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PubMed1985

Analysis of human blood monocyte activation at the level of gene expression. Expression of alpha interferon genes during activation of human monocytes by poly IC/LC and muramyl dipeptide.

Human monocytes were activated to secrete alpha interferon (IFN-alpha) by poly IC/LC but not by other monocyte activators, such as muramyl dipeptide (MDP). In contrast, monocytes were activated to secrete fibroblast growth factor (FGF) release by MDP but not by poly IC/LC. The amount of total RNA present in unactivated and activated human monocytes was similar. Using two 32P-labeled cDNA probes (pLM001 and HuIFN-alpha 2) for human IFN-alpha genes in hybridization studies, we analyzed messenger RNA species from this gene family in activated human monocytes. After activation with poly IC/LC, two other mRNA species (2.8 and 5.5 kb) were detected in addition to the 1.0 kb mRNA normally associated with IFN-alpha secretion. Unexpectedly, monocytes activated with MDP also contained 2.8 kb IFN-alpha mRNA. There was associated with this 2.8 kb IFN-alpha mRNA, found in MDP-activated monocytes, appreciable levels of intracellular IFN-alpha activity in the absence of detectable secreted IFN-alpha. Thus the secretion of IFN-alpha in activated human monocytes can be correlated with the appearance of a 1.0 kb mRNA species after poly IC/LC exposure. Secretion appears to be defective in MDP-stimulated monocytes even though they contain active intracellular IFN-alpha apparently translated from the 2.8 kb mRNA.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Dopamine and nonmodulating hypertension.

Sodium loading reduces aldosterone responses to angiotensin II (AII) when compared to the sodium restricted state. Recent investigations suggest that dopamine inhibits the aldosterone secretion and may contribute to the alteration in aldosterone response to AII with sodium intake, since administration of the dopamine antagonist, metoclopramide, enhances the aldosterone responses to AII on a high but not a low salt diet. Nonmodulating hypertension is characterized, in part, by a decreased aldosterone response to AII, raising the possibility that an increased dopaminergic inhibition of aldosterone secretion underlies the adrenal defect in nonmodulating hypertension. To assess this possibility, 69 patients with hypertension were characterized in relationship to their modulation status on a low sodium intake. Dopamine levels were significantly higher (P less than .05) in nonmodulators. To assess the physiologic relevance of these findings, the aldosterone response to AII infusion was assessed before and during administration of the dopamine antagonist, metoclopramide, in 13 patients. The adrenal response to AII did not change after metoclopramide in either hypertensive subgroup. Thus, it is unlikely that the adrenal defect is due to the increase in dopamine levels observed in nonmodulators. In the next study, the impact of dietary sodium intake on urinary dopamine levels was compared in normotensive and hypertensive subjects characterized as modulators and nonmodulators. Both modulators and normotensive subjects demonstrated an increase in urinary dopamine excretion in response to a high sodium intake--a feature that was not observed in the nonmodulators. Thus, the sodium retaining tendency of nonmodulators may reflect, at least in part, a reduction in intrarenal dopamine production in response to a sodium load.

Adrenal Glands↗
PubMed2003

The C-terminal T peptide of acetylcholinesterase enhances degradation of unassembled active subunits through the ERAD pathway.

The catalytic domain of acetylcholinesterase AChE(T) subunits is followed by a C-terminal T peptide which mediates their association with the proline-rich attachment domain (PRAD) of anchoring proteins. Addition of the T peptide induced intracellular degradation and concomitantly reduced to variable degrees the secretion of AChE species differing in their oligomerization capacity and of human alkaline phosphatase. The T peptide forms an amphiphilic alpha-helix, containing a series of conserved aromatic residues. Replacement of two, four or five aromatic residues gradually suppressed degradation and increased secretion. Co-expression with a PRAD- containing protein induced the assembly of PRAD-linked tetramers in the endoplasmic reticulum (ER) and allowed partial secretion of a dimerization- defective mutant; by masking the aromatic side chains, hetero-oligomerization rescued this enzyme from degradation. Degradation was due to ERAD, since it was not blocked by brefeldin A but was sensitive to proteasome inhibitors. Kifunensine reduced degradation, suggesting a cooperativity between the glycosylated catalytic domain and the non-glycosylated T peptide. This system appears particularly well suited to analyze the mechanisms which determine the degradation of correctly folded multidomain proteins in the ER.

