Ciliary neurotropic factor in skin biopsies of patients with amyotrophic lateral sclerosis.
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Aged↗
Biomedical subjects
J Hu
Publications and source records attributed to J Hu.
The role of 3'-5' exonucleolytic proofreading and mismatch repair in yeast mitochondrial DNA error avoidance.
In the D171G/D230A mutant generated at conserved aspartate residues in the Exo1 and Exo2 sites of the 3'-5' exonuclease domain of the yeast mitochondrial DNA (mtDNA) polymerase (pol-gamma), the mitochondrial genome is unstable and the frequency of mtDNA point mutations is 1500 times higher than in the wild-type strain and 10 times higher than in single substitution mutants. The 10(4)-fold decrease in the 3'-5' exonuclease activity of the purified mtDNA polymerase is associated with mismatch extension and high rates of base misincorporation. Processivity of the purified polymerase on primed single-stranded DNA is decreased and the Km for dNTP is increased. The sequencing of mtDNA point mutations in the wild-type strain and in proofreading and mismatch-repair deficient mutants shows that mismatch repair contributes to elimination of the transitions while exonucleolytic proofreading preferentially repairs transversions, and more specifically A to T (or T to A) transversions. However, even in the wild-type strain, A to T (or T to A) transversions are the most frequent substitutions, suggesting that they are imperfectly repaired. The combination of both mismatch repair and proofreading deficiencies elicits a mitochondrial error catastrophe. These data show that the faithful replication of yeast mtDNA requires both exonucleolytic proofreading and mismatch repair.
Base Sequence↗
TRANK, a novel cytokine that activates NF-kappa B and c-Jun N-terminal kinase.
We searched the expressed sequence tag database using sequence homology and identified a novel cytokine, which we have named TRANK (thioredoxin peroxidase-related activator of NF-kappa B and c-Jun N-terminal kinase). The predicted amino acid sequence of TRANK was highly homologous to that of the thiol-specific antioxidant proteins. Unlike these proteins, however, TRANK had a putative secretory signal polypeptide and was found to be secreted by cells. TRANK was expressed in most tissues and cell lines, and the gene that encodes it was mapped to chromosome Xp21-22.1. TRANK activated NF-kappa B and induced the degradation of the inhibitory subunit of NF-kappa B. In addition, TRANK up-regulated the expression of NF-kappa B-dependent gene products, ICAM-1, and inducible nitric oxide synthase. TRANK also activated c-Jun N-terminal kinase and induced the proliferation of normal human foreskin fibroblasts. Its homology with antioxidant proteins, wide distribution in tissues, and ability to activate NF-kappa B and c-Jun N-terminal kinase suggest that TRANK plays an important role in inflammation.
Amino Acid Sequence↗
Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand.
Endothelin-1 (ET-1) is a peptide hormone with potent vasoconstrictor properties that is synthesized and secreted predominantly by vascular endothelial cells. Its production is regulated by numerous stimuli including ischemia and hypoxia, and the enhanced levels that occur during myocardial ischemia may contribute to the progression of heart failure. We previously reported that ET-1 expression was induced by both hypoxia and transition metals in endothelial cells (ECs). Here we define an element in the proximal promoter of the ET-1 gene that is responsible for this induction. By using deletions and site directed mutagenesis of the human ET-1 promoter, in combination with electrophoretic gel mobility shifts and transient expression assays in human ECs, we identified an active hypoxia-inducible factor 1 (HIF-1) binding site starting at position -118 upstream of the transcription start site on the non-coding DNA strand. Mutation of this site eliminated induction by hypoxia without affecting basal (aerobic) expression, and the mutated sequence did not display hypoxia-specific binding of HIF-1.
Binding Sites↗
Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release.
