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PubMed1998

Toxicity of linoleic acid hydroperoxide to Saccharomyces cerevisiae: involvement of a respiration-related process for maximal sensitivity and adaptive response.

Linoleic acid hydroperoxide (LoaOOH) formed during free radical attack on long-chain unsaturated fatty acids is an important source of biomembrane damage and is implicated in the onset of atherosclerosis, hepatic diseases, and food rancidity. LoaOOH is toxic to wild-type Saccharomyces cerevisiae at a very low concentration (0.2 mM) relative to other peroxides. By using isogenic mutant strains, the possible roles of glutathione (gsh1 and gsh2), glutathione reductase (glr1), respiratory competence ([rho0] petite), and yAP-1p-mediated expression (yap1) in conferring LoaOOH resistance have been examined. Respiration-related processes were essential for maximal toxicity and adaptation, as evidenced by the fact that the [rho0] petite mutant was most resistant to LoaOOH but could not adapt. Furthermore, when respiration was blocked by using inhibitors of respiration and mutants defective in respiratory-chain components, cells became more resistant. An important role for reduced glutathione and yAP-1 in the cellular response to LoaOOH was shown, since the yap1 and glr1 mutants were more sensitive than the wild type. In addition, total glutathione peroxidase activity increased following treatment with LoaOOH, indicating a possible detoxification role for this enzyme. Yeast also showed an adaptive response when pretreated with a nonlethal dose of LoaOOH (0.05 mM) and subsequently treated with a lethal dose (0.2 mM), and de novo protein synthesis was required, since adaptation was abolished upon treatment of cells with cycloheximide (25 microg ml-1). The wild-type adaptive response to LoaOOH was independent of those for the superoxide-generating agents paraquat and menadione and also of those for the organic hydroperoxides cumene hydroperoxide and tert-butyl hydroperoxide. Pretreatment with LoaOOH induced resistance to hydrogen peroxide, while pretreatment of cells with malondialdehyde (a lipid peroxidation product) and heat shock (37 degrees C) gave cross-adaptation to LoaOOH, indicating that yeast has effective overlapping defense systems that can detoxify fatty acid hydroperoxides directly or indirectly.

Adaptation, Physiological↗
PubMed2005

Genetic variation of the Y chromosome in Chibcha-speaking Amerindians of Costa Rica and Panama.

Genetic variation of the Y chromosome in five Chibchan tribes (Bribri, Cabecar, Guaymi, Huetar, and Teribe) of Costa Rica and Panama was analyzed using six microsatellite loci (DYS19, DYS389A, DYS389B, DYS390, DYS391, and DYS393), the Y-chromosome-specific alphoid system (alphah), the Y-chromosome Alu polymorphism (YAP), and a specific pre-Columbian transition (C-->T) (M3 marker) in the DYS 199 locus that defines the Q-M3 haplogroup. Thirty-nine haplotypes were found, resulting in a haplotype diversity of 0.937. The Huetar were the most diverse tribe, probably because of their high levels of interethnic admixture. A candidate founder Y-chromosome haplotype was identified (15.1% of Chibchan chromosomes), with the following constitution: YAP-, DYS199*T, alphah-II, DYS19*13, DYS389A*17, DYS389B*10, DYS390*24, DYS391*10, and DYS393*13. This haplotype is the same as the one described previously as one of the most frequent founder paternal lineages in native American populations. Analysis of molecular variance indicated that the between-population variation was smaller than the within-population variation, and the comparison with mtDNA restriction data showed no evidence of differential structuring between maternally and paternally inherited genes in the Chibchan populations. The mismatch-distribution approach indicated estimated coalescence times of the Y chromosomes of the Q-M3 haplogroup of 3,113 and 13,243 years before present; for the mtDNA-restriction haplotypes the estimated coalescence time was between 7,452 and 9,834 years before present. These results are compatible with the suggested time for the origin of the Chibchan group based on archeological, linguistic, and genetic evidence.

Analysis of Variance↗
PubMed2001

Vitamin A deficiency among children--Federated States of Micronesia, 2000.

