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PubMed2004

AIRE functions as an E3 ubiquitin ligase.

Autoimmune regulator (AIRE) gene mutation is responsible for the development of autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy, an organ-specific autoimmune disease with monogenic autosomal recessive inheritance. AIRE is predominantly expressed in medullary epithelial cells of the thymus and is considered to play important roles in the establishment of self-tolerance. AIRE contains two plant homeodomain (PHD) domains, and the novel role of PHD as an E3 ubiquitin (Ub) ligase has just emerged. Here we show that the first PHD (PHD1) of AIRE mediates E3 ligase activity. The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity. These results add a novel enzymatic function for AIRE and suggest an indispensable role of the Ub proteasome pathway in the establishment of self-tolerance, in which AIRE is involved.

Amino Acid Sequence↗

PubMed1978

Myocardial inotrophy of CO2 in water- and air-breathing vertebrates.

A negative-inotropic effect of CO2 on myocardial contractility presumably occurs because increasing H+ concentration competes with Ca2+ at cellular membranes and proteins. Since air-breathing vertebrates have higher blood and tissue CO2 concentration than water breathers the question was raised whether the cardiac cell has a modified sensitivity to CO2 correlated with the evolutionary transition of vertebrates from water breathers to air breathers. The water-breathing fish, Salmo gairdneri, and the air-breathing turtle, Pseudemys scripta, were selected as experimental animals, since their total CO2 concentration differs markedly (3.0 and 16.0 mmol.kg-1). Electrically paced isometric ventricular strips from both species were subjected to a stepwise increase in PCO2 from 25 to 114 Torr (pH0 7.80 to 7.0; HCO3- 30 mM). Trout were additionally exposed to the same pH0 changes at 5 mM HCO3- by a stepwise increase in PCO2 (4.5-12 Torr). At each increase in PCO2 the turtle heart showed a lesser negative inotropic effect than trout. The present findings offer direct evidence that the negative inotropic effect of CO2 on heart muscle is inversely proportional to the in vivo levels of tissue CO2 concentration. The results obtained are discussed in relation to phylogenetical and ecological aspects of acid-base balance.

Animals↗

PubMed2004

Negative air ions created by water shearing improve erythrocyte deformability and aerobic metabolism.

UNLABELLED: To elucidate a potential mechanism by which negative air ions improve aerobic metabolism, changes in venous blood lactate levels, pH, erythrocyte deformability, and plasma superoxide dismutase activity and ceruloplasmin levels were examined during a 1-h exposure to negative air ions created by water shearing or corona discharge in nine adult healthy volunteers. The blood lactate level decreased from 1.3 +/- 0.3 to 1.0 +/- 0.2 mmol/l, pH increased from 7.388 +/- 0.025 to 7.417 +/- 0.036, and erythrocyte deformability improved from 37.0 +/- 2.2 to 35.1 +/- 3.0 s, expressed as the mean +/- s.d., when exposed to negative air ions created by water shearing, but did not change when exposed to negative air ions created by corona discharge. Other variables did not change in either exposure. The results obtained suggest that negative air ions created by water shearing improve aerobic metabolism by improving erythrocyte deformability. PRACTICAL IMPLICATIONS: The paper shows that negative air ions created by water shearing method improve aerobic metabolism only during a 1-h exposure, which may be caused by improvement of erythrocyte deformability, but negative air ions created by corona discharge have no effects. A potential mechanism is that negative air ions enter the circulating blood via the lungs and electrons of these ions are delivered to the plasma protein. Why negative air ions created by corona discharge have no effects is considered that water binding does not exist so that the lifetime of these ions is markedly short, by which the ions cannot reach the alveoli of the lungs sufficiently.

Adult↗

PubMed1996

Serum Clara cell protein (CC16): a new valid marker of the distal airway damages caused by air pollutants in rats.

Cell count, LDH, total protein, Clara cell protein (CC16) and lysozyme in bronchoalveolar lavage fluid (BAL) and serum were determined in rats. 30-50 ppm sulfur dioxide for 4 h. 12 h and 2 week exposure didn't produce any change of above parameters. 1.0 ppm, 0.5 ppm, 0.38 ppm, 0.25 ppm and 0.20 ppm ozone for 7 h exposure tests were performed. CC16, total protein and LDH in BAL had significantly changes in BAL in ozone groups. Only serum CC16 showed significant increase among ozone groups. Both BAL and serum CC16 were of the best exposure-response relationship with ozone concentration. The change of BAL fluid reached high peak 18-24 h after ozone exposure. Serum CC16 seemed to be a valid marker of the distal airway damages caused by air pollutants.