A common feature of many neurodegenerative disorders is an abundance of activated glial cells (astrocytes and microglia). In Alzheimer's disease (AD), activated astrocytes are in close apposition to and surrounding the amyloid plaques. The mechanisms by which the astrocytes become activated in AD and the consequences of reactive astrocytosis to disease progression are not known. We examined the possibility that the amyloid-beta (Abeta) peptide, a major constituent of the amyloid plaque, could act as a stimulus leading to activation. We found that treatment of rat cortical astrocyte cultures with aggregated Abeta 1-42 peptide induces activation, as assessed by reactive morphological changes and upregulation of selective glial mRNA and proteins, such as the inflammatory cytokine interleukin-1beta. Abeta also stimulates inducible nitric oxide synthase (iNOS) mRNA levels and nitric oxide (NO) release. Abeta 1-42, a major form of amyloid associated with neurotoxicity, activated astrocytes in a time- and dose-dependent manner, whereas a scrambled Abeta 1-42 sequence or Abeta 17-42 had little or no effect. We also determined that the Abeta activity can be found in a supernatant fraction containing soluble Abeta oligomers. Our data suggest that Abeta plays a role in the reactive astrocytosis of AD and that the inflammatory response induced upon glial activation is a critical component of the neurodegenerative process.
Amino Acid Sequence↗
Mapping of the human HPRP3 and HPRP4 genes encoding U4/U6-associated splicing factors to chromosomes 1q21.1 and 9q31-q33.
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Chromosome Mapping↗
Variations and clinical significance of coagulation and fibrinolysis parameters in patients with diabetes mellitus.
We observed the changes of parameters of coagulation and fibrinolytic system in order to understand the clinical implication of these variations in type II diabetic patients. Subjects consisted of 22 patients with type II diabetes mellitus and 25 healthy controls. Compared with the control, activated partial thromboplastin time, prothrombin time were shortened in the patients. The diabetic subjects also displayed higher levels of D-dimer, serum fibrin degradation products, median concentrations of fibrinogen (3.99 vs 2.96 g/L, P < 0.01) and von Willebrand factor (149% vs 87%, P < 0.01). Levels of antithrombin III activity or antigen were not different from control values. Simple linear regression analysis revealed a negative correlation between antithrombin III activity and fast blood glucose. Diabetic patients with vascular complications had significantly higher levels of fibrinogen and D-dimer than those without diabetic angiopathy. Our data demonstrated that patients with type II diabetes mellitus had a hypercoagulable state. We believed the activation of coagulation might contribute to the vascular complications in diabetics.
Adult↗
The comparative trial of TCu 380A IUD and progesterone-releasing vaginal ring used by lactating women.
The objective of this paper was to compare the efficacy, acceptability, safety, and bleeding pattern of TCu 380A intrauterine device (IUD) and progesterone-releasing vaginal ring used by breastfeeding women. The study population included 97 breastfeeding women using IUD and 100 women using vaginal ring. Of the IUD users, no insertion failure, perforation, or accidental pregnancy occurred in 12 months. There was one IUD expulsion. There were no discontinuations of IUD due to medical reasons other than expulsion. The total discontinuation rate was 2.3%. In the ring group, no accidental pregnancy occurred. The major reasons for discontinuation were ring use-related problems and vaginal problems. The total discontinuation rate was 65.4% within 1 year. The frequency of any one complaint among the ring users was higher than that among the IUD users. There were no differences in the proportion of women having no sexual activity and in the weight of their babies between the two groups. Compared with the IUD users, the median number of bleeding/spotting (B/S) episodes and B/S days of the vaginal ring users were fewer; consequently, the mean length of B/S-free interval was longer in all four reference periods; the mean length of B/S episode and segment were the same; the occurrence of amenorrhea was more frequent; in contrast, the proportions of normal bleeding patterns were fewer. The frequencies of prolonged bleeding, frequent bleeding, and infrequent bleeding patterns did not differ between the two groups. The percentage of irregular bleeding was fewer only in the first two reference periods. It is concluded that the TCu 380A IUD and progesterone-releasing vaginal ring used by breastfeeding women are safe and effective. The higher discontinuation rate of the ring users was mainly because of use-related problems. Breastfeeding women with TCu 380A IUD had better tolerance and acceptability. The TCu 380A IUD does not, but the progesterone-releasing vaginal ring does, suppress the recovery of ovarian function. However, once return of menstruation occurred, there were no differences in bleeding patterns between the two contraceptive methods.
Administration, Intravaginal↗
Lignans and sesquiterpene lactones from Artemisia sieversiana and Inula racemosa.
