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At least 217 records · Page 12Linked to original sources
PubMed2003

Isolations of N-methyl-D-aspartic acid-type glutamate receptor ligands from Micronesian sponges.

The bioassay-guided fractionation of the water-soluble extract of the marine sponge Cribrochalina olemda collected in Palau resulted in the isolation of a new amino acid cribronic acid (1): (2S,4R,5R)-5-hydroxy-4-sulfooxypiperidine-2-carboxylic acid. However, aqueous extracts of Stylotella aurantium and Axinella carteri collected in Yap State, Micronesia, afforded a known N-methyl-d-aspartic acid (NMDA)-type glutamate receptor agonist, (2S,4S)-4-sulfooxypiperidine-2-carboxylic acid (2), as a common active principle. Both 1 and 2 induced convulsive behaviors in mice upon intracerebroventricular (icv) injection with ED(50) values of 29 +/- 3.0 and 20 +/- 2.8 pmol/mouse, respectively. Radioligand binding assay using rat cerebrocortical membrane demonstrated that 1 and 2 inhibit the binding of the labeled NMDA receptor ligand [(3)H]CGP39653 at IC(50) values of 83 +/- 15 and 214 +/- 20 nM, respectively. However, 1 and 2 did not displace [(3)H]kainic acid or [(3)H]AMPA. These data indicated that 1 is a selective NMDA-type glutamate receptor ligand with potent convulsant activity in mice.

Animals↗
PubMed1998

New imidazole alkaloids and zinc complexes from the micronesian sponge Leucetta cf. chagosensis.

Four new imidazole alkaloids, 2-5, along with the known isonaamidine B (1) were isolated from a Pacific sponge, Leucetta cf. chagosensis, collected from Yap, Federated States of Micronesia. Among these, 4 and 5 are zinc complexes derived from isonaamidine B and isonaamidine D. The structures of the new compounds were elucidated from spectral data. Isonaamidine D (3) showed weakly antifungal activity against Aspergillus niger with MIC = 100 micrograms/mL.

Alkaloids↗
PubMed1998

New diketopiperazines from the sponge Dysidea chlorea.

Twelve new polychlorinated diketopiperazines (7-18), along with six known ones (1-6) and a known sterol (19), were isolated from the sponge Dysidea chlorea, collected from Yap, Federated States of Micronesia. The structures of dysamides I-T (7-18) were elucidated by spectroscopic methods, and one (8) was confirmed by chemical conversion. The stereochemistry of the dysamides is discussed.

Animals↗
PubMed1999

Six new spongian diterpenes from the sponge spongia matamata

Chemical investigation of the sponge Spongia matamata collected in Yap, Micronesia, has resulted in the isolation of six new spongian diterpenoids, 2-7, along with the known compound, spongia-13(16), 14-dien-19-oic acid (1). The structures were determined by spectroscopic methods.

Journal Article↗
PubMed1999

New nitrogenous bisabolene-type sesquiterpenes from a micronesian marine sponge, axinyssa species

Chemical investigation of an Axinyssa species of sponge collected at Yap Island afforded three new nitrogenous sesquiterpenes, 1-3, together with the known compound 3-formamidotheonellin (4). The structures of compounds 1, 3, and 4 were confirmed by spectroscopic methods, and compound 2 was tentatively identified by comparison of its (1)H and (13)C NMR data with those of 1, 3, and 4 and (1)H decoupling experiments.

Journal Article↗
PubMed2002

Genetic origins in a South American clefting population.

It has been proposed that susceptibility to clefting in South America is related to Amerindian ancestry, where clefting is present at a higher frequency than in the other admixed populations (Caucasian and African) that make up the diverse racial mix of current South Americans. To clarify the genetic origins and establish a method for genetic mapping, mitochondrial DNA variation and Y-chromosome markers were studied in a South American population affected with clefting. Two-hundred and seventeen subjects and matched controls were selected through the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). The case group showed a higher frequency of Native American haplogroups and a lower frequency of African haplogroups (p < 0.00001). In addition, the case group showed a much higher frequency of the specific native American haplogroup D than the control group (p < 0.00001). For the Y-chromosome markers, the case group showed a lower frequency of the African-specific marker, YAP (p = 0.002), and a higher frequency of the Native American-specific marker, DYS199 (p < 0.00001). Even though differences were found in the frequencies of the markers studied, the contribution of each founder population was similar for both groups. Results suggest a strong Native American maternal contribution and a strong Caucasian (Spanish and Portuguese) paternal contribution to the population studied. The implications of this finding include the possibility of using admixture mapping approaches to this population.