Air Pollutants↗

PubMedDate not supplied

Pulmonary surfactant protein C containing lipid films at the air-water interface as a model for the surface of lung alveoli.

The pulmonary surfactant lines as a complex monolayer of lipids and proteins the alveolar epithelial surface. The monolayer dynamically adapts the surface tension of this interface to the varying surface areas during inhalation and exhalation. Its presence in the alveoli is thus a prerequisite for a proper lung function. The lipid moiety represents about 90% of the surfactant and contains mainly dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG). The surfactant proteins involved in the surface tension adaption are called SP-A, SP-B and SP-C. The aim of the present investigation is to analyse the properties of monolayer films made from pure SP-C and from mixtures of DPPC, DPPG and SP-C in order to mimic the surfactant monolayer with minimal compositional requirement. Pressure-area diagrams were taken. Ellipsometric measurements at the air-water interface of a Langmuir film balance allowed measurement of the changes in monolayer thickness upon compression. Isotherms of pure SP-C monolayers exhibit a plateau between 22 and 25 mN/m. A further plateau is reached at higher compression. Structures of the monolayer formed during compression are reversible during expansion. Together with ellipsometric data which show a stepwise increase in film thickness (coverage) during compression, we conclude that pure SP-C films rearrange reversibly into multilayers of homogenous thickness. Lipid monolayers collapse locally and irreversibly if films are compressed to approximately 0.4 nm2/molecule. In contrast, mixed DPPG/SP-C monolayers with less than 5 mol% protein collapse in a controlled and reversible way. The pressure-area diagrams exhibit a plateau at 20 mN/m, indicating partial demixing of SP-C and DPPG.(ABSTRACT TRUNCATED AT 250 WORDS)

Air↗

PubMed2003

Reversible metaphyseal dysplasia, a novel bone phenotype, in two unrelated children with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: clinical and molecular studies.

We report the association of an undescribed, reversible metaphyseal dysplasia (RMD) with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in two patients, one homozygous and one heterozygous for a 13-bp deletion in exon 8 of the autoimmune regulator (AIRE) gene. One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a STOP codon in exon 10. Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiological examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiological resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. RMD may constitute a rare phenotypic variation of APECED, possibly resulting from autoimmunity directed against skeletal proteins. We also demonstrated AIRE expression in chondrocytes derived from human fetal growth plates, primary culture of human chondrocytes, and two chondrosarcoma cell lines, suggesting a potential role for abnormal AIRE expression in the development of RMD.

Adult↗

PubMed2005

Use of green fluorescent protein-expressing Aspergillus fumigatus conidia to validate quantitative PCR analysis of air samples collected on filters.

This study used green fluorescent protein (GFP)-expressing Aspergillus fumigatus conidia to compare quantitative PCR (qPCR) enumeration with direct epifluorescent microscopic filter counts of conidia collected on filters in a test chamber. In separate experiments this study initially compared white versus fluorescent light microscopy for counting A. fumigatus conidia, then compared fluorescent microscopy counting of corresponding filter halves, and finally compared qPCR enumeration to counting by fluorescent light microscopy. The use of GFP-expressing conidia with epifluorescent microscopy yielded significantly higher conidia counts (p = 0.026, n = 41, mean of 4.1 conidia per counting field) and 40% faster counting times when compared to conventional counting using white light microscopy. GFP-expressing conidia were aerosolized in a test chamber and collected onto filters. Filters were divided in half and GFP-expressing conidia enumerated. There was no significant difference in the average conidia count per field between corresponding filter halves (p = 0.3, n = 9 filters, mean of 7.8 conidia per counting field). Thus, one filter half could be counted optically and would provide a reliable estimate of filter loading of the corresponding half, which could then be analyzed by qPCR. Filters (n = 38) loaded with GFP conidia in the aerosol chamber were divided in half and analyzed by either fluorescent microscopy or qPCR. The estimated filter loadings ranged from 15-30,000 conidia per filter. There was a linear relationship with a nearly 1:1 ratio between qPCR and direct microscopic estimates of filter loading (y = 1.06x + 404; R(2) = 0.91) showing that the outlined qPCR analysis method is in agreement with an external reference method and is reliable for enumerating A. fumigatus conidia collected on filters. The comparative data derived using GFP-expressing conidia confirmed that qPCR provides sensitive and accurate quantification of DNA from airborne conidia collected on filters.

