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Biomedical subjects

X He

Publications and source records attributed to X He.

At least 55 records · Page 3Linked to original sources

Tissue-specific silencing of a transgene in rice.

In a transgenic rice line, a beta-glucuronidase reporter gene under the control of the rice tungro bacilliform virus promoter became gradually methylated, and gene activity was lost concomitantly. Methylation was observed only in the homozygous offspring and was initially restricted to the promoter region and accompanied by loss of expression in the vascular bundle tissue only. This expression pattern was similar to that of a promoter with a deletion of a vascular bundle expression element. The gene activity could be reestablished by treatment with 5-azacytidine. Methylation per se did not inhibit the binding to the promoter region of protein factors which also bound to the unmethylated sequence. Instead, promoter methylation enabled the alternative binding of a protein with specificity for sequence and methylation. In further generations of homozygous offspring the methylation spread into the transcribed region and gene activity was completely repressed also in nonvascular cells. The results indicate that different stages are involved in DNA methylation-correlated gene inactivation, and that at least one of them may involve the attraction of a sequence and methylation-specific DNA-binding protein.

Badnavirus↗

Centrality dependence of pi(+/-), K(+/-), p, and (-)p production from sqrt[s(NN)] = 130 GeV Au + Au collisions at RHIC.

Identified pi(+/-), K(+/-), p, and (-)p transverse momentum spectra at midrapidity in sqrt[s(NN)] = 130 GeV Au+Au collisions were measured by the PHENIX experiment at RHIC as a function of collision centrality. Average transverse momenta increase with the number of participating nucleons in a similar way for all particle species. Within errors, all midrapidity particle yields per participant are found to be increasing with the number of participating nucleons. There is an indication that K(+/-), p, and (-)p yields per participant increase faster than the pi(+/-) yields. In central collisions at high transverse momenta (p(T) > or =2 GeV/c), (-)p and p yields are comparable to the pi(+/-) yields.

Journal Article↗

Transverse-mass dependence of two-pion correlations in Au+Au collisions at square root[s(NN)] = 130 GeV.

Two-pion correlations in square root[s(NN)] = 130 GeV Au+Au collisions at RHIC have been measured over a broad range of pair transverse momentum k(T) by the PHENIX experiment at RHIC. The k(T) dependent transverse radii are similar to results from heavy-ion collisions at square root[s(NN)] = 4.1, 4.9, and 17.3 GeV, whereas the longitudinal radius increases monotonically with beam energy. The ratio of the outwards to sidewards transverse radii (R(out)/R(side)) is consistent with unity and independent of k(T).

Journal Article↗

Measurement of single electrons and implications for charm production in Au+Au collisions at square root[s(NN)] = 130 GeV.

Transverse momentum spectra of electrons from Au+Au collisions at square root[s(NN)] = 130 GeV have been measured at midrapidity by the PHENIX experiment at the Relativistic Heavy Ion Collider. The spectra show an excess above the background from photon conversions and light hadron decays. The electron signal is consistent with that expected from semileptonic decays of charm. The yield of the electron signal dN(e)/dy for p(T) > 0.8 GeV/c is 0.025+/-0.004(stat)+/-0.010(syst) in central collisions, and the corresponding charm cross section is 380+/-60(stat)+/-200(syst) microb per binary nucleon-nucleon collision.

Journal Article↗

Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.

Wnt signaling via the Frizzled (Fz) receptor controls cell polarity and movement during development, but the molecular nature of Wnt/Fz polarity signal transduction remains poorly defined. Here we report that in human cells and during Xenopus embryogenesis, Wnt/Fz signaling activates the small GTPase Rho, a key regulator of cytoskeleton architecture. Wnt/Fz activation of Rho requires the cytoplasmic protein Dishevelled (Dvl) and a novel Formin homology protein Daam1. Daam1 binds to both Dvl and Rho, and mediates Wnt-induced Dvl-Rho complex formation. Inhibition or depletion of Daam1 prevents Wnt/Fz activation of Rho and of Xenopus gastrulation, but not of beta-catenin signaling. Our study illustrates a molecular pathway from Wnt/Fz signaling to Rho activation in cell polarity signal transduction.