Acetylcholinesterase↗
PubMed2006

Leukaemia inhibitory factor and interleukin 11 levels in uterine flushings of infertile patients with endometriosis.

BACKGROUND: Exact aetiology of infertility in stage I/II endometriosis patients is not known. Interleukin 11 (IL-11) and leukaemia-inhibitory factor (LIF) are factors associated with implantation window in human eutopic endometrium. We decided to test whether there is an altered secretion of these factors, which could explain receptivity defect in patients with minimal endometriosis. METHODS: Uterine flushing and endometrial samples were collected 7-9 days after ovulation (implantation window) from infertile patients with stage I/II endometriosis (n = 14) and fertile, endometriosis-free controls (n = 21). IL-11 and LIF were assessed in uterine flushings in eutopic endometria in all patients by enzyme-linked immunosorbent assay (ELISA). In eutopic endometrium, semiquantitative RT-PCR was performed for LIF and IL-11 mRNA expressions. RESULTS: No statistically significant differences were found in uterine flushing in women with and without endometriosis with regard to IL-11 levels (0.0 pg/ml versus 0.0 pg/ml) and LIF (25.53 pg/ml versus 36.26 pg/ml). These results were confirmed by the results of RT-PCR, where there were also no differences between studied groups. CONCLUSIONS: There is no receptivity defect with regard to LIF and IL-11 secretions by eutopic endometrium in infertile women with endometriosis.

Adult↗
PubMed1992

A functional antibody mutant with an insertion in the framework region 3 loop of the VH domain: implications for antibody engineering.

We have studied the effects of a four residue insertion into the FR3 loop of the heavy chain variable region from the anti-NP antibody B1-8. The insertion mutant is obtained as secreted antibody without major defects in biosynthesis, indicating that antibody variable domains can accommodate length variation not only in complementarity determining regions (CDRs), but also in framework region (FR) loops. The B1-8 antigen binding site is not affected by the change in a neighbouring loop. FR3 insertions represent a new method of antibody engineering with a potential to obtain strong antigen binding by designing additional antigen contacting residues.

Amino Acid Sequence↗
PubMed1996

Physiological regulation of the human growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis: predominant impact of age, obesity, gonadal function, and sleep.

The growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis is subject to exquisite regulation by multiple internal physiological variables and external cues. This review and update summarizes the impact of age, obesity, gonadal function and sleep on the control of GH secretion by the pituitary gland, as regulated by the dominant hypothalamic regulatory peptides, GH-releasing hormone (GHRH) and somatostatin. Available studies show an exponential decline in the calculated daily GH-secretion rate as a function of age in healthy men, such that every 7 years of advancing age beyond age 18-21 results in an approximately 50% decline. There are also strongly negative correlations between the daily GH-secretion rate and indices of obesity, such as the body mass index (BMI). For each increase in BMI of 1.5 kg/m2, there is a 50% decrease in the amount of GH secreted per day. At puberty, and across a span of adult ages, gonadal steroid-hormone concentrations in blood positively determine GH release. In particular, serum estradiol and testosterone concentrations are proportionate to GH-secretory burst mass and mean serum GH concentrations. Deep sleep (stages 3 and 4) is accompanied by markedly increased pulsatile GH secretion that can be accounted for mechanistically by presumptive somatostatin withdrawal combined with hypothalamic GHRH release. Lastly, body composition (especially visceral adiposity) appears to be a dominant negative determinant of GH production, since the relationships between GH secretion and age, testosterone, or sleep are all attenuated or abolished by adiposity. Recent data using pulsatile GHRH treatment or pharmacological methods to reduce somatostatin secretion point to combined defects in GHRH release and somatostatin excess as the most plausible pathophysiology of hyposomatotropism accompanying obesity.

Adolescent↗
PubMed1988

Malabsorption in cystic fibrosis: mechanisms and treatment.

