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81.
Ethanolamine kinase (EKI) is the first committed step in phosphatidylethanolamine (PtdEtn) biosynthesis via the CDP-ethanolamine pathway. We identify a human cDNA encoding an ethanolamine-specific kinase EKI1 and the structure of the EKI1 gene located on chromosome 12. EKI1 overexpression in COS-7 cells results in a 170-fold increase in ethanolamine kinase-specific activity and accelerates the rate of [3H]ethanolamine incorporation into PtdEtn as a function of the ethanolamine concentration in the culture medium. Acceleration of the CDP-ethanolamine pathway does not result in elevated cellular PtdEtn levels, but rather the excess PtdEtn is degraded to glycerophosphoethanolamine. EKI1 has negligible choline kinase activity in vitro and does not influence phosphatidylcholine biosynthesis. Acceleration of the CDP-ethanolamine pathway also does not change the rate of PtdEtn formation via the decarboxylation of phosphatidylserine. The data demonstrate the existence of separate ethanolamine and choline kinases in mammals and show that ethanolamine kinase can be a rate-controlling step in PtdEtn biosynthesis. 相似文献
82.
The ACTG076 trial showed that a complex and expensive antiretroviral regimen reduced mother-to-child HIV transmission by 67%. A more recent Bangkok perinatal HIV study found that oral zidovudine (AZT) given during late pregnancy and labor to non-breast-feeding women reduced the rate of vertical HIV transmission by 51%. These latter findings are particularly interesting to countries unable to afford the more expensive and complex 076 regimen. The reaction to the results of the Bangkok trial may, however, threaten the health of Africa's poorest women and children. Within days of the release of the Thai data, investigators studying other regimens closed recruitment to the placebo arms of their trials, and it has recently become clear that the National Institutes for Health will probably fund no more placebo-controlled trials of interventions designed to reduce maternal HIV transmission. The use of antiretroviral drugs in Africa is unlikely to ever significantly reduce maternal HIV transmission and the incidence of pediatric AIDS. While most of Africa's women have no option to breast-feed, breast-feeding is responsible for one-third of maternal HIV transmission cases. The results of the Thai trials only partially address the needs of African women, for the nutritional, immunological, and birth spacing benefits of breast-feeding should be retained if possible, and formula feeding may stigmatize HIV-infected mothers. The short-course regimen is still expensive to developing countries, and the implementation of a costly, vertical program may also draw financial and human resources from other programs. Placebo-controlled trials to develop simple, cheap, and effective potentially non-drug interventions against vertical HIV transmission should be encouraged in settings in which antiretroviral drugs and formula feeding cannot be safely delivered. 相似文献
83.
Time-dependent changes in myosin heavy chain mRNA and protein isoforms in unloaded soleus muscle of rat 总被引:6,自引:0,他引:6
Stevens Laurence; Sultan Karim R.; Peuker Heidemarie; Gohlsch Barbel; Mounier Yvonne; Pette Dirk 《American journal of physiology. Cell physiology》1999,277(6):C1044
Time-dependent changes in myosin heavy chain(MHC) isoform expression were investigated in rat soleus muscleunloaded by hindlimb suspension. Changes at the mRNA level weremeasured by RT-PCR and correlated with changes in the pattern of MHCprotein isoforms. Protein analyses of whole muscle revealed that MHCIdecreased after 7 days, when MHCIIa had increased, reaching a transient maximum by 15 days. Longer periods led to inductions and progressive increases of MHCIId(x) and MHCIIb. mRNA analyses of whole muscle showedthat MHCIId(x) displayed the steepest increase after 4 days andcontinued to rise until 28 days, the longest time period investigated.MHCIIb mRNA followed a similar time course, although at lower levels.MHCI mRNA, present at extremely low levels in control soleus, peakedafter 4 days, stayed elevated until 15 days, and then decayed.Immunohistochemistry of 15-day unloaded muscles revealed that MHCIwas present in muscle spindles but at low amounts also in extrafusalfibers. The slow-to-fast transitions thus seem to proceed in the orderMHCI MHCIIa MHCIId(x) MHCIIb. Ourfindings indicate that MHCI is transiently upregulated in somefibers as an intermediate step during the transition from MHCI to MHCIIa. 相似文献
84.
85.