Chromosomes, Human, Y↗
PubMed2004

Environmental predictors of pre-European deforestation on Pacific islands.

Some Pacific island societies, such as those of Easter Island and Mangareva, inadvertently contributed to their own collapse by causing massive deforestation. Others retained forest cover and survived. How can those fateful differences be explained? Although the answers undoubtedly involve both different cultural responses of peoples and different susceptibilities of environments, how can one determine which environmental factors predispose towards deforestation and which towards replacement of native trees with useful introduced tree species? Here we code European-contact conditions and nine environmental variables for 81 sites on 69 Pacific islands from Yap in the west to Easter in the east, and from Hawaii in the north to New Zealand in the south. We thereby detect statistical decreases in deforestation and/or forest replacement with island rainfall, elevation, area, volcanic ash fallout, Asian dust transport and makatea terrain (uplifted reef), and increases with latitude, age and isolation. Comparative analyses of deforestation therefore lend themselves to much more detailed interpretations than previously possible. These results might be relevant to similar deforestation-associated collapses (for example, Fertile Crescent, Maya and Anasazi) or the lack thereof (Japan and highland New Guinea) elsewhere in the world.

Altitude↗
PubMed2025

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Pyrimidines↗
PubMed2000

Maternal and paternal lineages in Albania and the genetic structure of Indo-European populations.

Mitochondrial DNA HV1 sequences and Y chromosome haplotypes (DYS19 STR and YAP) were characterised in an Albanian sample and compared with those of several other Indo-European populations from the European continent. No significant difference was observed between Albanians and most other Europeans, despite the fact that Albanians are clearly different from all other Indo-Europeans linguistically. We observe a general lack of genetic structure among Indo-European populations for both maternal and paternal polymorphisms, as well as low levels of correlation between linguistics and genetics, even though slightly more significant for the Y chromosome than for mtDNA. Altogether, our results show that the linguistic structure of continental Indo-European populations is not reflected in the variability of the mitochondrial and Y chromosome markers. This discrepancy could be due to very recent differentiation of Indo-European populations in Europe and/or substantial amounts of gene flow among these populations.

Albania↗
PubMed2006

Prostate cancer incidence varies among males from different Y-chromosome lineages.

The incidence rate of prostate cancer in African-American males is two times higher than Caucasian men and ten times higher than Japanese men. The geographical specificity of Y haplogroups implies that males from different ethnic groups undoubtedly have various Y lineages with different Y-chromosomal characteristics that may affect their susceptibility or resistance to such a male-specific cancer. To confirm this hypothesis we studied the Y-chromosomal haplogroups of 92 Japanese prostate cancer patients comparing them with randomly selected 109 unrelated healthy Japanese male controls who were confirmed to be residents of the same geographical area. Males could be classified using three binary Y-chromosome markers (sex-determining region Y (SRY), YAP, 47z) into four haplogroups DE, O2b(*), O2b1, and untagged group. Our results confirmed that prostate cancer incidence varies among males from different Y-chromosome lineages. Males from DE and the untagged haplogroups are at a significantly higher risk to develop prostate cancer than O2b(*) and O2b1 haplogroups (P=0.01), odds ratio 2.17 and 95% confidence interval (1.16-4.07). Males from haplogroup DE are over-represented in the patient group showing a percentage of 41.3%. The underlying possible causes of susceptibility variations of different Y lineages for such a male-specific cancer tumorigenesis are discussed. These findings explain the lower incidence of prostate cancer in Japanese and other South East Asian males than other populations. To our knowledge, this is the first reliable study examining the association between prostate cancer and Y-chromosomal haplogroups, comparing prostate cancer patients with carefully selected matched controls.

Carcinoma↗
PubMed2003

Bidirectional integrin alphaIIbbeta3 signalling regulating platelet adhesion under flow: contribution of protein kinase C.

