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Biomedical subjects

A Yen

Publications and source records attributed to A Yen.

At least 19 recordsLinked to original sources
PubMed2006

Downregulation of topoisomerase IIbeta in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest.

Among the topoisomerase (topo) II isozymes (alpha and beta), topo IIbeta has been suggested to regulate differentiation. In this study, we examined the role of topo IIbeta in all-trans retinoic acid (ATRA)-induced differentiation of myeloid leukemia cell lines. Inhibition of topo IIbeta activity or downregulation of protein expression enhanced ATRA-induced differentiation/growth arrest and apoptosis. ATRA-induced apoptosis in topo IIbeta-deficient cells involved activation of the caspase cascade and was rescued by ectopic expression of topo IIbeta. Gene expression profiling led to the identification of peroxiredoxin 2 (PRDX2) as a candidate gene that was downregulated in topo IIbeta-deficient cells. Reduced expression of PRDX2 validated at the mRNA and protein level, in topo IIbeta-deficient cells correlated with increased accumulation of reactive oxygen species (ROS) following ATRA-induced differentiation. Overexpression of PRDX2 in topo IIbeta-deficient cells led to reduced accumulation of ROS and partially reversed ATRA-induced apoptosis. These results support a role for topo IIbeta in survival of ATRA-differentiated myeloid leukemia cells. Reduced expression of topo IIbeta induces apoptosis in part by impairing the anti-oxidant capacity of the cell owing to downregulation of PRDX2. Thus, suppression of topo IIbeta and/or PRDX2 levels in myeloid leukemia cells provides a novel approach for improving ATRA-based differentiation therapy.

Antineoplastic Agents↗
PubMed2005

Aeolian processes at the Mars Exploration Rover Meridiani Planum landing site.

The martian surface is a natural laboratory for testing our understanding of the physics of aeolian (wind-related) processes in an environment different from that of Earth. Martian surface markings and atmospheric opacity are time-variable, indicating that fine particles at the surface are mobilized regularly by wind. Regolith (unconsolidated surface material) at the Mars Exploration Rover Opportunity's landing site has been affected greatly by wind, which has created and reoriented bedforms, sorted grains, and eroded bedrock. Aeolian features here preserve a unique record of changing wind direction and wind strength. Here we present an in situ examination of a martian bright wind streak, which provides evidence consistent with a previously proposed formational model for such features. We also show that a widely used criterion for distinguishing between aeolian saltation- and suspension-dominated grain behaviour is different on Mars, and that estimated wind friction speeds between 2 and 3 m s(-1), most recently from the northwest, are associated with recent global dust storms, providing ground truth for climate model predictions.

Journal Article↗
PubMed2004

Chemistry of rocks and soils at Meridiani Planum from the Alpha Particle X-ray Spectrometer.

The Alpha Particle X-ray Spectrometer on the Opportunity rover determined major and minor elements of soils and rocks in Meridiani Planum. Chemical compositions differentiate between basaltic rocks, evaporite-rich rocks, basaltic soils, and hematite-rich soils. Although soils are compositionally similar to those at previous landing sites, differences in iron and some minor element concentrations signify the addition of local components. Rocky outcrops are rich in sulfur and variably enriched in bromine relative to chlorine. The interaction with water in the past is indicated by the chemical features in rocks and soils at this site.

Alpha Particles↗
PubMed2004

Jarosite and hematite at Meridiani Planum from Opportunity's Mossbauer Spectrometer.

Mossbauer spectra measured by the Opportunity rover revealed four mineralogical components in Meridiani Planum at Eagle crater: jarosite- and hematite-rich outcrop, hematite-rich soil, olivine-bearing basaltic soil, and a pyroxene-bearing basaltic rock (Bounce rock). Spherules, interpreted to be concretions, are hematite-rich and dispersed throughout the outcrop. Hematitic soils both within and outside Eagle crater are dominated by spherules and their fragments. Olivine-bearing basaltic soil is present throughout the region. Bounce rock is probably an impact erratic. Because jarosite is a hydroxide sulfate mineral, its presence at Meridiani Planum is mineralogical evidence for aqueous processes on Mars, probably under acid-sulfate conditions.

Extraterrestrial Environment↗
PubMed2004

Soils of Eagle crater and Meridiani Planum at the Opportunity Rover landing site.