Vitamin A, a fat-soluble, heat-stable nutrient (retinol) derived from animal sources and certain fruits and vegetables, forms the basic component of retinal pigments and plays a vital role in optimal health, growth, and development. Vitamin A deficiency (VAD) (serum retinol < or = 20 microg/dL [< or = 0.7 micromol/L] for subclinical VAD) can substantially increase the risk for childhood mortality from infectious and noninfectious causes. VAD impairs the mobilization and transport of iron and is usually associated with anemia and reduced growth. VAD is a major public health problem in parts of Africa, Asia, Latin America, and the Western Pacific. In Chuuk and Pohnpei, two of the four Federated States of Micronesia (FSM) (2000 population: 107,008), nutrition surveys during the early 1990s documented VAD prevalences among the highest in the world (CDC, unpublished data, 1991; U.S. Public Health Service, unpublished data, 1994). In response to these findings, FSM health authorities, with support of the United Nations Children's Fund (UNICEF), began distributing vitamin A supplements in 1993 and 1998 in Chuuk and Pohnpei, respectively. In November 1999, FSM requested assistance from CDC in VAD assessment surveys of children in Kosrae and Yap, the other two FSM states. This report summarizes levels of serum retinol and prevalence of VAD and other indicators of nutritional status among children aged 24-59 months in Kosrae and Yap. The findings indicated low serum retinol levels and high VAD prevalences but no substantial stunting or wasting. A comprehensive, long-term national strategy is needed in FSM to promote sustained improvement in vitamin A status.

Anemia↗
PubMed2002

Two Y-chromosome-specific polymorphisms 12f2 and DFFRY in the Japanese population and their relations to other Y-polymorphisms.

This study of male-specific genetic markers in the Japanese population was carried out in an attempt to refine the existing theories concerning its population genetics and migration events. We examined the relation between the constructed haplotypes of three biallelic Y-chromosome-specific markers (YAP, 47z and SRY) and the results of studying two other Y-specific polymorphisms of both 12f2 and DFFRY markers. The 12f2 marker was completely absent in 14.7% of Japanese males; all of them were haplotype II males. None of the Japanese males from other haplotypes or other East Asian populations showed any deletion of 12f2. In all haplotype II Japanese men, we found that DFFRY gene harbors a (C-->T) substitution polymorphism that was not found in any other population of this study. These results suggested that although haplotype II Japanese males share with the other haplotype II men from different geographical areas in having the YAP insertion on their Y-chromosomes, their Y-chromosomal structure is somewhat characteristically different. They are probably descendants of the ancestral Jomonese population who lived in Japan before the Yayoi immigrants entered Japan approximately 2300 years ago. These findings suggested that linkage studies between Y-specific markers are helpful in understanding the migratory patterns in East Asia. We also suggested that Japanese males have characteristically different Y-chromosomes compared with other populations.

Alleles↗
PubMed2004

[Therapeutic bronchoscopic treatment of postintubation tracheal stenosis: 5 cases].

Benign airway obstruction is known as curable by therapeutic bronchoscopic methods. Compared by surgical therapies it is comfortable and has no risks for the patients. For five patients who applied our clinic after tracheostomy and endotracheal intubation stenosis we used therapeutic bronchoscopic methods; "laser-stenotic silicon stent". In two patients after vaporization of membranous stricture by Neodimum Yttrium Aliminum Pevroskite Laser (Nd-YAP laser) who were seen posttracheostomy and postentubation; stenotic stent was implanted mechanically and/or by means of baloon dilatation. Membranous stricture area was coagulated by Nd-YAP-laser in other three cases and anatomic airway diameter was achieved mechanically and by baloon dilatation. In the follow up period we applied stenotic silicon stent implantation after second laser resection in whom restenosis observed. In conclusion; patients who had stenotic silicon stent implantation and having no problems in the follow up this therapeutic method is found to be curative.

Adult↗
PubMed1979

Cross-cultural differences in indicators of improvement from psychosis: the case of betel nut chewing.

