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PubMed2006

Quasi-isomeric gallium amides and imides GaNR2 and RGaNR (R = organic group): reactions of the digallene, Ar'GaGaAr' (Ar' = C6H3-2,6-(C6H3-2,6-Pri2)2) with unsaturated nitrogen compounds.

Reactions of the "digallene" Ar'GaGaAr'(1) (Ar' = C(6)H(3)-2,6-(C(6)H(3)-2,6-Pr(i)(2))(2)), which dissociates to green :GaAr' monomers in solution, with unsaturated N-N-bonded molecules are described. Treatment of solutions of :GaAr' with the bulky azide N(3)Ar(#) (Ar(#) = C(6)H(3)-2,6-(C(6)H(2)-2,6-Me(2)-4-Bu(t))(2)), afforded the red imide Ar'GaNAr(#) (2). Addition of the azobenzenes, ArylNNAryl (Aryl = C(6)H(4)-4-Me (p-tolyl), mesityl, and C(6)H(3)-2,6-Et(2)) yielded the 1,2-Ga(2)N(2) ring compound Ar'GaN(p-tolyl)N(p-tolyl)GaA' (3) or the products MesN=NC(6)H(2)-2,4-Me(2)-6-Ga(Me)Ar' (4) and 2,6-Et(2)C(6)H(3)N=NC(6)H(3)-2-Et-6-Ga(Et)Ar' (5). Reaction of GaAr' with N(2)CPh(2) yielded the 1,3-Ga(2)N(2) ring compound Ar'Ga(mu:eta(1)-N(2)CPh(2))(2)GaAr' (6), which is quasi-isomeric to 3. Calculations on simple model isomers showed that the Ga(I) amide GaNR(2) (R = Me) is much more stable than the isomeric Ga(III) imide RGaNR. This led to the synthesis of the first stable monomeric Ga(I) amide, GaN(SiMe(3))Ar' ' (8) (Ar' ' = C(6)H(3)-2,6-(C(6)H(2)-2,4,6-Me(3))(2) from the reaction of LiN(SiMe(3))Ar' ' (7) and "GaI". Compound 8 is also the first one-coordinate gallium species to be characterized in the solid state. The reaction of 8 with N(3)Ar' ' afforded the amido-imide derivative Ar' 'NGaN(SiMe(3))Ar' ' (9), a gallium nitrogen analogue of an allyl anion. All compounds were spectroscopically and structurally characterized. In addition, DFT calculations were performed on model compounds of the amide, imide, and cyclic 1,2- and 1,3-species to better understand their bonding. The pairs of compounds 2 and 8 as well as 3 and 6 are rare examples of quasi-isomeric heavier main group element compounds.

Journal Article↗

PubMed2006

Estrogen-induced upregulation of AR expression and enhancement of AR nuclear translocation in mouse fallopian tubes in vivo.

Female mice lacking AR display alterations in ovarian and uterine function. However, the biology of AR in the fallopian tube is not fully understood. To gain an insight into potential roles of AR in this tissue, we demonstrated that eCG treatment increased AR expression in a time-dependent manner and subsequent treatment with hCG decreased AR expression in mouse fallopian tubes. This expression pattern was positively associated with 17beta-estradiol and testosterone levels in vivo. Immunohistochemical analysis of fallopian tube epithelial cells revealed that nuclear localization of AR increased in parallel with decreased AR in the cytoplasm following eCG treatment. Moreover, we found that treatment with flutamide upregulated AR expression in immature mice in association with a decrease in serum testosterone levels, whereas the same treatment resulted in downregulation of AR expression in gonadotropin-stimulated mice with concomitant decreases in serum 17beta-estradiol concentrations, suggesting that androgen differs from estrogen in the regulation of AR expression. Furthermore, we demonstrated that DES increased both AR protein expression and nuclear location over a 48-h time course. DHT had rapid effects, with induction of AR expression and translocation at 6 h after injection, but unlike DES it had prolonged efficacy. In addition, we provided direct in vivo evidence that nuclear protein interaction between AR and p21(Cip1), a previously reported AR-regulated gene, was enhanced by gonadotropin stimulation. To our knowledge, this study provides the first demonstration to illustrate that estrogen as a principal regulator may contribute to regulate and activate AR in the fallopian tubes in vivo.