Malabsorption of nutrients in cystic fibrosis (CF) has a multifactorial origin. The factors involved in malabsorption include malfunction of the exocrine pancreas and liver, bile acid metabolism, and disordered intestinal resorptive processes. Therapeutic measures presently employed are only partially effective. Improvement of fat malabsorption is attained by using a pancreatic enzyme supplement consisting of pH-sensitive, enteric-coated microspheres (microsphere preparations) that prevent enzyme degradation in the stomach and travel with the chyme to the small intestine. Microsphere preparations, however, do not improve bile salt deficiency. The detergent Tween-80, given orally to simulate bile salt activity, does not improve fat absorption. The mucus viscosity is probably enhanced in the intestinal epithelium of CF patients and can be decreased by N-acetylcysteine, which breaks down sulfide bonds. However, the addition of a high oral dose of this mucus solvent to pancreatin preparations does not improve fat absorption. Further studies on the disturbed intestinal resorptive mechanism seem warranted since recent investigations point to an abnormal chloride secretion as the primary defect in the intestinal epithelia of CF patients.

Acetylcysteine↗
PubMed1983

Ocular manifestations of pituitary adenomas.

Fifty patients with pituitary adenomas were evaluated preoperatively by an ophthalmologist; of these, 68% had visual field defects, the most common (25%) a superior bitemporal depression and 16%, bitemporal hemianopsia. Almost 60% of patients with field defects had visual complaints; 38% had visual acuity in one eye of 20/60 or less. Patients with larger, nonsecreting tumors had more visual defects than patients with secreting pituitary adenomas.

Adenoma↗
PubMed1979

Testicular function in post pubertal male pseudohermaphroditism.

Testicular endocrine function was studied in twelve post pubertal patients with male pseudohermaphroditism and 46 XY chromosomal constitution. Patients were divided into three groups, four subjects who became feminized during puberty, five who became masculinized during puberty and three who were castrated before puberty. Serum dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, androstendione, testosterone, dihydrotestosterone, LH and FSH were determined by radioimmunoassay. Patients of the first group had the clinical characteristics of testicular feminization secondary to absence of the androgen receptor. One of the five patients of the second group had deficient testosterone secretion but no enzymatic defect could be demonstrated. One of the subjects castrated before puberty had a deficiency in 17,20-desmolase. Therefore, evidence of a failure of the fetal testes could be found in only two of the twelve patients studied.

Adolescent↗
PubMed2004

The Pseudomonas syringae type III effector AvrRpt2 functions downstream or independently of SA to promote virulence on Arabidopsis thaliana.

AvrRpt2, a Pseudomonas syringae type III effector protein, functions from inside plant cells to promote the virulence of P. syringae pv. tomato strain DC3000 (PstDC3000) on Arabidopsis thaliana plants lacking a functional copy of the corresponding RPS2 resistance gene. In this study, we extended our understanding of AvrRpt2 virulence activity by exploring the hypothesis that AvrRpt2 promotes PstDC3000 virulence by suppressing plant defenses. When delivered by PstDC3000, AvrRpt2 suppresses pathogen-related (PR) gene expression during infection, suggesting that AvrRpt2 suppresses defenses mediated by salicylic acid (SA). However, AvrRpt2 promotes PstDC3000 growth on transgenic plants expressing the SA-degrading enzyme NahG, indicating that AvrRpt2 does not promote bacterial virulence by modulating SA levels during infection. AvrRpt2 general virulence activity does not depend on the RPM1 resistance gene, as mutations in RPM1 had no effect on AvrRpt2-induced phenotypes. Transgenic plants expressing AvrRpt2 displayed enhanced susceptibility to PstDC3000 strains defective in type III secretion, indicating that enhanced susceptibility of these plants is not because of suppression of defense responses elicited by other type III effectors. Additionally, avrRpt2 transgenic plants did not exhibit increased susceptibility to Peronospora parasitica and Erysiphe cichoracearum, suggesting that AvrRpt2 virulence activity is specific to P. syringae.

Arabidopsis↗
PubMed2002

Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs.