The aerial parts of Artemisia sieversiana afforded, in addition to beta-sitosterol, stigmasterol and daucosterol, two novel lignans as well as one known and three new guaianolides. The roots of Inula racemosa gave beta-sitosterol, daucosterol and isoalantolactone. The structures were determined by a combination of spectral methods (IR, EIMS, 1H and 13C NMR, DEPT, COSY, NOESY and HETCOR). All isolates were subjected to antifungal tests. Isoalantolactone, a major sesquiterpene lactone of I. racemosa, was found to be active against the human pathogenic fungi. Aspergillus flavus, A. niger, Geotrichum candidum, Candida tropicalis and C. albicans at concentrations of 50, 50, 25, 25 and 25 micrograms/ml, respectively. The taxonomic significance of the characterized constituents is discussed briefly.
Antifungal Agents↗
Factorial trial of three interventions to reduce the progression of precancerous gastric lesions in Shandong, China: design issues and initial data.
In the fall of 1995, 3411 subjects in 13 rural villages in Linqu County, Shandong Province, China, began participating in a blinded, randomized 23 factorial trial to determine whether interventions can reduce the prevalence of dysplasia and other precancerous gastric lesions. One intervention is treatment for infection by Helicobacter pylori with amoxicillin and omeprazole. A second is dietary supplementation with capsules containing vitamin C, vitamin E, and selenium. A third is dietary supplementation with capsules containing steam-distilled garlic oil and Kyolic aged garlic extract. Investigators will evaluate histopathologic endpoints after gastroscopies with biopsies from seven standard sites in 1999. Initial data from pill counts and sampled blood levels of vitamin E, vitamin C, and S-allylcysteine indicate excellent compliance. Subjects have tolerated all interventions well, although 3.1% of those assigned to amoxicillin and omeprazole developed rashes, compared to 0.3% to those in the control group. Preliminary breath tests demonstrate substantial reductions in gastric urease activity, an indication of infection by Helicobacter pylori, among those assigned to amoxicillin and omeprazole.
Adult↗
Palmitoyl derivatives of interferon alpha: potential for cutaneous delivery.
Palmitoyl derivatives of interferon alpha2b (p-IFNalpha) were prepared by covalent attachment of the fatty acid to lysine residues in the protein through a reaction with N-hydroxysuccinimide palmitate ester. The p-IFNalpha was characterized by capillary electrophoresis (CE), mass spectrometry (MS), SDS-PAGE, and antiviral assay. Flow-through diffusion cells and human breast skins were used to measure cutaneous and percutaneous absorption. Formation of p-IFNalpha derivatives was demonstrated by CE to be dependent on reaction time and reagent: protein ratio. Electrospray MS of the crude p-IFNalpha mixture indicated three populations of IFNalpha derivatives with 10, 11, and 12 palmitoyl substitutions. The addition of palmitoyl residues to IFNalpha under the conditions described reduced the antiviral specific activity by 50%. However, the cutaneous absorption of p-IFNalpha was about 5-6 times greater than the parent protein. The amount of p-IFNalpha and IFN alpha in whole skin after 24 h of treatment was 2.106 +/- 1.216 microg/cm2 and 0.407 +/- 0.108 microg/cm2, respectively. Approximately two times higher flux was detected for p-IFNalpha compared to the nonfatty acylated IFNalpha. The total amount of drug diffused in 24 h was also approximately two times higher for the p-IFNalpha. The results indicate a potential for using fatty acylated derivatives of IFN alpha for dermal and transdermal delivery.
Acylation↗
M1 muscarinic receptors stimulate rapid and prolonged phases of neuronal nitric oxide synthase activity: involvement of different calcium pools.
This study shows that activation of M1 muscarinic receptors, when coexpressed in Chinese hamster ovary (CHO)-K1 cells with neuronal nitric oxide (NO) synthase (nNOS), produces early and late phases of elevation of both intracellular Ca2+ concentration and nNOS activity. We examined the relationship between receptor-mediated increases in intracellular Ca2+ concentration and activation of nNOS over both short and long intervals using guanosine 3',5'-cyclic monophosphate (cGMP) formation as a measure of nNOS activity. The rapid phase of nNOS activation was dependent on release of Ca2+ from intracellular stores in both the CHO M1/nNOS transfected cells and in neuroblastoma (N1E-115) cells, in which muscarinic receptors and nNOS are endogenously expressed. Two single point mutations in the M1 muscarinic receptor that have previously been shown to uncouple differentially the receptor from phosphoinositide hydrolysis produced parallel attenuation of the rapid phase of nNOS activation. Characterization of the prolonged phase of nNOS activation was done using the conversion of L-[3H]arginine to L-[3H]citrulline as well as cGMP formation following stimulation of M1 muscarinic receptors for 60 min. Both responses were dependent on influx of extracellular Ca2+ and were accompanied by prolonged formation of NO at functionally effective levels as late as 60 min following receptor activation. Therefore, this study demonstrates for the first time the existence of two mechanistically distinct phases of nNOS activation that are dependent on different sources of Ca2+.