Animals↗

PubMed1987

Influence of xid on anti-azophenylarsonate (Ar) antibody responses of (CBA/N x A/J)F1 mice: differential idiotype expression induced by only one of two Ar antigens.

The influence of an X chromosome-linked immune deficiency gene (xid) on several properties of the anti-azophenylarsonate (Ar) antibody responses of (CBA/N x A/J)F1 (NAF1) mice was examined. With respect to response magnitude, it was found that male, xid-expressing NAF1 mice showed about 1/3 the concentration of serum anti-Ar antibody as normal female NAF1 mice in hyperimmune responses to Brucella abortus (BA)-Ar. In responses induced by keyhole limpet hemocyanin (KLH)-Ar, males showed responses of about 1/8 to 1/2 the female levels, depending on the assay time point. The kinetics of the latter response were identical in mice of the two sexes. No significant difference could be detected in the time-dependent avidity maturation of the anti-Ar antibody elicited by KLH-Ar in xid vs. normal mice. The isotype profile of the day 38 anti-Ar primary response elicited by KLH-Ar in male NAF1 mice differed from that of the female mice in two ways: IgG2a levels were depressed, and a significantly lower number of the male mice demonstrated detectable IgG3 anti-Ar antibody production. The primary focus of htis work was to determine the effect of xid on the expression of the major cross-reactive idiotype--CRIA--of A strain mice. It was found that while a significant higher proportion of the female mice could be classified as high CRIA producers in responses to BA-Ar, no difference could be demonstrated if the inducing antigen was KLH-Ar. It is proposed that the difference observed with the two antigens may be due to the more selective activation by KLH-Ar of a small subset of high affinity Ar-specific clones--which may be enriched for CRIA + precursors--in both normal and immune defective mice. In contrast, BA-Ar may 'sample' more of the total anti-Ar repertoire and thus reveal within it an xid-determined depression in the proportion of CRIA + clones. Finally, it is noted that the influence of xid appears to be largely of a stochastic, and not an absolute character.

Animals↗

PubMedDate not supplied

A comparison of the cardiotonic effects of AR-L115 and AR-L57: evidence for distinct inotropic mechanisms.

AR-L57 and AR-L115 have been of interest as inotropic agents for management of heart failure. Although their physiological effects are well documented, their mechanism(s) of action are unclear. Both AR-L57 and AR-L115 increased contractile force of cat papillary muscles in concentration-dependent manners; these effects were independent of either alpha- or beta-adrenoceptor stimulation. To determine if these effects occurred via a cAMP-dependent mechanism, cardiotonic actions were studied in the presence of carbachol. Muscarinic stimulation of papillary muscles attenuated contractile responses to AR-L115 thus implying a cAMP-mediated response. By contrast, carbachol did not alter the dose-response profile to AR-L57. In addition, AR-L115 potentiated the inotropic actions of isoproterenol whereas AR-L57 was ineffective. Both AR-L57 and ouabain increased diastolic resting tension in papillary muscles--a phenomenon associated with a state of Ca2+ overload; AR-L115 was without effect. In anesthetized dogs, i.v. AR-L57 and AR-L115 increased contractility and heart rate while reducing mean arterial blood pressure. Both agents had similar rates of onset (10-15 s) and durations of action (40-60 min). Although in vitro studies clearly indicate that AR-L57 and AR-L115 enhance inotropic state by distinct mechanisms, their in vivo cardiovascular profiles are comparable.

Anesthesia↗

PubMed2003

Enhanced G(i) signaling selectively negates beta2-adrenergic receptor (AR)--but not beta1-AR-mediated positive inotropic effect in myocytes from failing rat hearts.

