abnormal prostatic growth by growth factors is important in determining their role in the development and maintenance of prostate cancer. Better understanding of such mechanisms is essential for the development of novel therapeutic strategies in the control and treatment of prostate cancer.

Cell Division↗
PubMed1994

Relationship between Phylogeny and Pathotype for the Bacterial Blight Pathogen of Rice.

Several transposable elements were isolated from the genome of Xanthomonas oryzae pv. oryzae. These elements and an avirulence gene isolated from X. oryzae pv. oryzae were used as hybridization probes for a collection of X. oryzae pv. oryzae strains from the Philippines. Each of the sequences was present in multiple copies in all strains examined and showed distinct patterns of hybridizing bands. Phenograms were derived from the restriction fragment length polymorphism data obtained for each of the individual probes and for pooled data from multiple probes. The phenograms derived from the different probes differed in topology and, on the basis of bootstrap analysis, were not equally robust. For all of the probes, including the avirulence gene, some groups (even some haplotypes) consisted of multiple races. The strains were grouped into four major clusters on the basis of the two probes giving the highest bootstrap values. These groups were inferred to represent phylogenetic lineages. Three of the six races of X. oryzae pv. oryzae appeared in more than one of the lineages, and another was present in two sublineages. For three of the races, strains representing different phenetic groups were inoculated on rice cultivars carrying 10 resistance genes. Two new races were differentiated, corresponding to pathogen lineages identified by DNA typing. On the basis of DNA and pathotypic analyses, together with information on the spatial and temporal distribution of the pathogen types from this and other studies, a general picture of X. oryzae pv. oryzae evolution in the Philippines is presented.

Journal Article↗
PubMed1994

Regulation and targeting of recombination in extrachromosomal substrates carrying immunoglobulin switch region sequences.

We have used extrachromosomal substrates carrying immunoglobulin heavy-chain S mu and S gamma 3 switch region sequences to study activation and targeting of recombination by a transcriptional enhancer element. Substrates are transiently introduced into activated primary murine B cells, in which recombination involving S-region sequences deletes a conditionally lethal marker, and recombination is measured by transformation of Escherichia coli in the second step of the assay. Previously we found that as many as 25% of replicated substrates recombined during 40-h transfection of lipopolysaccharide (LPS)-stimulated primary cells and that efficient recombination was dependent on the presence of S-region sequences as well as a transcriptional activator region in the constructs (H. Leung and N. Maizels, Proc. Natl. Acad. Sci. USA 89:4154-4158, 1992). Here we show that recombination of the switch substrates is threefold more efficient in LPS-cultured primary B cells than in the T-cell line EL4; the activities responsible for switch substrate recombination thus appear to be more abundant or more active in cells which can carry out chromosomal switch recombination. We test the role of the transcriptional activator region and show that the immunoglobulin heavy-chain intron enhancer (E mu) alone stimulates recombination as well as E mu combined with a heavy-chain promoter and that mutations that diminish enhancer-dependent transcription 500-fold diminish recombinational activation less than 2-fold. These observations suggest that the enhancer stimulates recombination by a mechanism that does not depend on transcript production or that is insensitive to the level of transcript production over a very broad range. Furthermore, we find that E mu stimulates recombination when located either upstream or downstream of S mu but that the position of the recombinational activator does affect the targeting of recombination junctions, suggesting that the relatively imprecise targeting of switch junctions in vivo may reflect the availability of many potential activator sites within each switch region.

Animals↗
PubMed1992

Transcriptional regulatory elements stimulate recombination in extrachromosomal substrates carrying immunoglobulin switch-region sequences.

We have developed a sensitive genetic assay to analyze DNA sequences and regulatory elements required for immunoglobulin heavy chain isotype switch recombination. Recombination substrates containing mu and gamma 3 chain switch (S)-region sequences, S mu and S gamma 3, are transiently introduced into primary murine B cells cultured with lipopolysaccharide to induce isotype switching. Recombination involving S-region sequences deletes a conditionally lethal marker, the leftward promoter of phage lambda (lambda PL), enabling recovered plasmids to transform Escherichia coli. In substrates carrying S mu-lambda PL-S gamma 3, about 2% of replicated molecules undergo deletion of lambda PL during transfection; insertion of either the immunoglobulin heavy chain promoter and enhancer sequences or cytomegalovirus IE1 promoter region upstream of S mu increases recombination 10-fold or more to 25% of replicated molecules. Guanosine-rich S-region sequences are essential for efficient recombination of these substrates.

Animals↗
PubMed1992

The erbB-3 gene in human pancreatic cancer.

Abnormalities of the type 1 growth factor receptor family have been implicated in the pathogenesis of pancreatic cancer. There is evidence for a potential autocrine loop involving overexpression of the epidermal growth factor (EGF) receptor and its ligands, as well as overexpression of the erbB-2 receptor. A third member of this receptor family, erbB-3, has recently been recognized and found to be abnormally expressed in some types of human cancer. In this study we show that overexpression of the erbB-3 protein occurs very frequently in carcinoma of the exocrine pancreas and also in chronic pancreatitis. We found no evidence of amplification or rearrangement of the erbB-3 gene by Southern blot analysis of DNA from pancreatic cancer cells lines.

Amino Acid Sequence↗
PubMed1992

Assessment of genetic diversity and population structure of Xanthomonas oryzae pv. oryzae with a repetitive DNA element.

A repetitive DNA element cloned from Xanthomonas oryzae pv. oryzae was used to assess the population structure and genetic diversity of 98 strains of X. oryzae pv. oryzae collected between 1972 and 1988 from the Philippine Islands. Genomic DNA from X. oryzae pv. oryzae was digested with EcoRI and analyzed for restriction fragment length polymorphisms (RFLPs) with repetitive DNA element as a probe. Twenty-seven RFLP types were identified; there was no overlap of RFLP types among the six races from the Philippines. Most variability (20 RFLP types) was found in strains of races 1, 2, and 3, which were isolated from tropical lowland areas. Four RFLP types (all race 5) were found among strains isolated from cultivars grown in the temperate highlands. The genetic diversity of the total population of X. oryzae pv. oryzae was 0.93, of which 42% was due to genetic differentiation between races. The genetic diversities of strains collected in 1972 to 1976, 1977 to 1981, and 1982 to 1986, were 0.89, 0.90, and 0.92, respectively, suggesting a consistently high level of variability in the pathogen population over the past 15 years. Cluster analysis based on RFLP banding patterns showed five groupings at 85% similarity. The majority of strains from a given race were contained within one cluster, except for race 3 strains, which were distributed in three of the five clusters.

DNA, Bacterial↗
PubMed1991

Cloning and characterization of repetitive DNA sequences from genomes of Oryza minuta and Oryza australiensis.

The value of genome-specific repetitive DNA sequences for use as molecular markers in studying genome differentiation was investigated. Five repetitive DNA sequences from wild species of rice were cloned. Four of the clones, pOm1, pOm4, pOmA536, and pOmPB10, were isolated from Oryza minuta accession 101141 (BBCC genomes), and one clone, pOa237, was isolated from Oryza australiensis accession 100882 (EE genome). Southern blot hybridization to different rice genomes showed strong hybridization of all five clones to O. minuta genomic DNA and no cross hybridization to genomic DNA from Oryza sativa (AA genome). The pOm1 and pOmA536 sequences showed cross hybridization only to all of the wild rice species containing the C genome. However, the pOm4, pOmPB10, and pOa237 sequences showed cross hybridization to O. australiensis genomic DNA in addition to showing hybridization to the O. minuta genomic DNA.

Base Sequence↗