Platelet adhesion on von Willebrand factor (vWf) requires the co-ordinated adhesive function of glycoprotein Ib/V/IX and integrin alphaIIbbeta3. Recent evidence [Nesbitt, Kulkarni, Giuliano, Gonclaves, Dopheide, Yap, Harper, Salem and Jackson (2002) J. Biol. Chem. 277, 2965-2972] suggests that outside-in signals from both receptors play important roles in regulating platelet-adhesion dynamics under flow. In the present study, we have examined the mechanisms utilized by protein kinase C (PKC) to promote irreversible platelet adhesion on vWf. We demonstrate that PKC is primarily activated downstream of integrin alphaIIbbeta3, not glycoprotein Ib, during platelet adhesion on vWf. This integrin alphaIIbbeta3-dependent PKC activation establishes a positive-feedback loop that promotes further integrin alphaIIbbeta3 activation, calcium mobilization and firm platelet adhesion. This feedback loop appears to be most relevant at relatively low cytosolic calcium concentrations (mean Delta[Ca(2+)](i);100 nM) as artificially elevating calcium (mean Delta[Ca(2+)](i) > 500 nM) induces integrin alphaIIbbeta3 activation and irreversible platelet adhesion independent of PKC. Our studies demonstrate the existence of a complex signalling relationship operating between PKC, cytosolic calcium and integrin alphaIIbbeta3 that serves to regulate platelet-adhesion dynamics under flow. Furthermore, we have established the existence of PKC-dependent and -independent pathways regulating integrin alphaIIbbeta3 activation and stable platelet adhesion on vWf.

Calcium↗
PubMed2004

Expression of YAP4 in Saccharomyces cerevisiae under osmotic stress.

YAP4, a member of the yeast activator protein ( YAP ) gene family, is induced in response to osmotic shock in the yeast Saccharomyces cerevisiae. The null mutant displays mild and moderate growth sensitivity at 0.4 M and 0.8 M NaCl respectively, a fact that led us to analyse YAP4 mRNA levels in the hog1 (high osmolarity glycerol) mutant. The data obtained show a complete abolition of YAP4 gene expression in this mutant, placing YAP4 under the HOG response pathway. YAP4 overexpression not only suppresses the osmosensitivity phenotype of the yap4 mutant but also relieves that of the hog1 mutant. Induction, under the conditions tested so far, requires the presence of the transcription factor Msn2p, but not of Msn4p, as YAP4 mRNA levels are depleted by at least 75% in the msn2 mutant. This result was further substantiated by the fact that full YAP4 induction requires the two more proximal stress response elements. Furthermore we find that GCY1, encoding a putative glycerol dehydrogenase, GPP2, encoding a NAD-dependent glycerol-3-phosphate phosphatase, and DCS2, a homologue to a decapping enzyme, have decreased mRNA levels in the yap4 -deleted strain. Our data point to a possible, as yet not entirely understood, role of the YAP4 in osmotic stress response.

DNA-Binding Proteins↗
PubMed2000

Patterns of male-specific inter-population divergence in Europe, West Asia and North Africa.

We typed 1801 males from 55 locations for the Y-specific binary markers YAP, DYZ3, SRY10831 and the (CA)n microsatellites YCAII and DYS413. Phylogenetic relationships of chromosomes with the same binary haplotype were condensed in seven large one-step networks, which accounted for 95% of all chromosomes. Their coalescence ages were estimated based on microsatellite diversity. The three largest and oldest networks undergo sharp frequency changes in three areas. The more recent network 3.1A clearly discriminates between Western and Eastern European populations. Pairwise Fst showed an overall increment with increasing geographic distance but with a slope greatly reduced when compared to previous reports. By sectioning the entire data set according to geographic and linguistic criteria, we found higher Fst-on-distance slopes within Europe than in West Asia or across the two continents.

Africa, Northern↗
PubMed2005

The Y-chromosomal heritage of the Azores Islands population.

The Azores, a Portuguese archipelago located in the north Atlantic Ocean, had no native population when the Portuguese first arrived in the 15th century. The islands were populated mainly by the Portuguese, but Jews, Moorish prisoners, African slaves, Flemish, French and Spaniards also contributed to the initial settlement. To understand the paternal origins and diversity of the extant Azorean population, we typed genomic DNA samples from 172 individuals using a combination of 10 Y-biallelic markers (YAP, SRY-1532, SRY-2627, 92R7, M9, sY81, Tat, SRY-8299, 12f2 and LLY22g) and the following Y-chromosomal STR systems: DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393 and DYS385. We identified nine different haplogroups, most of which are frequent in Europe. Haplogroup J* is the second most frequent in the Azores (13.4%), but it is modestly represented in mainland Portugal (6.8%). The other non-European haplogroups, N3 and E3a, which are prevalent in Asia and sub-Saharan Africa, respectively, have been found in the Azores (0.6% and 1.2%, respectively) but not in mainland Portugal. Microsatellite data indicate that the mean gene diversity (D) value for all the loci analysed in our sample set is 0.590, while haplotype diversity is 0.9994. Taken together, our analysis suggests that the current paternal pool of the Azorean population is, to a great extent, of Portuguese descent with significant contributions from people with other genetic backgrounds.