BACKGROUND: Myocardial contractile response to beta1- and beta2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G(i) signaling and the ratio of beta2/beta1 are often increased. Because beta2-AR but not beta1-AR couples to G(s) and G(i) with the G(i) coupling negating the G(s)-mediated contractile response, we determined whether the heart failure-associated augmentation of G(i) signaling contributes differentially to the defects of these beta-AR subtypes and, if so, whether inhibition of G(i) or selective activation of beta2-AR/G(s) by ligands restores beta2-AR contractile response in the failing heart. METHODS AND RESULTS: Cardiomyocytes were isolated from 18- to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either beta-AR subtype-mediated inotropic effect was markedly diminished, whereas G(i) proteins and the beta2/beta1 ratio were increased. Disruption of G(i) signaling by pertussis toxin (PTX) enabled beta2- but not beta1-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of beta2-AR ligands revealed that the contractile response mediated by most beta2-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G(s) and G(i) activation. In contrast, fenoterol, another beta2-AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX. CONCLUSIONS: We conclude that enhanced G(i) signaling is selectively involved in the dysfunction of beta2- but not beta1-AR in failing SHR hearts and that disruption of G(i) signaling by PTX or selective activation of beta2-AR/G(s) signaling by fenoterol restores the blunted beta2-AR contractile response in the failing heart.

Adrenergic beta-1 Receptor Antagonists↗

PubMed1986

Investigation into the pathogenesis of atrophic rhinitis in pigs. II. AR induction and protection after intramuscular injections cell-free filtrates and emulsions containing AR toxin of Pasteurella multocida.

The intramuscular administration of the cell-free culture filtrates of two AR pathogenic Pasteurella multocida (PM) isolates caused Atrophic Rhinitis (AR) in piglets. The culture filtrate of a non-AR-pathogenic PM isolate did not cause AR lesions after intramuscular injection. The severity of the AR lesions appeared to be correlated with the quantity of injected toxin. As the quantity of administered toxin increased, the piglets showed clinical growth retardation, icterus and mortality. Besides lesions typical of AR, severe liver degeneration was observed at necropsy; this liver degeneration was sometimes accompanied by fibrosis. After emulgation of the cell-free culture filtrates in incomplete Freunds adjuvant, AR was caused by administration of the toxin-containing emulsions in piglets of 3 and 6 weeks of age. An experimental water-in-oil emulsion containing the AR toxin of Pasteurella multocida caused AR when intramuscularly injected in 1- to 4-week-old piglets. A PM-AR toxin challenge method is described. After injection of the toxin into piglets born from sows vaccinated against AR, protection was demonstrated. Ten of the 12 piglets (83%) challenged at the age of 3 weeks showed protection. Six animals of the 12 pigs (50%) injected with the toxin at the age of 6 weeks, showed no protection. Differences in protection were noted between and within the litters. After injection with the toxin, all piglets of 3 and 6 weeks of age born from non-vaccinated sows showed deviations typical of AR.

Animals↗

PubMed2002

Immunoreactive AR and genetic alterations in subjects with androgen resistance and undetectable AR levels in genital skin fibroblast ligand-binding assays.