This paper uses a case from the Micronesian Island of Yap to illustrate that indicators of improvement from an episode of schizophrenic psychosis can vary tremendously from culture to culture. At times, the clinician must search diligently for such indicators since the patient will not verbalize any perception of improvement. A 39-year-old Yapese woman was evaluated by a psychiatrist and was found to have been psychotic for several years, suffering from gross delusions, and auditory hallucinations, flattened affect, and social isolation. In addition, she had discontinued chewing betel nut that was used daily by virtually all of her fellow islanders on Yap. Two months after beginning treatment with twice monthly injectable antipsychotic medication she was still delusional, with flat affect, and heard the same voices. She was slightly less socially withdrawn and she had interestingly resumed chewing betel nut. It seemed that she had given up betel nut chewing during the socially withdrawn phase of her illness and had resumed it as she improved and became less autistically preoccupied. In her culture, betel chewing was a main avenue of social intercourse and an intrinsic part of almost all social activities. In her particular case, the resumption of betel chewing was a primary indicator of her improvement from psychosis and reintegration into her social group.

Adult↗
PubMed2005

Active hypothermic growth: a novel means for increasing total interferon-gamma production by Chinese-hamster ovary cells.

When grown under hypothermic conditions, CHO (Chinese-hamster ovary) cells become growth-arrested in the G0/G1 phase of the cell cycle and also often exhibit increased recombinant-protein production. We have shown in the accompanying paper [Fox, Tan, Tan, Wong, Yap and Wang (2005) Biotechnol. Appl. Biochem. 41, 255-264] that the positive effect of low temperature on recombinant-protein production is due to elevated mRNA levels and not due to G0/G1-phase growth arrest and that a cell line can still show growth-associated productivity at low temperature. This finding led to the hypothesis that improved total production of recombinant protein would be achieved by stimulating cells to actively grow at low temperature, a culture condition previously unreported in the literature. In the present study we have validated this hypothesis by stimulating hypothermic (32 degrees C) growth through the use of different growth factors. Hypothermic growth was stimulated in fetal-bovine-serum-supplemented adherent cultures using basic fibroblast growth factor or insulin. Hypothermic growth was also stimulated in suspension cultures normally grown in protein-free medium by using supplementation with fetal bovine serum. These methods resulted in up to 7.7- and 4.9-fold increases in total recombinant-protein production compared with the 37 and 32 degrees C control cultures respectively. This proof-of-concept study will motivate the creation of cell lines capable of growing at low temperatures for use in industrial processes.

Animals↗
PubMed2026

Role of semaphorin 4f in cardiac fibroblasts to regulate matrix production through actin remodeling and YAP/TAZ activation.

Cardiac fibrosis remains a critical determinant of adverse outcomes in heart disease, yet effective anti-fibrotic therapies are lacking. While multiple semaphorin family members participate in cardiovascular pathophysiology, the role of semaphorin 4f (Sema4f) in cardiac fibrosis remains unexplored. This study investigates the role and mechanisms of Sema4f in fibrotic remodeling post-myocardial infarction (MI). We employed flow cytometry to characterize cell type-specific Sema4f expression patterns in post-MI hearts. Lineage-specific knockout mice (fibroblast vs. myeloid) were subjected to left anterior descending ligation to assess functional consequences. Proteomic analysis of Sema4f-deficient cardiac fibroblasts was conducted to identify downstream effectors. Key pathways were subsequently validated using pharmacological inhibitors. We found that Sema4f expression was markedly upregulated during the fibrotic phase post-MI, primarily due to fibroblast activation. Fibroblast-, but not myeloid-, specific Sema4f deletion significantly reduced fibrosis and improved cardiac function. Proteomic profiling revealed that Sema4f deficiency led to downregulation of pro-fibrotic gene expression, which was associated with impaired actin cytoskeletal remodeling and decreased nuclear translocation of YAP/TAZ. Pharmacological inhibition of either actin remodeling or YAP/TAZ activity attenuated fibrosis, whereas YAP/TAZ activation abolished the anti-fibrotic effects of Sema4f knockout. Our study provides the first evidence demonstrating the functional role of Sema4f in cardiac fibroblast activation and fibrosis progression. We have identified a fibroblast-specific mechanism mediated by the Sema4f-actin cytoskeleton-YAP/TAZ axis, offering novel mechanistic insights into fibrosis regulation and revealing a promising therapeutic target for cardiac fibrosis with potential clinical applications.