Air Pollution, Indoor↗

PubMed2006

Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator.

Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire(-/-) dendritic cells (DC) activate naive T cells more efficiently than do Aire(+/+) DC. Expression array analyses of Aire(-/-) DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire(-/-) DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire(-/-) DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire(-/-) DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire(-/-) mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.

Animals↗

PubMed2002

Interaction of nominally soluble proteins with phospholipid monolayers at the air-water interface.

The interactions of carbonmonoxyhemoglobin (HbCO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and polyhistidine with phospholipid monolayers at the air-water interface were studied at physiological pH and ionic strength. HbCO and GAPDH both interact more strongly with monolayers containing negatively charged lipids. The interaction of HbCO and GAPDH with lipid monolayers decreases with increasing pH. Both the HbCO-monolayer and the GAPDH-monolayer interactions can be modeled as diffusion-limited processes, with kinetic data fit to a stretched exponential equation. The significance of these kinetics are discussed. Polyhistidine interacts only with monolayers containing lipids with negatively charged headgroups. In total, the results presented are consistent with an HbCO-lipid interaction with a large electrostatic component, a GAPDH-lipid interaction with comparable electrostatic and hydrophobic components, and a polyhistidine-lipid interaction that is solely electrostatic.

Air↗

PubMed2003

Surfactant protein A enhances apoptotic cell uptake and TGF-beta1 release by inflammatory alveolar macrophages.

The phagocytosis of apoptotic inflammatory cells by alveolar macrophages (AMs) is a key component of inflammation resolution within the air space. Surfactant protein A (SP-A) has been shown to stimulate the phagocytosis of apoptotic neutrophils (PMNs) by normal AMs. We hypothesized that SP-A promotes the resolution of alveolar inflammation by enhancing apoptotic PMN phagocytosis and anti-inflammatory cytokine release by inflammatory AMs. Using an LPS lung inflammation model, we determined that SP-A stimulates the phagocytosis of apoptotic PMNs threefold by normal AMs and AMs isolated after LPS injury. Furthermore, SP-A enhances transforming growth factor-beta1 (TGF-beta1) release from both AM populations. Inflammatory AMs release twofold more TGF-beta1 in culture than do normal AMs. SP-A and apoptotic PMNs together stimulate TGF-beta1 release equivalently from normal and inflammatory cultured AMs (330% of unstimulated release by normal AMs). In summary, SP-A enhances apoptotic PMN uptake, stimulates AM TGF-beta1 release, and modulates the amount of TGF-beta1 released when AMs phagocytose apoptotic PMNs. These findings support the hypothesis that SP-A promotes the resolution of alveolar inflammation.

Acute Disease↗

PubMed2005

Partial SP-B deficiency perturbs lung function and causes air space abnormalities.

Surfactant protein B (SP-B) is required for function of newborn and adult lung, and partial deficiency has been associated with susceptibility to lung injury. In the present study, transgenic mice were produced in which expression of SP-B in type II epithelial cells was conditionally regulated. Concentrations of SP-B were maintained at 60-70% of that normally present in control. Immunostaining for SP-B demonstrated cellular heterogeneity in expression of the protein. In subsets of type II cells in which SP-B staining was decreased, immunostaining for pro-SP-C was increased and lamellar body ultrastructure was disrupted, consistent with focal SP-B deficiency. Fluorescence-activated cell sorting analyses of freshly isolated type II cells identified a population of cells with low SP-B content and a smaller population with increased SP-B content, confirming nonuniform expression of the SP-B transgene. Focal air space enlargement, without cellular infiltration or inflammation, was observed. Pressure-volume curves indicated that maximal tidal volume was unchanged; however, hysteresis was modestly altered and residual volumes were significantly decreased in the SP-B-deficient mice. Chronic, nonuniform SP-B deficiency perturbed pulmonary function and caused air space enlargement.