Helicobacter pylori (H. pylori) infection is widely accepted as the most important factor in the pathogenesis of duodenal ulcer. However, in parallel with more effective eradication of H. pylori, the prevalence of H. pylori is changing, and H. pylori-negative peptic ulcer disease appears to be increasing. When making a diagnosis of H. pylori-negative peptic ulcer disease, it is essential to avoid misclassification because of inaccurate diagnosis. In addition, secondary causes may need to be excluded with appropriate investigations. In the absence of H. pylori, nonsteroidal anti-inflammatory drug usage is the most common cause of peptic ulcer; surreptitious nonsteroidal anti-inflammatory drug usage is a cause of unexplained ulcer disease in up to 60% of patients. Hypersecretory syndromes such as Zollinger-Ellison syndrome, although rare, need to be excluded. Once all known etiological factors are excluded, there remains a group of patients with so-called "idiopathic ulcers." The interplay of etiological factors in the pathogenesis of idiopathic peptic ulcer disease is poorly defined but may include a genetic predisposition, altered acid secretion, rapid gastric emptying, defective mucosal defense mechanisms, psychological stress, and smoking. The management of idiopathic peptic ulcers is not defined; they appear to be more resistant to standard therapy, can be associated with more frequent complications, and those that relapse may require long-term maintenance therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

Immunomagnetic depletion of malignant cells from autologous bone marrow graft: from experimental models to clinical trials.

Using experimental modes with normal allogeneic bone marrow (BM) contaminated with Burkitt or neuroblastoma cell lines, and a liquid culture assay, we demonstrated that, when used in optimal conditions, the immunomagnetic depletion technique permitted a reproducible elimination of 3-4 log malignant cells. Results were very similar to those obtained with the complement lysis procedure in Burkitt lymphoma. This immunomagnetic procedure was used in 123 cases of autologous bone marrow transplantation (ABMT) in children with neuroblastoma. The analysis of the cases demonstrated, first, that the procedure induced a significant loss of mononuclear cells but was not toxic for BM precursors. Delays to engraftment observed in a few patients were probably due to the combination of pejorative factors, especially the damage caused to the micro-environment by previous heavy and prolonged chemotherapy or the double ABMT programme. Second, patients presented with profound T-cell defect with undetectable IL2 secretion up to 1 year post-graft but they all had normal NK functions from the first month post-graft, these functions exceeding normal values on the second and third months post-graft. Finally, in 20 cases, dual-immunofluorescence staining permitted the demonstration that the autograft contained malignant cells before purging that were eliminated by the immunomagnetic depletion.

Bone Marrow↗
PubMed2004

Constitutive expression of peroxisome proliferator-activated receptor alpha-regulated genes in dwarf mice.

Defects in growth hormone secretion or signaling in mice are associated with decreased body weights (dwarfism), increased longevity, increased resistance to stress, and decreases in factors that contribute to cardiovascular disease and cancer. Peroxisome proliferators (PP) alter a subset of these changes in wild-type mice through activation of the nuclear receptor family member PP-activated receptor alpha (PPARalpha). We tested the hypothesis that an overlap in the transcriptional programs between untreated dwarf mice and PP-treated wild-type mice underlies these similarities. Using transcript profiling, we observed a statistically significant overlap in the expression of genes differentially regulated in control Snell dwarf mice (Pit-1dw) compared with phenotypically normal heterozygote (+/dw) control mice and those altered by the PP 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid (WY-14,643) in +/dw mice. The genes included those involved in beta- and omega-oxidation of fatty acids (Acox1, Cyp4a10, Cyp4a14) and those involved in stress responses (the chaperonin, T-complex protein1epsilon) and cardiovascular disease (fibrinogen). The levels of some of these gene products were also altered in other dwarf mouse models, including Ames, Little, and growth hormone receptor-null mice. The constitutive increases in PPARalpha-regulated genes may be partly caused by increased expression of PPARalpha mRNA and protein as observed in the livers of control Snell dwarf mice. These results indicate that some of the beneficial effects associated with the dwarf phenotype may be caused by constitutive activation of PPARalpha and regulated genes.

Animals↗
PubMed2006

Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior.

A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF(Met/Met)) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF(Met) was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF(Met/Met) mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.

Alleles↗
PubMed2006

Inhibition of Staphylococcus aureus growth on tellurite-containing media by Lactobacillus reuteri Is dependent on CyuC and thiol production.

Lactobacillus reuteri inhibits Staphylococcus aureus growth on Baird-Parker agar. This activity required the presence of tellurite and was not shared with other lactic acid bacteria or an L. reuteri mutant defective in cystine metabolism. Secreted products generated from L. reuteri cystine metabolism and thiols were shown to augment tellurite toxicity.