Defects of the AR cause a wide range of abnormalities of male development, ranging from individuals with mild defects of virilization to those with complete female phenotypes. In parallel with this phenotypic spectrum, a large number of different mutations have been identified that alter the synthesis or functional activity of the receptor protein. This report aims to categorize the alterations of immunoreactive AR (IRAR) expression and the underlying genetic changes in a single category of patient: those in whom ligand binding is undetectable in genital skin fibroblasts. Our study found a wide range in the levels of IRAR that are detectable in fibroblast strains established from 27 such individuals. A large proportion (19 of 27) express significant amounts of AR protein, as detected using a sensitive Western blot technique. In a smaller number (8/27), AR expression was undetectable. Intact IRAR was identified in16 of the 19 fibroblast strains in which AR expression could be detected. The AR gene was analyzed in 14 strains from this group. In 13 instances, single amino acid substitutions were identified within the ligand-binding domain of the receptor protein. In three of the remaining patients (3 of 19), truncation of the receptor protein was suggested by the rapid migration of the IRAR in SDS-polyacrylamide gels. In those three patients, production of the shortened immunoreactive receptor was traced to mutations that interrupted the AR open reading frame. By contrast, only one of the eight patient samples with no detectable IRAR carried a mutation that resulted in a single amino acid substitution. An interruption of the AR open reading frame was identified in six of the eight strains in which immunoreactive receptor was absent. In the remaining strain, no mutation was present within or surrounding the eight coding exons. This study serves to define the effects that mutations of the AR have on the levels of expressed immunoreactive receptor protein. In addition, it demonstrates the type of information that can be obtained if an immunoblot assay were to be used as a component of a screening method to analyze samples from patients with defects of the AR. Finally, the study suggests that in some androgen-resistant patients, defects outside the AR open reading frame may result in major alterations of AR expression.

Androgen-Insensitivity Syndrome↗

PubMed2005

Reactions of the heavier group 14 element alkyne analogues Ar'EEAr' (Ar' = C6H3-2,6(C6H3-2,6-Pri2)2; E = Ge, Sn) with unsaturated molecules: probing the character of the EE multiple bonds.

Reactions of the alkyne analogues Ar'EEAr' (Ar' = C6H3-2,6(C6H3-2,6-Pr(i)2)2; E = Ge (1); Sn (2)) with unsaturated molecules are described. Reaction of 1 and 2 with azobenzene afforded the new hydrazine derivatives Ar'E{(Ph)NN(Ph)}EAr' (E = Ge (3); Sn (4)). Treatment of 1 with Me3SiN3 gave the cyclic singlet diradicaloid Ar'Ge{mu2-(NSiMe3)}2GeAr' (5), whereas 2 afforded the monoimide bridged Ar'Sn{mu2-N(SiMe3)}SnAr' (6). Reaction of 1 with t-BuNC or PhCN yielded the adduct Ar'GeGe(CNBu(t))Ar' (7) or the ring compound (8). In contrast, the tin compound 2 did not react with either t-BuNC or PhCN. Treatment of 1 with N2CH(SiMe3) generated Ar'Ge{mu2-CH(SiMe3)}{mu2:eta2-N2CH(SiMe3)}{mu2-N2CH(SiMe3)}GeAr' (9) which contains ligands in three different bridging modes and no Ge-Ge bonding. Reaction of 1 with an excess of N(2)O gave a germanium peroxo species Ar'(HO)Ge(mu2-O)(mu2:eta2-O2)Ge(OH)Ar' (10) which features a ring. Oxidation of 1 by tetracyanoethylene (TCNE) led to cleavage of the Ge-Ge bond and formation of a large multiring system of formula Ar'Ge3+{(TCNE)2-}3{(GeAr')+}3. The digermyne 1 also reacted with 1 equiv of PhCPh to give the 1,2-digermacyclobutadiene 12, which has a ring, and with Me(3)SiCCH or PhCC-CCPh to activate a flanking C6H3-2,6-Pr(i)2 ring and give the tricyclic products 13 and 14. The "distannyne" 2 did not react with these acetylenes. Overall, the experiments showed that 1 is highly reactive toward unsaturated molecules, whereas the corresponding tin congener 2 is much less reactive. A possible explanation of the reactivity differences in terms of the extent of the singlet diradical character of the Ge-Ge and Sn-Sn bonds is discussed.

Journal Article↗

PubMed2004

Ab initio calculations of stationary points on the benzene-Ar and p-difluorobenzene-Ar potential energy surfaces: barriers to bound orbiting states.