Adaptor Proteins, Signal Transducing↗

Suppression of hadrons with large transverse momentum in central Au+Au collisions at root square[s(NN)] = 130 GeV.

Transverse momentum spectra for charged hadrons and for neutral pions in the range 1 GeV/c<p(T)<5 GeV/c have been measured by the PHENIX experiment at RHIC in Au+Au collisions at root square[s(NN)] = 130 GeV. At high p(T) the spectra from peripheral nuclear collisions are consistent with scaling the spectra from p+p collisions by the average number of binary nucleon-nucleon collisions. The spectra from central collisions are significantly suppressed when compared to the binary-scaled p+p expectation, and also when compared to similarly binary-scaled peripheral collisions, indicating a novel nuclear-medium effect in central nuclear collisions at RHIC energies.

Journal Article↗

Synthesis and electronic properties of low-dimensional bis(benzene) vanadium reduced mesoporous niobium oxide composites.

The first bis(benzene) vanadium mesoporous niobium oxide composite was synthesized and characterized. The XRD pattern of this material shows a peak (100) centered at 45 A, identical to that of starting material. The nitrogen adsorption and desorption analyses of this material exhibit a slight decrease of BET surface area from 580 m(2) g(-1) to 467 m(2) g(-1) and a concomitant decrease in pore size and volume from 28 A and 0.500 cm(3) g(-1) to 25 A and 0.363 cm(3) g(-1), respectively. The powder EPR spectrum shows eight lines which can be assigned to (51)V from bis(benzene) vanadium as well as other resonances that can be assigned to the corresponding cation. The presence of two or more organometallic vanadium species was further confirmed by UV, (1)H-MAS NMR, and XPS methods. Broadened and shifted Nb 3/2, 5/2 peaks were also observed, providing further evidence that the mesoporous transition metal oxide framework was reduced by the organometallic. SQUID magnetometer measurements on this material show paramagnetic behavior with a small contribution of spin glass behavior. The conductivity of this material was 10(-4) ohm(-1) cm(-1), significantly greater than that measured for the analogous bis(benzene) chromium composite previously studied. Since alkali-metal reduced mesoporous niobium oxide materials are insulating, this conductivity was attributed to the low-dimensional bis-arene vanadium phase in the pores and rationalized according to the balance between the Hubbard potential and the bandwidth estimated for the relevant organometallic species. A bis-1,3,5-tri-tert-butylbenzene yttrium composite was also synthesized; however, complete loss of ligand upon reduction of the mesostructure was observed, indicating that this dopant behaves more like an alkali naphthalene reagent in its reactions with mesoporous niobium oxide than other bis(arene) complexes investigated by our group.

Journal Article↗

Yeast Dam1p has a role at the kinetochore in assembly of the mitotic spindle.

During mitosis, replicated chromosomes are separated to daughter cells by the microtubule-based mitotic spindle. Chromosomes attach to the mitotic spindle through specialized DNA/protein structures called kinetochores, but the mechanism of attachment is not well understood. We show here that the yeast microtubule-binding protein, Dam1p, associates physically and functionally with kinetochores, suggesting a role in kinetochore attachment to the spindle. An epitope-tagged version of Dam1p colocalizes with the integral kinetochore component Ndc10p/Cbf2p in immunofluorescence analysis of chromosome spreads. In addition, Dam1p is associated preferentially with centromeric DNA as shown by chromatin immunoprecipitation experiments, and this association depends on Ndc10p/Cbf2p. We also demonstrate genetic interactions between DAM1 and CTF19 or SLK19 genes encoding kinetochore proteins. Although the defect caused by the dam1-1 mutation leads to activation of the spindle checkpoint surveillance system and consequent persistence of sister chromatid cohesion, the metaphase arrest spindle abnormally elongates, resulting in virtually complete chromosome missegregation. Execution point experiments indicate that Dam1p has a role in formation of a metaphase spindle and in anaphase spindle elongation. Finally, we have observed that the protein encoded by the dam1-1 allele becomes delocalized at the nonpermissive temperature, correlating with the subsequent onset of the mutant phenotype. Our studies are consistent with a role for Dam1p in attachment of sister chromatids through the kinetochore to the mitotic spindle before chromosome segregation.