Chromosomes, Human, Y↗
PubMed2001

Ultrafast folding of WW domains without structured aromatic clusters in the denatured state.

Ultrafast-folding proteins are important for combining experiment and simulation to give complete descriptions of folding pathways. The WW domain family comprises small proteins with a three-stranded antiparallel beta-sheet topology. Previous studies on the 57-residue YAP 65 WW domain indicate the presence of residual structure in the chemically denatured state. Here we analyze three minimal core WW domains of 38-44 residues. There was little spectroscopic or thermodynamic evidence for residual structure in either their chemically or thermally denatured states. Folding and unfolding kinetics, studied by using rapid temperature-jump and continuous-flow techniques, show that each domain folds and unfolds very rapidly in a two-state transition through a highly compact transition state. Folding half-times were as short as 17 micros at 25 degrees C, within an order of magnitude of the predicted maximal rate of loop formation. The small size and topological simplicity of these domains, in conjunction with their very rapid two-state folding, may allow us to reduce the difference in time scale between experiment and theoretical simulation.

Amino Acid Sequence↗
PubMed2000

A novel pro-Arg motif recognized by WW domains.

WW domains mediate protein-protein interactions through binding to short proline-rich sequences. Two distinct sequence motifs, PPXY and PPLP, are recognized by different classes of WW domains, and another class binds to phospho-Ser-Pro sequences. We now describe a novel Pro-Arg sequence motif recognized by a different class of WW domains using data from oriented peptide library screening, expression cloning, and in vitro binding experiments. The prototype member of this group is the WW domain of formin-binding protein 30 (FBP30), a p53-regulated molecule whose WW domains bind to Pro-Arg-rich cellular proteins. This new Pro-Arg sequence motif re-classifies the organization of WW domains based on ligand specificity, and the Pro-Arg class now includes the WW domains of FBP21 and FE65. A structural model is presented which rationalizes the distinct motifs selected by the WW domains of YAP, Pin1, and FBP30. The Pro-Arg motif identified for WW domains often overlaps with SH3 domain motifs within protein sequences, suggesting that the same extended proline-rich sequence could form discrete SH3 or WW domain complexes to transduce distinct cellular signals.

Amino Acid Sequence↗
PubMed2007

Apoptosis, proliferation and differentiation patterns are influenced by Zebularine and SAHA in pancreatic cancer models.

OBJECTIVE: Pancreatic cancer continues to be an urgent clinical problem. We used the novel DNA methyltransferase inhibitor Zebularine and the histone deacetylase inhibitor SAHA to investigate the epigenetic influence on viability and differentiation of the pancreatic cancer cell lines YAP C, DAN G and Panc-89 in vitro and in vivo. MATERIAL AND METHODS: Cell vitality, proliferation and expression of PDX-1, cytokeratin 7 and 20, chromogranin A, vimentin, bax and bcl-2 were determined on the protein and mRNA level in vitro and in a subcutaneous xenograft model. RESULTS: A time- and dose-dependent increase of apoptosis, paralleled by decreased proliferation, was observed after incubation with single agents or a combination therapy with lower concentrations. This was associated with up-regulation of pro-apoptotic bax and a phenotypic stabilization by the enhanced expression of cytokeratin 7. In vivo, growth of xenografts was delayed with the most pronounced effect in Panc-89 after 1 week of daily intraperitoneal injections of Zebularine paralleled with CK7 up-regulation and down-regulation of dedifferentiation markers. CONCLUSIONS: Epigenetic modulation via inhibition of DNA methyltransferase and histone deacetylase induces apoptosis in human pancreatic cancer cells in vitro and delays xenograft growth in vivo, which is associated with a morphological/molecular phenotypic stabilization. These compounds may therefore be suitable as adjunctive therapeutic agents in the treatment of pancreatic cancer.

Animals↗