Acetylcholine↗
Apolipoprotein E attenuates beta-amyloid-induced astrocyte activation.
A common feature of Alzheimer's disease pathology is an abundance of activated glia, indicative of an inflammatory reaction in the brain. The relationship between glial activation and neurodegeneration is not known, although several cytokines and inflammatory mediators produced by activated glia have the potential to initiate or exacerbate the progression of neuropathology. As beta-amyloid (A beta) is one of several stimuli that can activate glia, it is important to determine how A beta-induced glial activation is influenced by other proteins present in the plaque, such as apolipoprotein E (apoE). We examined the effect of native preparations of apoE on activation of rat cortical astrocyte cultures by A beta1-42. The apoE source was conditioned medium from human embryonic kidney 293 cells stably transfected with human apoE3 or apoE4 cDNA. By morphological criteria, apoE inhibited A beta-induced astrocyte activation in three experimental paradigms: apoE pretreatment blocked subsequent A beta-induced activation, A beta aged in the presence of apoE did not activate astrocytes, and apoE addition to activated astrocytes transiently reversed the activated phenotype. No apoE isoform selectivity was observed. The effect of apoE appears to be specific to A beta, as apoE did not attenuate cyclic AMP-induced astrocyte activation. These data suggest that apoE may modulate the ability of A beta to induce inflammatory responses in the brain.
Amyloid beta-Peptides↗
Risk factors for glioma in adults: a case-control study in northeast China.
A case-control study of risk factors for glioma in adults was carried out in Heilongjiang province in northeast China. Between September 1989 and May 1995, 218 histologically confirmed cases of glioma requiring surgery for tumor removal (139 astrocytoma glioma and 79 other glioma) and 436 controls with non-neoplastic and non-neurological disease were recruited and personally interviewed in the wards of six major hospitals. Controls were matched by sex, age, and area of residence. Occupational, lifestyle, and medical information was obtained through a standardized questionnaire. Use of liquor was associated with cancer risk. Compared with males who never drank liquor, males with total lifetime liquor consumption of less than 1000 liters had an adjusted odds ratio (OR) of 1.60 (95% CI: 0.89-2.88) and for more than 1000 liters, 2.73 (95% CI: 1.06-7.08). Statistically significant associations were also found for diseases related to the brain (OR: 5.75; 95% CI: 1.08-30.47) and trauma to the head requiring medical attention (OR: 4.09; 95% CI: 2.51-10.31). Increased consumption of vegetables and of fruit were each associated with decreased glioma risk. Compared with lowest quartile intake, adjusted risks associated with highest quartile intake were 0.51 (95% CI: 0.29-0.89) for total vegetables and 0.28 (95% CI: 0.16-0.51) for total fruit.
Adult↗
Design and implementation of a CORBA-based genome mapping system prototype.
MOTIVATION: CORBA (Common Object Request Broker Architecture), as an open standard, is considered to be a good solution for the development and deployment of applications in distributed heterogeneous environments. This technology can be applied in the bioinformatics area to enhance utilization, management and interoperation between biological resources. RESULTS: This paper investigates issues in developing CORBA applications for genome mapping information systems in the Internet environment with emphasis on database connectivity and graphical user interfaces. The design and implementation of a CORBA prototype for an animal genome mapping database are described. AVAILABILITY: The prototype demonstration is available via: http://www.ri.bbsrc.ac.uk/ark_corba/. CONTACT: jian.hu@bbsrc.ac.uk
Chromosome Mapping↗
Increased large arterial stiffness and impaired acetylcholine induced skin vasodilatation in women with previous gestational diabetes mellitus.