Hindshaker (hsh), a spontaneous, autosomal recessive mouse mutation, displays a developmentally dependent tremor of the hindquarters due to hypomyelination in the CNS. This myelin deficit is followed by progressive, but incomplete, recovery by postnatal day 42. Herein we describe the construction of a genomic contig spanning the interval between the markers D3Mit187 (42.4 cM) and D3Mit232 (45.2 cM) on mouse chromosome 3, which we have previously shown to contain the hsh mutation. A physical map, covering approximately 3.5 Mb, was constructed from a series of overlapping yeast and bacterial artificial chromosomes. A 1.2- to 1.4-Mb segment central to the contig was compared extensively with the syntenic regions in human (chromosome 1q21-q23) and rat (chromosome 2). We present new data on 10 genes erroneously assigned to this area and on another 6 genes previously assigned elsewhere. For absent genes, our work suggests that they are telomeric to the region encompassed in our map. Accordingly, our findings both map the area surrounding the hsh mutation and present important corrections to the current maps in an area rich in genes related to the nervous system. 相似文献
86.
NMR spectra of ubiquitin in the presence of bicelles at a concentration of 25% w/v have been recorded under sample spinning conditions for different angles of rotation. For an axis of rotation equal to the magic angle, the (1)H/(15)N HSQC recorded without any (1)H decoupling in the indirect dimension corresponds to the classical spectrum obtained on a protein in an isotropic solution and allows the measurement of scalar J-couplings (1) J (NH). For an angle of rotation smaller than the magic angle, the bicelles orient with their normal perpendicular to the spinning axis, whereas for an angle of rotation greater than the magic angle the bicelles orient with their normal along the spinning axis. This bicelle alignment creates anisotropic conditions that give rise to the observation of residual dipolar couplings in ubiquitin. The magnitude of these dipolar couplings depends directly on the angle that the rotor makes with the main magnetic field. By changing this angle in a controlled manner, residual dipolar couplings can be either scaled up or down thus offering the possibility to study simultaneously a wide range of dipolar couplings in the same sample. 相似文献
87.
L-Carnitine transport in human placental brush-border membranes is mediated by the sodium-dependent organic cation transporter OCTN2 总被引:1,自引:0,他引:1
Lahjouji K Elimrani I Lafond J Leduc L Qureshi IA Mitchell GA 《American journal of physiology. Cell physiology》2004,287(2):C263-C269
Maternofetal transport of L-carnitine, a molecule that shuttles long-chain fatty acids to the mitochondria for oxidation, is thought to be important in preparing the fetus for its lipid-rich postnatal milk diet. Using brush-border membrane (BBM) vesicles from human term placentas, we showed that L-carnitine uptake was sodium and temperature dependent, showed high affinity for carnitine (apparent Km = 11.09 ± 1.32 µM; Vmax = 41.75 ± 0.94 pmol·mg protein1·min1), and was unchanged over the pH range from 5.5 to 8.5. L-Carnitine uptake was inhibited in BBM vesicles by valproate, verapamil, tetraethylammonium, and pyrilamine and by structural analogs of L-carnitine, including D-carnitine, acetyl-D,L-carnitine, and propionyl-, butyryl-, octanoyl-, isovaleryl-, and palmitoyl-L-carnitine. Western blot analysis revealed that OCTN2, a high-affinity, Na+-dependent carnitine transporter, was present in placental BBM but not in isolated basal plasma membrane vesicles. The reported properties of OCTN2 resemble those observed for L-carnitine uptake in placental BBM vesicles, suggesting that OCTN2 may mediate most maternofetal carnitine transport in humans. membrane transport; valproate; maternofetal; xenobiotics; acylcarnitine 相似文献
88.