Animals↗

PubMed1988

D-penicillamine metabolism in an in-vivo model of inflamed synovium.

Oxidation to disulphides is the chief metabolic transformation of D-penicillamine (D-pen) in patients with rheumatoid arthritis. Oxidation also occurs in many biological fluids in-vitro. Reduction of oxygen species may accompany the oxidation of D-pen under appropriate conditions and may mediate the anti-rheumatic action of D-pen. The transformation of D-pen therefore was examined in an in-vivo model of inflamed synovium. Subcutaneous air-pouches of groups of rats were treated with saline, 10% serum or 10% zymosan activated serum (ZAS). The transformation of D-pen to low molecular weight (LMW) metabolites and protein conjugates within the pouch was then assessed. The concentrations of total protein were significantly higher in the serum and ZAS-treated groups than in the saline-treated group and the inflammatory cell counts were significantly higher in the ZAS-treated group than in either of the other groups, as expected. D-pen oxidised rapidly to LMW metabolites and smaller amounts of D-pen-protein conjugate (D-pen-protein) in the air pouches of all animals. The rates of oxidation to LMW metabolites were greater in the ZAS-treated animals than the saline-treated group (p less than 0.005). The concentrations of D-pen-protein conjugate were also greater for the serum-treated and ZAS-treated animals than for the saline controls (p less than 0.005 in each case) at all times. Oxidation of D-pen therefore occurs at this site of inflammation and is influenced by local conditions. This may be important to understanding the forms in which D-pen exists in inflamed synovial joints and the way it may exert its antirheumatic activity.

Animals↗

PubMed1999

The independent effect of propofol anesthesia on whole body protein metabolism in humans.

BACKGROUND: The purpose of this study was to examine the effect of general anesthesia with propofol in the absence of surgical stimulation on whole body protein metabolism. METHODS: Six unpremedicated patients were studied. General anesthesia included propofol (120 microg x kg(-1) x min(-1)), vecuronium bromide, and oxygen-enriched air. Changes in protein breakdown, protein oxidation, and synthesis were measured by an isotope dilution technique using a constant infusion of the stable isotope tracer L-[1-13C]leucine (0.008 mg x kg(-1) x min(-1)) before and during 100 min of propofol anesthesia. The plasma concentrations of glucose, lactate, non-esterified fatty acids, and cortisol were measured before and during anesthesia. RESULTS: An isotopic steady state of plasma [1-13C]alpha-ketoisocaproate (taken to represent the intracellular leucine precursor pool enrichment for protein synthesis) and expired 13C-carbon dioxide were obtained before and during propofol infusion. Whole body protein breakdown decreased during propofol anesthesia by 6% (P < 0.05), whereas protein synthesis and oxidation did not change significantly. Plasma concentration of cortisol decreased after 90 min of propofol anesthesia (P < 0.05). No significant changes of plasma concentrations of glucose, lactate, and non-esterified fatty acids occurred during propofol administration. CONCLUSIONS: Propofol anesthesia did not significantly affect whole body protein synthesis and oxidation but caused a small, although significant, decrease in whole body protein breakdown, possibly mediated through the suppression of plasma cortisol concentration.

Adult↗

PubMed1995

Leukocyte-derived neutrophil chemotactic factor-2 produced by infiltrated leukocytes in allergic inflammation model in rats is macrophage inflammatory protein-2.

In the air pouch-type allergic inflammation model in rats, leukocytes collected from the pouch fluid 4 h after the antigen challenge produced proteinaceous chemotactic factors for neutrophils. The leukocytes from the immunized rats produced significantly higher amount of the chemotactic factors than that from the non-immunized rats. The major chemotactic factor, leukocyte-derived neutrophil chemotactic factor (LDNCF)-2, was purified and found to be identical with rat macrophage inflammatory protein (MIP)-2 by N-terminal amino acid sequence analysis. Expression of MIP-2 mRNA was higher in the leukocytes from the immunized rats than that from the non-immunized rats. Possible roles of LDNCF-2 (MIP-2) in neutrophil infiltration in the allergic inflammation is discussed.