Animals↗
PubMed1987

CTAB precipitation of cestode DNA.

DNA probes are proving extremely valuable in the characterization o f cestodes - as well as other parasites. In this article, Kok Wei Yap and Andrew Thompson discuss some of the problems of DNA isolation, stressing the need for a gentle and economical procedure such as CTAB precipitation.

Journal Article↗
PubMed2006

Of mice and men: cancer gene discovery using comparative oncogenomics.

With the proliferation of high-throughput technologies to profile the cancer genome, methods to distinguish causal from bystander genetic events are needed. Two recent reports by Zender et al. and Kim et al. in Cell use genetically defined mouse models to serve as biological filters to mine the human cancer genome. Integration of high-resolution copy number profiles of mouse tumor models and human tumors identified cIAP1 and Yap as oncogenes in human hepatocellular carcinoma, while NEDD9 was identified as a metastasis gene in human melanoma. Together, these reports demonstrate that a comparative oncogenomics approach can identify genes causally involved in oncogenesis and metastasis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73.

Upon DNA damage signaling, p73, a member of the p53 tumor suppressor family, accumulates to support transcription of downstream apoptotic genes. p73 interacts with Yes-associated protein 1 (Yap1) through its PPPY motif, and increases p73 transactivation of apoptotic genes. The ubiquitin E3 ligase Itch, like Yap1, interacts with p73. Given the fact that both Itch and Yap1 bind p73 via the PPPY motif, we hypothesized that Yap may also function to stabilize p73 by displacing Itch binding to p73. We show that the interaction of Yap1 and p73 was necessary for p73 stabilization. Yap1 competed with Itch for binding to p73, and prevented Itch-mediated ubiquitination of p73. Treatment of cells with cisplatin leads to an increase in p73 accumulation and induction of apoptosis, but both were dramatically reduced in the presence of Yap1 siRNA. Altogether, our findings attribute a central role to Yap1 in regulating p73 accumulation and function under DNA damage signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Using flexible loop mimetics to extend phi-value analysis to secondary structure interactions.

Chemical synthesis allows the incorporation of nonnatural amino acids into proteins that may provide previously untried probes of their folding pathway and thermodynamic stability. We have used a flexible thioether linker as a loop mimetic in the human yes kinase-associated protein (YAP 65) WW domain, a three-stranded, 44-residue, beta-sheet protein. This linkage avoids problems of incorporating sequences that constrain loops to the extent that they significantly change the nature of the denatured state with concomitant effects on the folding kinetics. An NMR solution structure shows that the thioether linker had little effect on the global fold of the domain, although the loop is apparently more dynamic. The thioether variants are destabilized by up to 1.4 kcal/mol (1 cal = 4.18 J). Preliminary Phi-value analysis showed that the first loop is highly structured in the folding transition state, and the second loop is essentially unstructured. These data are consistent with results from simulated unfolding and detailed protein-engineering studies of structurally homologous WW domains. Previously, Phi-value analysis was limited to studying side-chain interactions. The linkers used here extend the protein engineering method directly to secondary-structure interactions.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Minimal mutation of the cytoplasmic tail inhibits the ability of E-cadherin to activate Rac but not phosphatidylinositol 3-kinase: direct evidence of a role for cadherin-activated Rac signaling in adhesion and contact formation.