The potential energy surfaces of the van der Waals complexes benzene-Ar and p-difluorobenzene-Ar have been investigated at the second-order Møller-Plesset (MP2) level of theory with the aug-cc-pVDZ basis set. Calculations were performed with unconstrained geometry optimization for all stationary points. This study has been performed to elucidate the nature of a conflict between experimental results from dispersed fluorescence and velocity map imaging (VMI). The inconsistency is that spectra for levels of p-difluorobenzene-Ar and -Kr below the dissociation thresholds determined by VMI show bands where free p-difluorobenzene emits, suggesting that dissociation is occurring. We proposed that the bands observed in the dispersed fluorescence spectra are due to emission from states in which the rare gas atom orbits the aromatic chromophore; these states are populated by intramolecular vibrational redistribution from the initially excited level [S. M. Bellm, R. J. Moulds, and W. D. Lawrance, J. Chem. Phys. 115, 10709 (2001)]. To test this proposition, stationary points have been located on both the benzene-Ar and p-difluorobenzene-Ar potential energy surfaces (PESs) to determine the barriers to this orbiting motion. Comparison with previous single point CCSD(T) calculations of the benzene-Ar PES has been used to determine the amount by which the barriers are overestimated at the MP2 level. As there is little difference in the comparable regions of the benzene-Ar and p-difluorobenzene-Ar PESs, the overestimation is expected to be similar for p-difluorobenzene-Ar. Allowing for this overestimation gives the barrier to movement of the Ar atom around the pDFB ring via the valley between the H atoms as < or = 204 cm(-1) in S0 (including zero point energy). From the estimated change upon electronic excitation, the corresponding barrier in S1 is estimated to be < or = 225 cm(-1). This barrier is less than the 240 cm(-1) energy of 30(2), the vibrational level for which the anomalous "free p-difluorobenzene" bands were observed in dispersed fluorescence from p-difluorobenzene-Ar, supporting our hypothesis for the origin of these bands.

Journal Article↗

PubMed2002

Alpha 1-adrenergic receptor responses in alpha 1AB-AR knockout mouse hearts suggest the presence of alpha 1D-AR.

Two functional alpha(1)-adrenergic receptor (AR) subtypes (alpha(1A) and alpha(1B)) have been identified in the mouse heart. However, it is unclear whether the third known subtype, alpha(1D)-AR, is also present. To investigate this, we determined whether there were alpha(1)-AR responses in hearts from a novel mouse model lacking alpha(1A)- and alpha(1B)-ARs (double knockout) (ABKO). In Langendorff-perfused hearts, alpha(1)-ARs were stimulated with phenylephrine. For ABKO hearts, phenylephrine reduced left ventricular pressure and coronary flow (to 87 +/- 2% and 86 +/- 4% of initial, respectively, n = 11, P < 0.01). These effects were blocked by prazosin and 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-8-azaspirol[4,5]decane-7,9-dione] dihydrochloride, suggesting that alpha(1D)-AR-mediated responses were present. In contrast, right ventricular trabeculae from ABKO hearts did not respond to phenylephrine, suggesting that in ABKO perfused hearts, the effects of phenylephrine were not mediated by direct actions on cardiomyocytes. A novel finding was that alpha(1)-AR stimulation caused positive inotropy in the wild-type mouse heart, in contrast to negative inotropy observed in mouse cardiac muscle strips. We conclude that mouse hearts lacking alpha(1A)- and alpha(1B)-ARs retain functional alpha(1)-AR responses involving decreases of coronary flow and ventricular pressure that reflect alpha(1D)-AR-mediated vasoconstriction. Furthermore, alpha(1)-AR inotropic responses depend critically on the experimental conditions.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2004

Cyclin D1 binding to the androgen receptor (AR) NH2-terminal domain inhibits activation function 2 association and reveals dual roles for AR corepression.