Cell Cycle Proteins↗

Ca(2+) binding protein frequenin mediates GDNF-induced potentiation of Ca(2+) channels and transmitter release.

Molecular mechanisms underlying long-term neurotrophic regulation of synaptic transmission and plasticity are unknown. We report here that long-term treatment of neuromuscular synapses with glial cell line-derived neurotrophic factor (GDNF) potentiates spontaneous and evoked transmitter release, in ways very similar to presynaptic expression of the Ca(2+) binding protein frequenin. GDNF enhances the expression of frequenin in motoneurons, and inhibition of frequenin expression or activity prevents the synaptic action of GDNF. GDNF also facilitates Ca(2+) influx into the nerve terminals during evoked transmission by enhancing Ca(2+) currents. The effect of GDNF on Ca(2+) currents is blocked by inhibition of frequenin expression, occluded by overexpression of frequenin, and is selective to N-type Ca(2+) channels. These results identify an important molecular target that mediates the long-term, synaptic action of a neurotrophic factor.

Animals↗

Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release.

SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.

ADAM Proteins↗

Influence of benzodiazepine binding site ligands on fear-conditioned contextual memory.

Eight compounds that bind to the benzodiazepine binding site on the gamma-amino butyric acid(A) (GABA(A)) receptor were assessed for their influence on contextual memory, an aspect of memory affected in various cognitive disorders including Alzheimer's disease. Using a Pavlovian fear-conditioning paradigm, each ligand was evaluated in C57Bl/6 mice in regards to its direct affect on contextual memory and whether the ligand could attenuate scopolamine-induced contextual memory impairment. Of the eight ligands tested, one impaired contextual memory (agonist), six attenuated scopolamine-induced contextual memory impairment (inverse agonists), and one antagonized the ability of an inverse agonist to attenuate scopolamine-induced contextual memory impairment. Hence, further demonstrating the bi-directional influence benzodiazepine binding site ligands are able to exert on memory modulation. This study serves as an initial starting point in the development of pharmacological tools to be used in deciphering how GABA(A) receptors influence contextual memory.

Animals↗

Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.

To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of </=0.2 microM in whole blood assay (WBA). Although the P3' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3', an N-methylamide at P4' provided the best cyclophane analogue, SL422 (WBA IC(50) = 0.22 microM, LPS-mouse ED(50) = 15 mg/kg, po), whereas a morpholinylamide at P4' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC(50) = 0.067 microM, LPS-mouse ED(50) = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K(i) values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.

ADAM Proteins↗

Molecular analysis of kinetochore-microtubule attachment in budding yeast.

The complex series of movements that mediates chromosome segregation during mitosis is dependent on the attachment of microtubules to kinetochores, DNA-protein complexes that assemble on centromeric DNA. We describe the use of live-cell imaging and chromatin immunoprecipitation in S. cerevisiae to identify ten kinetochore subunits, among which are yeast homologs of microtubule binding proteins in animal cells. By analyzing conditional mutations in several of these proteins, we show that they are required for the imposition of tension on paired sister kinetochores and for correct chromosome movement. The proteins include both molecular motors and microtubule associated proteins (MAPs), implying that motors and MAPs function together in binding chromosomes to spindle microtubules.

Biological Transport↗

[Risk factors of lung cancer and relevant comprehensive preventive strategy--a cohort study in Xuanwei, Yunnan Province, China].