Murphy MP Echtay KS Blaikie FH Asin-Cayuela J Cocheme HM Green K Buckingham JA Taylor ER Hurrell F Hughes G Miwa S Cooper CE Svistunenko DA Smith RA Brand MD 《The Journal of biological chemistry》2003,278(49):48534-48545
Although the physiological role of uncoupling proteins (UCPs) 2 and 3 is uncertain, their activation by superoxide and by lipid peroxidation products suggest that UCPs are central to the mitochondrial response to reactive oxygen species. We examined whether superoxide and lipid peroxidation products such as 4-hydroxy-2-trans-nonenal act independently to activate UCPs, or if they share a common pathway, perhaps by superoxide exposure leading to the formation of lipid peroxidation products. This possibility can be tested by blocking the putative reactive oxygen species cascade with selective antioxidants and then reactivating UCPs with distal cascade components. We synthesized a mitochondria-targeted derivative of the spin trap alpha-phenyl-N-tert-butylnitrone, which reacts rapidly with carbon-centered radicals but is unreactive with superoxide and lipid peroxidation products. [4-[4-[[(1,1-Dimethylethyl)-oxidoimino]methyl]phenoxy]butyl]triphenylphosphonium bromide (MitoPBN) prevented the activation of UCPs by superoxide but did not block activation by hydroxynonenal. This was not due to MitoPBN reacting with superoxide or the hydroxyl radical or by acting as a chain-breaking antioxidant. MitoPBN did react with carbon-centered radicals and also prevented lipid peroxidation by the carbon-centered radical generator 2,2'-azobis(2-methyl propionamidine) dihydrochloride (AAPH). Furthermore, AAPH activated UCPs, and this was blocked by MitoPBN. These data suggest that superoxide and lipid peroxidation products share a common pathway for the activation of UCPs. Superoxide releases iron from iron-sulfur center proteins, which then generates carbon-centered radicals that initiate lipid peroxidation, yielding breakdown products that activate UCPs. 相似文献
89.
Nayernia K Vauti F Meinhardt A Cadenas C Schweyer S Meyer BI Schwandt I Chowdhury K Engel W Arnold HH 《The Journal of biological chemistry》2003,278(48):48377-48385
Lis1 protein is the non-catalytic component of platelet-activating factor acetylhydrolase 1b (PAF-AH 1B) and associated with microtubular structures. Hemizygous mutations of the LIS1 gene cause type I lissencephaly, a brain abnormality with developmental defects of neuronal migration. Lis1 is also expressed in testis, but its function there has not been determined. We have generated a mouse mutant (LIS1GT/GT) by gene trap integration leading to selective disruption of a Lis1 splicing variant in testis. Homozygous mutant males are infertile with no other apparent phenotype. We demonstrate that Lis1 is predominantly expressed in spermatids, and spermiogenesis is blocked when Lis1 is absent. Mutant spermatids fail to form correct acrosomes and nuclei appear distorted in size and shape. The tissue architecture in mutant testis appears severely disturbed displaying collapsed seminiferous tubules, mislocated germ cells, and increased apoptosis. These results provide evidence for an essential and hitherto uncharacterized role of the Lis1 protein in spermatogenesis, particularly in the differentiation of spermatids into spermatozoa. 相似文献
90.
Sabrane K Gambaryan S Brandes RP Holtwick R Voss M Kuhn M 《The Journal of biological chemistry》2003,278(20):17963-17968
Atrial natriuretic peptide (ANP) plays a key regulatory role in arterial blood pressure homeostasis. We recently generated mice with selective deletion of the ANP receptor, guanylyl cyclase-A (GC-A), in vascular smooth muscle (SMC GC-A knockout (KO) mice) and reported that resting arterial blood pressure was completely normal in spite of clear abolition of the direct vasodilating effects of ANP (Holtwick, R., Gotthardt, M., Skryabin, B., Steinmetz, M., Potthast, R., Zetsche, B., Hammer, R. E., Herz, J., and Kuhn M. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7142-7147). The purpose of this study was to clarify mechanisms compensating for the missing vasodilator responses to ANP. In particular, we analyzed the effect of the endothelial, cGMP-mediated vasodilators C-type natriuretic peptide and nitric oxide (NO). In isolated arteries from SMC GC-A KO mice, the vasorelaxing sensitivity to sodium nitroprusside and the endothelium-dependent vasodilator, acetylcholine, was significantly greater than in control mice. There was no difference in responses to C-type natriuretic peptide or to the activator of cGMP-dependent protein kinase I, 8-para-chlorophenylthio-cGMP. The aortic expression of soluble GC (sGC), but not of endothelial NO synthase or cGMP-dependent protein kinase I, was significantly increased in SMC GC-A KO mice. Chronic oral treatment with the NO synthase inhibitor N(w)-nitro-l-arginine methyl ester increased arterial blood pressure, the effect being significantly enhanced in SMC GC-A KO mice. We conclude that SMC GC-A KO mice exhibit a higher vasodilating sensitivity to NO. This can be attributed to an enhanced expression of sGC, whereas the expression and/or activity levels of downstream cGMP-effector pathways are not involved. Increased vasodilating responsiveness to endothelial NO contributes to compensate for the missing vasodilating effect of ANP in SMC GC-A KO mice. 相似文献