Classic cadherins are adhesion-activated cell signaling receptors. In particular, homophilic cadherin ligation can directly activate Rho family GTPases and phosphatidylinositol 3-kinase (PI3-kinase), signaling molecules with the capacity to support the morphogenetic effects of these adhesion molecules during development and disease. However, the molecular basis for cadherin signaling has not been elucidated, nor is its precise contribution to cadherin function yet understood. One attractive hypothesis is that cadherin-activated signaling participates in stabilizing adhesive contacts (Yap, A. S., and Kovacs, E. M. (2003) J. Cell Biol. 160, 11-16). We now report that minimal mutation of the cadherin cytoplasmic tail to uncouple binding of p120-ctn ablated the ability of E-cadherin to activate Rac. This was accompanied by profound defects in the capacity of cells to establish stable adhesive contacts, defects that were rescued by sustained Rac signaling. These data provide direct evidence for a role of cadherin-activated Rac signaling in contact formation and adhesive stabilization. In contrast, cadherin-activated PI3-kinase signaling was not affected by loss of p120-ctn binding. The molecular requirements for E-cadherin to activate Rac signaling thus appear distinct from those that stimulate PI3-kinase, and we postulate that p120-ctn may play a central role in the E-cadherin-Rac signaling pathway.

Animals↗
PubMed1998

The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn.

Cadherin cell-cell adhesion molecules form membrane-spanning molecular complexes that couple homophilic binding by the cadherin ectodomain to the actin cytoskeleton. A fundamental issue in cadherin biology is how this complex converts the weak intrinsic binding activity of the ectodomain into strong adhesion. Recently we demonstrated that cellular cadherins cluster in a ligand-dependent fashion when cells attached to substrata coated with the adhesive ectodomain of Xenopus C-cadherin (CEC1-5). Moreover, forced clustering of the ectodomain alone significantly strengthened adhesiveness (Yap, A.S., W.M. Brieher, M. Pruschy, and B.M. Gumbiner. Curr. Biol. 7:308-315). In this study we sought to identify the determinants of the cadherin cytoplasmic tail responsible for clustering activity. A deletion mutant of C-cadherin (CT669) that retained the juxtamembrane 94-amino acid region of the cytoplasmic tail, but not the beta-catenin-binding domain, clustered upon attachment to substrata coated with CEC1-5. Like wild-type C-cadherin, this clustering was ligand dependent. In contrast, mutant molecules lacking either the complete cytoplasmic tail or just the juxtamembrane region did not cluster. The juxtamembrane region was itself sufficient to induce clustering when fused to a heterologous membrane-anchored protein, albeit in a ligand-independent fashion. The CT669 cadherin mutant also displayed significant adhesive activity when tested in laminar flow detachment assays and aggregation assays. Purification of proteins binding to the juxtamembrane region revealed that the major associated protein is p120(ctn). These findings identify the juxtamembrane region of the cadherin cytoplasmic tail as a functionally active region supporting cadherin clustering and adhesive strength and raise the possibility that p120(ctn) is involved in clustering and cell adhesion.

Amino Acid Sequence↗
PubMed2006

Gramene: a bird's eye view of cereal genomes.

Rice, maize, sorghum, wheat, barley and the other major crop grasses from the family Poaceae (Gramineae) are mankind's most important source of calories and contribute tens of billions of dollars annually to the world economy (FAO 1999, http://www.fao.org; USDA 1997, http://www.usda.gov). Continued improvement of Poaceae crops is necessary in order to continue to feed an ever-growing world population. However, of the major crop grasses, only rice (Oryza sativa), with a compact genome of approximately 400 Mbp, has been sequenced and annotated. The Gramene database (http://www.gramene.org) takes advantage of the known genetic colinearity (synteny) between rice and the major crop plant genomes to provide maize, sorghum, millet, wheat, oat and barley researchers with the benefits of an annotated genome years before their own species are sequenced. Gramene is a one stop portal for finding curated literature, genetic and genomic datasets related to maps, markers, genes, genomes and quantitative trait loci. The addition of several new tools to Gramene has greatly facilitated the potential for comparative analysis among the grasses and contributes to our understanding of the anatomy, development, environmental responses and the factors influencing agronomic performance of cereal crops. Since the last publication on Gramene database by D. H. Ware, P. Jaiswal, J. Ni, I. V. Yap, X. Pan, K. Y. Clark, L. Teytelman, S. C. Schmidt, W. Zhao, K. Chang et al. [(2002), Plant Physiol., 130, 1606-1613], the database has undergone extensive changes that are described in this publication.