The soils at the Opportunity site are fine-grained basaltic sands mixed with dust and sulfate-rich outcrop debris. Hematite is concentrated in spherules eroded from the strata. Ongoing saltation exhumes the spherules and their fragments, concentrating them at the surface. Spherules emerge from soils coated, perhaps from subsurface cementation, by salts. Two types of vesicular clasts may represent basaltic sand sources. Eolian ripples, armored by well-sorted hematite-rich grains, pervade Meridiani Planum. The thickness of the soil on the plain is estimated to be about a meter. The flatness and thin cover suggest that the plain may represent the original sedimentary surface.

Extraterrestrial Environment↗
PubMed2004

The Opportunity Rover's Athena science investigation at Meridiani Planum, Mars.

The Mars Exploration Rover Opportunity has investigated the landing site in Eagle crater and the nearby plains within Meridiani Planum. The soils consist of fine-grained basaltic sand and a surface lag of hematite-rich spherules, spherule fragments, and other granules. Wind ripples are common. Underlying the thin soil layer, and exposed within small impact craters and troughs, are flat-lying sedimentary rocks. These rocks are finely laminated, are rich in sulfur, and contain abundant sulfate salts. Small-scale cross-lamination in some locations provides evidence for deposition in flowing liquid water. We interpret the rocks to be a mixture of chemical and siliciclastic sediments formed by episodic inundation by shallow surface water, followed by evaporation, exposure, and desiccation. Hematite-rich spherules are embedded in the rock and eroding from them. We interpret these spherules to be concretions formed by postdepositional diagenesis, again involving liquid water.

Atmosphere↗
PubMed2004

Basaltic rocks analyzed by the Spirit Rover in Gusev Crater.

The Spirit landing site in Gusev Crater on Mars contains dark, fine-grained, vesicular rocks interpreted as lavas. Pancam and Mini-Thermal Emission Spectrometer (Mini-TES) spectra suggest that all of these rocks are similar but have variable coatings and dust mantles. Magnified images of brushed and abraded rock surfaces show alteration rinds and veins. Rock interiors contain </=25% megacrysts. Chemical analyses of rocks by the Alpha Particle X-ray Spectrometer are consistent with picritic basalts, containing normative olivine, pyroxenes, plagioclase, and accessory FeTi oxides. Mössbauer, Pancam, and Mini-TES spectra confirm the presence of olivine, magnetite, and probably pyroxene. These basalts extend the known range of rock compositions composing the martian crust.

Extraterrestrial Environment↗
PubMed2004

Chemistry of rocks and soils in Gusev Crater from the alpha particle x-ray spectrometer.

The alpha particle x-ray spectrometer on the Spirit rover determined major and minor elements of soils and rocks in Gusev crater in order to unravel the crustal evolution of planet Mars. The composition of soils is similar to those at previous landing sites, as a result of global mixing and distribution by dust storms. Rocks (fresh surfaces exposed by the rock abrasion tool) resemble volcanic rocks of primitive basaltic composition with low intrinsic potassium contents. High abundance of bromine (up to 170 parts per million) in rocks may indicate the alteration of surfaces formed during a past period of aqueous activity in Gusev crater.

Alpha Particles↗
PubMed2004

Mineralogy at Gusev Crater from the Mössbauer spectrometer on the Spirit Rover.

Mössbauer spectra measured on Mars by the Spirit rover during the primary mission are characterized by two ferrous iron doublets (olivine and probably pyroxene) and a ferric iron doublet (tentatively associated to nanophase ferric iron oxide). Two sextets resulting from nonstoichiometric magnetite are also present, except for a coating on the rock Mazatzal, where a hematite-like sextet is present. Greater proportions of ferric-bearing phases are associated with undisturbed soils and rock surfaces as compared to fresh rock surfaces exposed by grinding. The ubiquitous presence of olivine in soil suggests that physical rather than chemical weathering processes currently dominate at Gusev crater.

Extraterrestrial Environment↗
PubMed2004

The Spirit Rover's Athena science investigation at Gusev Crater, Mars.