Amino Acid Sequence↗

PubMed2000

Novel mutations of the autoimmune regulator gene in two siblings with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the first multiple autoimmune disease that has been shown to be caused by mutations of a single gene named autoimmune regulator (AIRE). Fourteen different mutations of the AIRE gene have been identified in 61 patients from 55 families with APECED. However, there has been no report documenting AIRE gene mutations in the Asian population. We report on 2 siblings with variable manifestations of APECED who were born to a Japanese mother and a Korean father. The 11yr-old girl had intractable thrush and ungual candidiasis, hypoparathyroidism, and occipital alopecia. The 9-yr-old boy had mild ungual candidiasis alone. Direct sequencing revealed novel frameshift mutations of the AIRE gene: an insertion of a cytosine at nucleotide 29635 at the exon 10 (29635insC), which should lead to a premature termination at the codon 371, producing a truncated protein missing the second plant homeodomain-type zinc finger motif and the third LXXLL motif, and a deletion of a guanine at nucleotide 33031 at the exon 13 (33031delG), which should result in a premature termination at the codon 520, yielding a truncated protein missing the third LXXLL motif. The mother was heterozygous for 29635insC, and the father was heterozygous for 33031delG. The frameshift mutations were undetected in 40 alleles of 20 Japanese control subjects. The results imply that the C-terminus of AIRE protein including the third LXXLL motif plays a critical role in the development of APECED, and that the phenotypic spectrum can vary between siblings with the same mutations.

Child↗

PubMed1982

[Analysis of the basic protein fractions of the outer membrane in E. coli strains differing in survivability in air].

The study of the spectrum of the main fractions of proteins contained in the outer membrane of E. coli strains has revealed the relationship between the composition of protein fractions in the outer membrane and the level of the survival of these bacteria in the air. The increased survival capacity of E. coli strain K12 after the transfer of pSA 50 plasmid has been found to correlate with the appearance of 2 molecular fractions in the outer membrane. The positions of these fractions correspond to the molecular weights 70,000 daltons and 80,000 daltons.

Air Microbiology↗

PubMed1990

Amino acid metabolism after intense exercise.

We studied postexercise amino acid metabolism, in the whole body and across the forearm. Seven volunteers were infused with L-[alpha-15N]lysine and L-[1-13C]-leucine twice [one time during 3 h after cycle exercise (75% VO2max), and one time in the resting state]. Whole body protein breakdown was estimated from dilution of L-[alpha-15N]lysine and L-[1-13C]ketoisocaproic acid (KIC) enrichments in plasma. Leucine oxidation was calculated from 13CO2 enrichments in expired air. Whole body protein breakdown was not increased above resting levels during the recovery period. Leucine oxidation was decreased after exercise (postexercise 13 +/- 2.3 vs. resting 19 +/- 3.2 mumol.kg-1.h-1; P less than 0.02), while nonoxidative leucine disposal was increased (115 +/- 6.1 vs. 103 +/- 5.6 micrograms.kg-1.min-1; P less than 0.02). After exercise, forearm net lysine balance was unchanged (87 +/- 25 vs. 93 +/- 28 nmol.100 ml-1.min-1), but there were decreases in forearm muscle protein degradation (219 +/- 51 vs. 356 +/- 85 nmol.100 ml-1.min-1; P less than 0.05) and synthesis (132 +/- 41 vs. 255 +/- 69 nmol.100 ml-1.min-1; P less than 0.01). In conclusion, after exercise 1) whole body protein degradation is not increased, 2) leucine disposal is directed away from oxidative and toward nonoxidative pathways, 3) forearm protein synthesis is decreased. Postexercise increases in whole body protein synthesis occur in tissues other than nonexercised muscle.

Adult↗

PubMed2002

Limited conformational change of beta-lactoglobulin when adsorbed at the air-water interface.

Detailed insight can be obtained from proteins at and near the air-water interface using external reflection IR and circular dichroism techniques. Besides information on local protein concentrations and surface layer thickness, it is shown that beta-lactoglobulin displays a limited unfolding at the interface. The conformational change is comparable to that observed upon heat-induced aggregation of the protein and can be understood in view of the high surface concentration of the protein (approximately 40% volume fraction). The layer thickness and the conformational properties of the protein do not depend on the bulk concentration. After adsorption of beta-lactoglobulin to a preformed lipid monomolecular layer a similar conformational change is induced, suggesting that the folding properties of the protein itself determine the extent of conformational changes at the interfaces.

Adsorption↗