The androgen receptor (AR) is a member of the nuclear receptor superfamily, the activity of which is critical for the development and progression of prostate cancer. We and others have previously demonstrated that cyclin D1 is a potent corepressor of the AR. Although cyclin D1 is suspected to recruit histone deacetylases to the AR complex, previous studies have demonstrated that this activity alone is insufficient for cyclin D1 function. Here, we uncover a novel, secondary means of cyclin D1-mediated repression, through modulation of AR amino-carboxy terminal interactions. We show that cyclin D1 predominantly binds the N-terminal domain of the AR, dependent on the AR 23FxxLF27 motif. Through this motif, cyclin D1 abrogates the ability of the AR N-terminal domain to interact with the C terminus. Secondary amino-terminal domain sites capable of fostering interaction with the C terminus were refractory to cyclin D1 action, indicating that the ability of cyclin D1 to modulate AR amino-carboxy terminal interactions is specific to 23FxxLF27. Deletion of the N-terminal cyclin D1 binding site severely compromised AR activity (due to loss of FxxLF) but unmasked a repressor action through interaction with the AR C terminus. In summary, these data reveal novel, unexpected mechanisms of cyclin D1 activity and demonstrate that this function of cyclin D1 is critical for AR modulation.

Adenocarcinoma↗

PubMed2002

Recovery of Listeria monocytogenes from vacuum-sealed packages of frankfurters: comparison of the U.S. Department of Agriculture (USDA) food safety and inspection service product composite enrichment method, the USDA Agricultural Research Service (ARS) product composite rinse method, and the USDA-ARS package rinse method.

This study compared three methods for the recovery of Listeria monocytogenes from commercially prepared and vacuum-packaged frankfurters that were inoculated with a five-strain mixture of this pathogen at averages of 22 and 20,133 CFU per package over three trials. The presence and levels of the pathogen were determined by (i) the U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS) product composite enrichment method, involving the selective enrichment of a 25-g composite of product and the subsequent plating of this product onto selective agar plates; (ii) the USDA Agricultural Research Service (ARS) product composite rinse method, involving the rinsing of a 25-g composite of product with 0.1% peptone water and the subsequent plating of a portion of the rinse fluid directly onto selective agar plates; and (iii) the USDA-ARS package rinse method, involving the use of 25 ml of 0.1% peptone water to rinse the entire contents of a package and the subsequent plating of a portion of the rinse fluid directly onto selective agar plates. For packages inoculated with 20,133 CFU. L. monocytogenes was recovered at a frequency (percentage of packages positive) of 100% by each of the three methods. The pathogen was recovered at efficiencies (percentages of recovery of L. monocytogenes) of 43 and 94% with the USDA-ARS product rinse method and the USDA-ARS package rinse method, respectively. For packages inoculated with 22 CFU, L. monocytogenes was recovered at frequencies of 17, 10, and 100% by the USDA-FSIS product composite enrichment method, the USDA-ARS product composite rinse method, and the USDA-ARS package rinse method, respectively. The pathogen was recovered at efficiencies of 20 and 95% with the USDA-ARS product composite rinse method and the USDA-ARS package rinse method, respectively. In a related study, the USDA-ARS package rinse method was the only method that detected the pathogen in 60 packages from each of five brands of frankfurters purchased from local grocery stores. These data establish that the USDA-ARS package rinse method is markedly more sensitive, as well as demonstrably more rapid and facile, than either the approved USDA-FSIS product composite enrichment method or the USDA-ARS product composite rinse method in determining the presence or absence of L. monocytogenes and establishing the levels of the pathogen that may be on the surface of ready-to-eat foods such as frankfurters.

Animals↗

PubMed1999

Expression of size-polymorphic androgen receptor (AR) gene in ovarian endometriosis according to the number of cytosine, adenine, and guanine (CAG) repeats in AR alleles.