The Mars Exploration Rover Spirit and its Athena science payload have been used to investigate a landing site in Gusev crater. Gusev is hypothesized to be the site of a former lake, but no clear evidence for lacustrine sedimentation has been found to date. Instead, the dominant lithology is basalt, and the dominant geologic processes are impact events and eolian transport. Many rocks exhibit coatings and other characteristics that may be evidence for minor aqueous alteration. Any lacustrine sediments that may exist at this location within Gusev apparently have been buried by lavas that have undergone subsequent impact disruption.

Atmosphere↗
PubMed2001

Retinoic acid causes MEK-dependent RAF phosphorylation through RARalpha plus RXR activation in HL-60 cells.

Retinoic acid (RA) is known to cause the myeloid differentiation of HL-60 human myeloblastic leukemia cells in a process requiring MEK-dependent ERK2 activation. This RA-induced ERK2 activation appears after approximately 4 h and persists until the cells are differentiated and G0 arrested (Yen et al, 1998). This motivates the question of whether RA also activated RAF as part of a typical RAF/MEK/MAPK cascade. Retinoic acid is shown here to also increase the phosphorylation of RAF, but in an unusual way. Surprisingly, increased RAF phosphorylation is first detectable after 12 to 24 hours by phosphorylation-induced retardation of polyacrylamide gel electrophoretic mobility. The RA-induced increased RAF phosphorylation is still apparent after 72 hours of treatment when most cells are differentiated and G0 arrested. There is a progressive dose-response relationship with 10(-8), 10(-7), and 10(-6) M RA. The RA-induced RAF phosphorylation corresponds to increased in vitro kinase activity. Inhibition of MEK with a PD98059 dose which inhibits ERK2 phosphorylation and subsequent cell differentiation also inhibits RAF phosphorylation. RA-induced MEK-dependent RAF phosphorylation is not due to changes in the amount of cellular MEK. The induced RAF phosphorylation, as well as anteceding ERK2 activation, depends on ligand-induced activation of both an RARalpha receptor and an RXR receptor. This and the slow kinetics of activation suggest a need for prior RA-induced gene expression. In summary, RA induces a MEK-dependent prolonged RAF activation, whose slow onset occurs after ERK2 activation but still well before cell cycle arrest and cell differentiation. The RA-induced increased RAF phosphorylation thus differs from typical mitogenic growth factor signaling, features that may contribute to cell cycle arrest and differentiation instead of division as the cellular outcome.

Cell Differentiation↗
PubMed2001

Retinoic acid-induced blr1 expression requires RARalpha, RXR, and MAPK activation and uses ERK2 but not JNK/SAPK to accelerate cell differentiation.

Upstream signaling requirements of retinoic acid (RA)-induced blr1 expression and downstream signaling consequences of blr1 over-expression in a human myeloid leukemia cell line demonstrate that mitogen-activated protein kinase (MAPK) signaling complexes are involved in both avenues. RA-induced myeloid differentiation and G1/G0 growth arrest of HL-60 cells is known to require the activation of the RARalpha and RXR retinoid receptors, as well as activation of the MAPK, ERK2. Transcriptional activation of the Burkitt's lymphoma receptor 1 (blr1) gene occurs early during RA-induced differentiation of HL-60 cells and requires these same three activating processes. The use of retinoid ligands that activate either the RARalpha or the RXR retinoid receptors revealed that blr1 mRNA induction was detectable only when both RARalpha and RXR were activated. Neither the RARalpha nor RXR selective ligands alone induced expression of blr1, but the combination of the two ligands induced the expression of blr1 to the same extent as RA. The MAPKK (MEK) inhibitor, PD98059, was used to determine whether extracellular signal-regulated kinase (ERK2) activation was necessary for induction of blr1 mRNA. PD98059 inhibited induced blr1 mRNA expression, due to RA or activated RARalpha plus RXR ligands, indicating that ERK2 activation is necessary for blr1 mRNA expression. Previous studies showed that ectopic expression of blr1 also caused increased MAPK activation, in particular ERK2, and subsequently accelerated RA-induced differentiation and G1/G0 growth arrest. Inhibition of ERK2 activation inhibited differentiation of blr1 transfectants, suggesting that the accelerated differentiation reflected blr1-enhanced ERK2 activation. The present data also demonstrate that ectopic expression of blr1 increased JNK/SAPK activity, but JNK/ SAPK activation was not needed for accelerated RA-induced differentiation and growth arrest. The results show that the signals known to be required for HL-60 differentiation, activated RARalpha, RXR, and ERK2, are necessary for blr1 mRNA expression. Downstream consequences of blr1 overexpression include enhanced MAPK signaling.