OBJECTIVE: To systematically analyze the risk factors of lung cancer in Xuanwei, Yunnan Province, an area with a high prevalence of lung cancer, and in view of the above to propose a comprehensive preventive strategy. METHODS: A cohort study of 42,434 Xuanwei farmers who were born 1917-195, and still alive on 1st January 1976 was carried out from 1992 to 1996 with a follow-up time of 21 years. The data collection was done in two steps. A retrospective cohort study was conducted in the form of questionnaire survey in 1992 to understand the health situation of the interviewees from 1st January 1976 to 31st December 1991. In the second stage, a prospective cohort study was conducted to review the death records of the interviewees from 1st January 1992 to 31st December 1996. The data thus collected were analyzed by the Mantel-Haenszel analysis method, COX model and risk state analysis method. RESULTS: Indoor air pollution caused by biturminous coal burning is the major risk factor of lung cancer in Xuanwei. Stove improvement decreased the lung cancer mortality rate in both male and female subjects, but its beneficial can be recognized at least 10 years after. Smoking is another important risk factor of lung cancer in males in Xuanwei. In course of a long time since stove improvement smoking will become the major risk factor of lung cancer. The risky factors can be arranged in sequence of riskiness from high to low as bituminous coal burning, family history of lung cancer, personal history of chronic bronchitis, and smoking in males; and bituminous coal burning, family history of lung cancer, and personal history of chronic bronchitis in females. The risk state classification model established upon the basis of risk state analysis can be used in identifying effectively high risk population quantitatively for local administrators of health as well as for local residents. CONCLUSION: According to the comprehensive strategy for lung cancer control in Xuanwei, priority should be given to primary prevention with three steps: firstly to further reduce indoor air pollution by means of stove improvement and ventilation improvement, secondly strengthen smoking cessation, and thirdly to carry out chemoprevention and susceptibility study of lung cancer among high risk populations.

Air Pollution, Indoor↗

Paradoxical intrathymic positive selection in mice with only a covalently presented agonist peptide.

The Y-Ae mAb and the 1H3.1 alphabeta T cell antigen receptor (TCR) are both specific for the I-Ealpha52-68 peptide bound to the I-A(b) major histocompatibility complex (MHC) class II molecule. Antigen-presenting cells (APCs) from I-A(b+) mice with a natural or transgenic (Tg) I-Ealpha chain activate mature 1H3.1 T cells and cause the deletion of 1H3.1 TCR Tg thymocytes. However, 1H3.1 T cells were neither activated nor inactivated by confrontation with APCs from I-Ab-Ep mice in which I-A(b) molecules are occupied only by the covalently associated Ealpha52-68 peptide. Instead, immature 1H3.1 TCR Tg thymocytes were efficiently positively selected into the CD4 lineage in the I-Ab-Ep thymus. This selection relied on specific recognition of the Ealpha52-68/I-A(b) complex because it was blocked by Y-Ae. 1H3.1 TCR Tg T cells maturing in the I-Ab-Ep thymus efficiently populated the periphery, displayed a naive phenotype, and were specifically reactive to the Ealpha52-68 peptide or to I-A(b+)I-Ealpha(+) APCs, indicating that 1H3.1 T cells were not antagonized in I-Ab-Ep mice. The data identify major histocompatibility complex class II molecules with only a covalently attached self-peptide as a ligand for in vivo positive selection of T cells specific for the same peptide.

Animals↗

Measurement of the midrapidity transverse energy distribution from square root of [(s)NN] = 130 GeV Au + Au collisions at RHIC.

The first measurement of energy produced transverse to the beam direction at the Relativistic Heavy-Ion Collider at Brookhaven National Laboratory is presented. The midrapidity transverse energy density per participating nucleon rises steadily with the number of participants, closely paralleling the rise in charged-particle density, such that / remains relatively constant as a function of centrality. The energy density calculated via Bjorken's prescription for the 2% most central Au+Au collisions at square root[s(NN)] = 130 GeV is at least epsilon(Bj) = 4.6 GeV/fm(3), which is a factor of 1.6 larger than found at sqrt[s(NN)] = 17.2 GeV ( Pb+Pb at CERN).

Journal Article↗