OBJECTIVE: Gestational diabetes is associated with increased risk of developing noninsulin-dependent diabetes (NIDDM) later in life. By the time that a diagnosis of NIDDM is established, functional disturbances in the vascular system may be observed. This study was planned to assess macro- and microvascular function in nonpregnant women without signs of diabetes two to four years after a pregnancy complicated with gestational diabetes. DESIGN: Cross-sectional study. SETTING: Vascular research laboratory in the obstetric unit of a university hospital. PARTICIPANTS: Seventeen nonpregnant, healthy women with a history of gestational diabetes and 20 nonpregnant control women of similar age without previous diabetes. METHODS: For quantification of the mechanical properties in large arterial vessels the wall movements of the abdominal aorta and left common carotid artery were recorded with an ultrasonic tracking system. Microvascular perfusion in the skin of the hand and foot was recorded by a laser Doppler technique to assess the vasodilatory response induced by transcutaneous acetylcholine. RESULTS: Women in the gestational diabetes group showed evidence of increased wall stiffness in the common carotid artery and a lower maximum incremental velocity of the pulsatile vessel diameter change in both aorta and carotid artery compared with controls. Acetylcholine induced vasodilatation in both hand and foot was lower in women with previous gestational diabetes compared with controls. CONCLUSION: Abnormal vascular function was found in asymptomatic women with a history of gestational diabetes. It is speculated that these abnormalities might be early evidence of vascular complications associated with subsequent NIDDM.
Acetylcholine↗
Liposome-mediated transfection of fetal lung epithelial cells: DNA degradation and enhanced superoxide toxicity.
Cationic liposomes, 1:1 (mol/mol) 1,2-dioleoyldimethylammonium chloride-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, were used to transfect primary cultures of distal rat fetal lung epithelial cells with pCMV4-based plasmids. A DNA-to-lipid ratio of 1:10 to 1:15 (wt/wt) optimized DNA uptake over a 24-h exposure. At a fixed DNA-to-lipid ratio of 1:15, chloramphenicol acetyltransferase (CAT) reporter gene expression declined at lipid concentrations > 2.5 nmol/cm2 cell surface area, whereas DNA uptake remained concentration dependent. CAT expression peaked 48 h after removal of the liposome-DNA complex, declining thereafter. Reporter gene expression was increased, and supercoiled cDNA degradation was reduced by the addition of 0.2 mM nicotinamide and 10 microM chloroquine. Rat fetal lung epithelial cells transfected with two different expression cassettes had an increased susceptibility to superoxide-mediated cytotoxicity. This could be attributed to a nonspecific delivery of exogenous DNA or some other copurified factor. The DNA-dependent increase in superoxide-mediated cytotoxicity, but not basal levels of cytotoxicity, was inhibited by the addition of 0.2 mM nicotinamide and 10 microM chloroquine.
Animals↗
Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis.
Annexin I is a 36 kilodalton (kD) calcium-dependent phospholipid-binding protein which may have anti-inflammatory properties. Previous investigations which sampled lower respiratory tract epithelial lining fluid (ELF) via bronchoalveolar lavage (BAL) have demonstrated that annexin I can be degraded in inflammatory lung disease. We analyzed BAL fluid from patients with cystic fibrosis (CF) to determine the effects of lung inflammation on the structure and activity of annexin I. Intact annexin I was absent in 17 out of 20 BAL fluid samples from patients with CF, due largely to degradation to a 33 kD protein. The three CF BAL fluids in which annexin I was detectable had very little or no unopposed neutrophil elastase activity in contrast to the 17 in which no annexin I was detectable. Annexin I was present in all BAL fluid samples from 10 normal volunteer (NV) subjects and 12 patients with interstitial lung disease (ILD). The 33 kD annexin I breakdown product was not detectable in samples from NV, but was detectable only in ILD patients with relatively high percentages of neutrophils on BAL differential cell counts. Annexin I appeared to be cleaved by neutrophil elastase at the N-terminal portion between Val-36 and Ser-37 to yield the 33 kD protein. Cleavage of the N-terminal portion of annexin I was accompanied by a marked change in the annexin I isoelectric point (pI) value (from 6.0 to 8.5-9.0) and greatly diminished annexin I functional activity. Our findings demonstrate that annexin I degradation in epithelial lining fluid is closely related to lung inflammation.
Amino Acid Sequence↗