Cell Differentiation↗
PubMed2001

Polyomavirus small t antigen prevents retinoic acid-induced retinoblastoma protein hypophosphorylation and redirects retinoic acid-induced G0 arrest and differentiation to apoptosis.

Polyomavirus small t antigen (ST) impedes late features of retinoic acid (RA)-induced HL-60 myeloid differentiation as well as growth arrest, causing apoptosis instead. HL-60 cells were stably transfected with ST. ST slowed the cell cycle, retarding G2/M in particular. Treated with RA, the ST transfectants continued to proliferate and underwent apoptosis. ST also impeded the normally RA-induced hypophosphorylation of the retinoblastoma tumor suppressor protein consistent with failure of the cells to arrest growth. The RA-treated transfectants expressed CD11b, an early cell surface differentiation marker, but inducible oxidative metabolism, a later and more mature functional differentiation marker, was largely inhibited. Instead, the cells underwent apoptosis. ST affected significant known components of RA signaling that result in G0 growth arrest and differentiation in wild-type HL-60. ST increased the basal amount of activated ERK2, which normally increases when wild-type cells are treated with RA. ST caused increased RARalpha expression, which is normally down regulated in RA-treated wild-type cells. The effects of ST on RA-induced myeloid differentiation did not extend to monocytic differentiation and G0 arrest induced by 1,25-dihydroxy vitamin D3, whose receptor is also a member of the steroid-thyroid hormone superfamily. In this case, ST abolished the usually induced G0 arrest and retarded, but did not block, differentiation without inducing apoptosis, thus uncoupling growth arrest and differentiation. In sum, the data show that ST disrupted the normal RA-induced program of G0 arrest and differentiation, causing the cells to abort differentiation and undergo apoptosis.

Antigens, Viral, Tumor↗
PubMed2000

Retinoic acid-induced blr1 expression promotes ERK2 activation and cell differentiation in HL-60 cells.

Retinoids are known to induce the differentiation and cell cycle arrest of human myeloid leukemia cells in vitro. Differential display was used to identify putative early regulatory genes that are differentially expressed in HL-60 human promyelocytic leukemia cells treated with retinoic acid. One of the cDNAs cloned encodes sequences identifying Burkitt's lymphoma receptor 1 (BLR1), a recently described chemokine receptor. Northern blot analysis demonstrates that blr1 mRNA expression increases within 9 h of retinoic acid treatment, well before functional differentiation or G(1)/G(0) growth arrest at 48 h or onset of morphological changes, suggesting a possible regulatory function. The expression of blr1 mRNA is transient, peaking at 72 h when cells are differentiated. blr1 mRNA also is induced by other differentiation-inducing agents, 1alpha,25-dihydroxyvitamin D(3) and DMSO. Induction of blr1 mRNA by retinoic acid is not blocked by the protein synthesis inhibitor cycloheximide. In HL-60 cells stably transfected with blr1 cDNA, ectopic expression of blr1 causes an increase in ERK2 MAPK activation and promotes retinoic acid-induced G(1)/G(0) growth arrest and cell differentiation. The early expression of blr1 mRNA during differentiation, its ability to increase ERK2 activation, and its enhancement of retinoic acid-induced differentiation suggest that blr1 expression may be involved in retinoic acid-induced HL-60 differentiation.

Alternative Splicing↗
PubMed2000

Application of membrane-based dendrimer/DNA complexes for solid phase transfection in vitro and in vivo.

In this study a general description of the use of solid support membranes as the device for DNA delivery mediated by PAMAM dendrimers is presented. In contrast to the other DNA carriers, dendrimer/DNA complexes retain the ability to transfect after drying, which enabled coating or incorporation of complexes into poly(DL-lactide-co-glycolide) or collagen-based bioerodable membranes. These studies provide support for the use of this technology for in vitro and in vivo transfection of skin cells. Expression of luciferase or green fluorescent protein from pCF1-Luc and pEGFP1 plasmids indicated that dendrimer/DNA complexes can mediate transfection after dissociation from the solid support and/or when retained on the surface of the membranes. Modification of the membranes by incorporation of an anionic lipid, phosphatidyl glycerol (PG) at 1-5% concentrations, resulted in more efficient in situ transfection, particularly with dendrimer/DNA complexes formed at the low charge ratios (1-5). We also report data supporting the feasibility of membrane-based dendrimer/DNA complexes, particularly formed at lower than neutralizing conditions, for topical in vivo delivery of DNA to hairless mouse skin.