An increase in androgen receptor (AR) caused by estrogen is recognized as one of the biological phenomena related to estrogen-induced growth in uterine endometrium. The A/B region of AR gene in X chromosome involves the cytosine, adenine, and guanine (CAG) repeats. Random X chromosome inactivation with AR alleles in individual cells occurs in females. Therefore, approximately either paternal or maternal single dominant polymorphic AR mRNA must be expressed in neoplastic tissue originated from monoclone. This prompted us to determine deviated number of CAG repeats in AR mRNA to understand clonality in ovarian endometriosis. In all cases of heterozygous AR alleles, although paternal and maternal AR mRNAs from normal eutopic uterine endometrium were consistently expressed as AR alleles, either paternal or maternal single dominant AR mRNA expression was found in an individual ovarian endometrioma. Therefore, an individual ovarian endometrioma might be formed from an independent monoclonal ovarian endometriotic endometrial cell after inactivation of either AR allele in X chromosome.

Adenine↗

PubMed2000

Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21-22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia.

We report on a four-generation inbred family including 10 individuals affected with a form of craniotubular dysplasia (CTD). All affected patients were born to consanguineous healthy parents; this finding, together with the equal sex ratio among affected individuals and the occurrence of only normal individuals among their offspring, indicates that the disease in this family is an autosomal recessive (AR) trait. Taking into account the segregation pattern of the disease in the family and the radiological characteristics of two young CTD patients, the most likely diagnosis for the defect is AR craniometaphyseal dysplasia (CMD). CMD is a CTD, with both autosomal dominant (AD) and recessive forms. The description of the present genealogy confirms the AR pattern of inheritance of some cases of CMD and contributes to a better delineation of the clinical spectrum of AR CMD, suggesting a more pronounced diaphyseal involvement in the AR compared with the AD CMD. Through genomewide scanning, we mapped the AR CMD to a 7 cM interval, between D6S302 and D6S1639, at 6q21-22 region. We have also excluded the positional candidate COL10A1 gene as being the responsible for this disorder. Curiously, a form of AR spondylocostal dysplasia (SD) also segregates in the family, including one affected individual with both conditions. The gene DLL3, mapped to 19q13 region, was recently found to be responsible for one form of AR SD; however, we did not find evidence of linkage between this 19q region and the SD segregating in our family, thus implying in genetic heterogeneity for AR SD.

Adult↗

PubMed1999

The Rotational Spectrum of Ar-SiH(4) and Ar-SiD(4).

Microwave spectra of Ar-(28)SiH(4), Ar-(29)SiH(4), Ar-(30)SiH(4), and Ar-(28)SiD(4) were recorded using a pulsed molecular beam Fourier transform microwave spectrometer. The K = 0 and K = 1 components of the J = 3 <-- 2 through the J = 7 <-- 6 transitions were measured and assigned in the 9-24 GHz region. For the primary (28)Si isotopic species, Ar-(28)SiH(4) and Ar-(28)SiD(4), a K = 0, A symmetry, a K = 0, F symmetry, a doubly degenerate K = 1, E symmetry, and an l/K-doubled, K = 1, F symmetry rotational progression are observed at the approximately 1 K rotational temperature of the supersonic expansion. The rotational constants for the K = 0, A state for Ar-(28)SiH(4) and Ar-(28)SiD(4) are B = 1700.40624(9) MHz and 1630.687073(22) MHz and the centrifugal distortion constants are D(J) = 29.089(3) and 20.0198(8) kHz and H(J) = -1.91(3) and -0.851(8) Hz, respectively, where type A expanded uncertainties with a coverage factor, k = 3, are given here and elsewhere. The values of the rotational constants for the K = 0, A, and F states and for the K = 1, E state are in good agreement with the infrared-determined values for Ar-(28)SiH(4). The measured linear Stark effect of the E-state transitions was analyzed to give a dipole moment of 9.24(8) x 10(-32) C. m [0.0277(2) D]. Copyright 1999 Academic Press.

Journal Article↗

PubMed2005

Ligand rotation in [Ar(R)N]3M-N2-M'[N(R)Ar]3(M, M' = MoIII, NbIII; R = iPr and tBu) dimers.