Agar↗
PubMed2004

Improved production of heterologous proteins by a glucose repression-defective mutant of Kluyveromyces lactis.

The secreted production of heterologous proteins in Kluyveromyces lactis was studied. A glucoamylase (GAA) from the yeast Arxula adeninivorans was used as a reporter protein for the study of the secretion efficiencies of several wild-type and mutant strains of K. lactis. The expression of the reporter protein was placed under the control of the strong promoter of the glyceraldehyde-3-phosphate dehydrogenase of Saccharomyces cerevisiae. Among the laboratory strains tested, strain JA6 was the best producer of GAA. Since this strain is known to be highly sensitive to glucose repression and since this is an undesired trait for biomass-oriented applications, we examined heterologous protein production by using glucose repression-defective mutants isolated from this strain. One of them, a mutant carrying a dgr151-1 mutation, showed a significantly improved capability of producing heterologous proteins such as GAA, human serum albumin, and human interleukin-1beta compared to the parent strain. dgr151-1 is an allele of RAG5, the gene encoding the only hexokinase present in K. lactis (a homologue of S. cerevisiae HXK2). The mutation in this strain was mapped to nucleotide position +527, resulting in a change from glycine to aspartic acid within the highly conserved kinase domain. Cells carrying the dgr151-1 allele also showed a reduction in N- and O-glycosylation. Therefore, the dgr151 strain may be a promising host for the production of heterologous proteins, especially when the hyperglycosylation of recombinant proteins must be avoided.

Amino Acid Sequence↗
PubMed1992

PMI40, an intron-containing gene required for early steps in yeast mannosylation.

We have previously described a temperature-sensitive pmi40-1 mutant of Saccharomyces cerevisiae which is defective in glycosylation and secretion because of a thermolabile phosphomannose isomerase (PMI) activity. Inactivation of PMI at the restrictive temperature of 37 degrees C prevents synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions and results in cell death. Here, we report the isolation of the PMI40 gene by complementation of the corresponding mutation. The PMI40 gene contains an efficiently spliced intron which differs from the majority of those so far identified in S. cerevisiae in that it is short and the branch-forming structure has an AACTAAC motif replacing the highly conserved consensus TACTAAC. The 48.2-kDa protein predicted to be encoded by PMI40 contains amino acid sequences corresponding to those of internal peptides derived from purified S. cerevisiae PMI. Deletion of the PMI40 coding sequence results in a strain requiring D-mannose for growth. The PMI40 gene is located on chromosome V, and its transcription is increased 12-fold when cells are grown on D-mannose as sole carbon source instead of D-glucose. PMI enzyme activity, however, is not increased in D-mannose-grown cells, and PMI protein levels remain constant, suggesting that the PMI40 gene is subject to additional levels of regulation.

Amino Acid Sequence↗
PubMed1995

PHR1, a pH-regulated gene of Candida albicans, is required for morphogenesis.

Candida albicans, like many fungi, exhibits morphological plasticity, a property which may be related to its biological capacity as an opportunistic pathogen of humans. Morphogenesis and alterations in cell shape require integration of many cellular functions and occur in response to environmental signals, most notably pH and temperature in the case of C. albicans. In the course of our studies of differential gene expression associated with dimorphism of C. albicans, we have isolated a gene, designated PHR1, which is regulated in response to the pH of the culture medium. PHR1 expression was repressed at pH values below 5.5 and induced at more alkaline pH. The predicted amino acid sequence of the PHR1 protein was 56% identical to that of the Saccharomyces cerevisiae Ggp1/Gas1 protein, a highly glycosylated cell surface protein attached to the membrane via glycosylphosphatidylinositol. A homozygous null mutant of PHR1 was constructed and found to exhibit a pH-conditional morphological defect. At alkaline pH, the mutant, unlike the parental type, was unable to conduct apical growth of either yeast or hyphal growth forms. This morphological aberration was not associated with defective cytoskeletal polarization or secretion. The results suggest that PHR1 defines a novel function required for apical cell growth and morphogenesis.

Amino Acid Sequence↗