Arabidopsis↗
PubMed1978

Effect of a short term fast on the distribution of cytoplasmic albumin messenger ribonucleic acid in rat liver. Evidence for formation of free albumin messenger ribonucleoprotein particles.

Recently, using molecular hybridization techniques with albumin [3H]cDNA, we have determined that in normally fed rats 98% of total liver polyribosomal albumin mRNA sequences are found in membrane-bound polyribosomes (Yap, S. H., Strair, R. K., and Shafritz, D. A. (1977) Proc. Natl. Acad. Sci. U. S. A. 74, 5397-5401). We now observe that a 24- to 30-h withdrawal of food leads to major changes in the amount and subcellular distribution of albumin mRNA molecules. The total amount of cytoplasmic albumin mRNA per liver and concentration of albumin mRNA per unit of membrane-bound polyribosomal RNA are decreased. However, the proportion of albumin mRNA present in the postribosomal supernatant fraction increases dramatically in a short term fast, so that it now represent 60% of total cytoplasmic albumin mRNA sequences. Most of the albumin mRNA sequences in the postribosomal supernatant fraction sediment between 30 S and 50 S. These findings suggest that albumin mRNA is probably stored in the messenger ribonucleoprotein fraction during the fasting state.

Albumins↗
PubMed2000

mtDNA lineage analyses: origins and migrations of Micronesians and Polynesians.

The islands of Micronesia and Polynesia collectively comprise the last major region of the globe to be settled by humans. Both of these groups of islands were colonized within the last 4,000 years by Austronesian-speaking agriculturists. Based on biogeographic and linguistic patterns, central-eastern Micronesia and Polynesia are included by many in a single category called Remote Oceania. Similarities of biologic, linguistic, and cultural traits within Remote Oceania highlight a question central to Oceanic studies: Are similarities among islands due to a common origin of isolated communities, to ongoing interactions among islands, or both? Analyses of mitochondrial DNA (mtDNA) sequences reveal that most remote Oceanic populations are polyphyletic. These polyphyletic populations violate the assumptions of many genetic distance and population demography models and so are problematic to interpret. The majority of mtDNA sequences from Micronesian and Polynesian populations are derived from Asia, whereas others are inferred to have originated in New Guinea. These data support an Island Southeast Asian origin and a colonization route along the north coast of New Guinea. The Marianas and Yap proper (main island) appear to have been independently settled directly from Island Southeast Asia, and both have received migrants from Central-Eastern Micronesia since then. Palau clearly demonstrates a complex prehistory including a significant influx of lineages from New Guinea. Thus genetic similarities among Micronesian and Polynesian populations result, in some cases, from a common origin, and in others, from extensive gene flow.

DNA, Mitochondrial↗
PubMedDate not supplied

Directional mating and a rapid male population expansion in a hybrid Uruguayan population.

The Uruguayan population has been considered as mainly European descent, with a negligible Native American or African contributions. Based on serological and molecular markers, recent studies demonstrate that these two populations had an important influence in the conformation of the present one. To the Northeastern region of Uruguay, a 20% Native American contribution was estimated using autosomal markers and a 62% Native American female origin based on mitochondrial markers. In this paper, we analyze four Y chromosome markers, two biallelic loci (M3 and YAP) and two microsatellites (DYS389I and DYS391), to characterize the male genetic contribution of a sample from the Northeastern city of Tacuarembó. We take different approaches to estimate the origin of male contributions to the population of Tacuarembó; Native American contribution ranges between 1.60% and 8.31%, confirming strong directional mating, which was also detected before with mitochondrial markers. Furthermore, the male population of Tacuarembó presents the characteristic of a population that suffered a bottleneck and a posterior expansion, confirmed using two microsatellite-based statistics to analyze the past population growth; patrilocality and migration could be responsible of those characteristics.

Chromosomes, Human, Y↗