Earlier calculations on the model N2-bridged dimer (micro-N2)-{Mo[NH2]3}2 revealed that ligand rotation away from a trigonal arrangement around the metal centres was energetically favourable resulting in a reversal of the singlet and triplet energies such that the singlet state was stabilized 13 kJ mol(-1) below the D(3d) triplet structure. These calculations, however, ignored the steric bulk of the amide ligands N(R)Ar (R =iPr and tBu, Ar = 3,5-C6H3Me2) which may prevent or limit the extent of ligand rotation. In order to investigate the consequences of steric crowding, density functional calculations using QM/MM techniques have been performed on the Mo(III)Mo(III) and Mo(III)Nb(III) intermediate dimer complexes (mu-N(2))-{Mo[N(R)Ar]3}2 and [Ar(R)N]3Mo-(mu-N2)-Nb[N(R)Ar]3 formed when three-coordinate Mo[N(R)Ar]3 and Nb[N(R)Ar]3 react with dinitrogen. The calculations indicate that ligand rotation away from a trigonal arrangement is energetically favourable for all of the ligands investigated and that the distortion is largely electronic in origin. However, the steric constraints of the bulky amide groups do play a role in determining the final orientation of the ligands, in particular, whether the ligands are rotated at one or both metal centres of the dimer. Analogous to the model system, QM/MM calculations predict a singlet ground state for the (mu-N2)-{Mo[N(R)Ar]3}2 dimers, a result which is seemingly at odds with the experimental triplet ground state found for the related (mu-N2)-{Mo[N(tBu)Ph]3}2 system. However, QM/MM calculations on the (mu-N2)-{Mo[N(tBu)Ph]3}2 dimer reveal that the singlet-triplet gap is nearly 20 kJ mol(-1) smaller and therefore this complex is expected to exhibit very different magnetic behaviour to the (mu-N2)-{Mo[N(R)Ar]3}2 system.

Journal Article↗

PubMed1994

Comparison of the two major ARS elements of the ura4 replication origin region with other ARS elements in the fission yeast, Schizosaccharomyces pombe.

We have previously reported that the replication origin region located near the ura4 gene on chromosome III of the fission yeast, Schizosaccharomyces pombe, contains three closely spaced origins, each associated with an autonomously replicating sequence (ARS) element. Here we report the nucleotide sequences of two of these ARS elements, ars3002 and ars3003. The two ARS elements are located on either side of a transcribed 1.5 kb open reading frame. Like 11 other S. pombe ARS elements whose sequences have previously been determined in other laboratories, the 2 new ARS elements are unusually A+T-rich. All 13 ARS elements contain easily unwound stretches of DNA. Each of the ARS elements contains numerous copies, at a higher than expected frequency, of short stretches of A+T-rich DNA in which most of the Ts are on one strand and most of the As are on the complementary strand. We discuss the potential significance for ARS function of these multiple asymmetric A+T-rich sequences.

Base Composition↗

PubMed1999

Significance of the CAG repeat length in the androgen receptor gene (AR) for the transactivation function of an M780I mutant AR.

Mutations in the androgen receptor gene (AR) cause a wide spectrum of androgen insensitivity syndromes (AIS). Mutation analysis of patients with AIS has revealed that the same missense mutation of the AR gene can give rise to strongly divergent phenotypes suggesting the influence of modifying factors. The polymorphic CAG repeat in the first exon of the AR gene may be such a modifying factor. The influence of the length of the CAG repeat on the transactivation function of the M780I-mutant AR (causing partial and complete AIS) has been determined by cotransfection of HeLa cells with various CAG-AR expression vectors and a highly androgen-responsive luciferase reporter gene construct. The transcriptional activity of the M780I mutant AR can be, in contrast to the wild-type AR, considerably enhanced by non-physiologically high androgen concentrations. Furthermore, an inverse relationship between the number of the CAG repeats in the mutant AR and its activity has been observed.

Amino Acid Substitution↗