Administration, Topical↗
PubMed2000

Opposing effects of androgen and estrogen on pituitary-adrenal function in nonpregnant primates.

Maternal administration of androstenedione produces a sustained fall in maternal plasma adrenocorticotropic hormone (ACTH) concentrations in the pregnant nonhuman primate. We hypothesize a negative feedback influence on the maternal hypothalamo-pituitary-adrenal (HPA) axis by androgens in primates. This may reflect an important maternal adaptation during pregnancy in primates preventing premature induction of labor by maternal stress. However, androstenedione is precursor for placental estradiol-17beta synthesis, and infusion of androstenedione into pregnant primates elevates maternal plasma estradiol-17beta to term concentrations. Thus, it could be argued that 1) the effects attributed to androstenedione on the maternal HPA axis are mediated by estrogen rather than by androgen and 2) the negative influence of androgens may be on placental ACTH rather than, or in addition to, pituitary ACTH. To discriminate between androgenic and estrogenic effects of androstenedione on pituitary and/or placental ACTH function in primates we measured plasma ACTH, cortisol, and dehydroepiandrosterone sulfate (DHEAS) concentrations in nonpregnant baboons after treatment with either androstenedione or estradiol-17beta. Nine female baboons were studied between 14 and 22 days postpartum prior to estrous cycling. After 2 days of baseline, a continuous i.v. infusion of androstenedione (1.5 mg/kg per h in 10% intralipid, IL) was started at 0900 h and maintained for 9 days in 3 baboons. A similar protocol was carried out in another 3 baboons that received a continuous i.v. infusion of estradiol-17beta (10 microg/kg per h in 10% IL) instead of androstenedione. Three additional baboons received continuous i.v. IL vehicle alone and served as controls. Arterial blood samples (0.5 ml) for measurement of plasma hormones were taken during baseline and after 1, 3, 5, 7, and 9 days of infusion. Baseline plasma ACTH, DHEAS, and cortisol concentrations were similar among all groups. Plasma ACTH did not change during IL, increased following estradiol-17beta, and fell during androstenedione treatment. Accordingly, plasma cortisol and DHEAS concentrations were also unaltered by IL, and both steroids increased during estradiol-17beta treatment. In contrast, plasma cortisol and DHEAS remained unaltered from baseline during androstenedione treatment, despite the fall in plasma ACTH measured at this time. These data in the nonpregnant baboon 1) are consistent with negative feedback on pituitary ACTH by androgens and 2) demonstrate a positive influence on pituitary-adrenal function by estrogen in primates.

Adrenal Glands↗
PubMed2000

Increased myometrial contracture frequency at 96-140 days accelerates fetal cardiovascular maturation.

Fetal cardiovascular responses to an altered intrauterine environment of increased myometrial contractures induced by oxytocin (OT) pulses to the ewe over the final 50 days of gestation were studied in chronically instrumented sheep. Ewes received saline (Cntl) or long-term OT treatment (LTOT, 600 microU x kg(-1) x min(-1) in 5-min pulses every 20 min) from 96 days gestational age. Fetal baroreflex responses to sodium nitroprusside (SNP) and phenylephrine (PE) were studied at 133 days gestation. OT increased contractures in LTOT ewes. Fetal blood pressure (FBP) was higher, and fetal heart rate (FHR) and slope of daily change in FBP and FHR were lower in LTOT fetuses. Fetal SNP-induced hypotension resulted in a narrow R-R interval variation range in LTOT fetuses; Cntl fetuses showed early breakdown in compensation. Baroreflex response slope during PE-induced fetal hypertension was lower in LTOT than in Cntl fetuses. Although the cortisol-to-ACTH ratio was lower in LTOT fetuses, fetal plasma ACTH and cortisol changes were similar in control and LTOT fetuses. We hypothesize that contracture-induced alterations in the intrauterine environment accelerate fetal cardiovascular development through mild hypoxemia, repetitive fetal pituitary-adrenal stimulation, and/or physical stimulation.

Animals↗