The proteasome regulator PA28alpha/beta can enhance antigen presentation without affecting 20S proteasome subunit composition

PA28alpha/beta is a regulatory complex of the 20S proteasome which consists of two IFN-gamma inducible subunits. Both subunits, alpha and beta, contribute equally to the formation of hexa- or heptameric rings which can associate with the 20S proteasome. Previously, we have shown that overexpression of the PA28alpha subunit enhanced the MHC class I-restricted presentation of two viral epitopes and that purified PA28alpha/beta accelerated T cell epitope generation by the 20S proteasome in vitro, indicating a role for PA28alpha/beta in antigen presentation. This conclusion was recently confirmed in PA28beta gene targeted mice which were severely deficient in MHC class I-restricted antigen presentation. These mice displayed a defect in the assembly of immunoproteasomes, suggesting that a lack of the proteasome subunits LMP2, LMP7, and MECL-1 may account for the deficiency in antigen presentation. In this study we investigated whether the effect of PA28alpha/beta on antigen presentation is dependent on a change of proteasome subunit composition. We have analyzed the assembly and subunit composition of proteasomes in fibroblast transfectants overexpressing both, alpha and beta subunits of PA28. In these transfectants we found a marked enhancement in the presentation of the immunodominant H-2Ld-restricted pp89 epitope of murine cytomegalovirus, although the 20S proteasome composition was the same as in recipient cells. We, therefore, conclude that PA28alpha/beta can enhance antigen processing independently of changes in 20S proteasome subunit composition or assembly.     

Liberation of histamine and serotonin and vascular permeability in an acute aseptic inflammatory focus

Degranulation of mast cells of a peritoneal suspension and of the mesentery of the small intestine and liberation of histamine and serotonin in albino rats with acute aseptic peritonitis were shown to begin during the first minute after injury and to reach a maximum at the fifth minute. By the 15th minute the concentrations of the free amines had fallen sharply and did not differ significantly from the initial levels. The dynamics of the immediate phase of increased vascular permeability corresponded to the dynamics of the free amines. The most marked increase in vascular permeability was observed at the 10th–15th minutes. By the 20th minute it was appreciably lower. Preliminary exhaustion of histamine and serotonin reserves reduced the degree of disturbance of vascular permeability only during the first 15 min after application of the inflammatory agent. It is conculted that histamine and serotonin cause disturbance of vascular permeability in acute aseptic peritonitis chiefly during the first 15 min after injury.Department of Pathological Physiology, Khar'kov Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 12, pp. 660–664, December, 1977.     

Tuning of striate neurons to cross-shaped figures in conditions of local blockade of intracortical inhibition

The recently observed selective sensitivity to cross-shaped and angular figures was studied in 85 primary visual cortex (field 17) neurons in cats before and after local blockade of GABA_A ergic inhibition by microiontophoretic application of the GABA antagonist bicuculline. Two opposite effects were seen: half of the neurons studied showed decreases or complete loss of sensitivity to crosses, and a third of the cells showed increases or the appearance of sensitivity to crosses. These data provide evidence for significant roles for intracortical inhibition in providing sensitivity to crosses and intersecting lines in two types of visual cortex neurons, the effects on these two types of neuron being opposite. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti, Vol. 49, No. 2, pp. 271–278, March–April, 1999.     

Effect of improved glycemic control by continuous subcutaneous insulin infusion on hormonal responses to insulin-induced hypoglycemia in type 1 diabetics

Glucose counter-regulatory capacity and the hormonal responses to insulin-induced hypoglycemia were studied in eight type 1 diabetics before and after improvement of metabolic control by continuous subcutaneous insulin infusion (CSII). The intensified treatment resulted in a decrease in mean glycosylated hemoglobin from 11.6 +/- 0.5 to 9.3 +/- 0.4% within a mean period of 14 weeks. During a constant rate infusion of insulin (2.4 U/h), steady state levels of glucose appeared in all subjects. The steady state glucose level was identical before and after CSII. The counter-regulatory hormonal responses showed significantly higher epinephrine levels, while glucagon, growth hormone, and cortisol were not influenced. In parallel with the heightened epinephrine response the pulse rate response was significantly enhanced. The restitution of blood glucose after insulin hypoglycemia was not modified. It is concluded that a more vigorous catecholaminergic response to hypoglycemia is achieved after improved metabolic control by CSII.     

The nephronophthisis complex

Summary The clinical and morphological findings are described in 27 children with nephronophthisis. Seventeen children were considered as sporadic cases. In 10 familial cases the presumed mode of inheritance was autosomal recessive. The clinical picture was rather uniform: polyuria-polydipsia, hyposthenuria, anemia, growth retardation, and azotemia with progressive renal failure. Six patients presented with tapeto-retinal degeneration. In a further seven children other ocular changes were detected. Two female siblings showed additional non-renal manifestations: mental retardation, pulmonary emphysema, skeletal anomalies, and congenital hepatic fibrosis.Renal histology displayed a chronic sclerosing tubulo-interstitial nephropathy with extensive tubular atrophy and dedifferentiation. Medullary cysts were frequently found in end-stage kidneys. Immunofluorescence was either non-specific or completely negative. On electron microscopy, the tubular basement membrane changes predominated: thickening, lamellation, splitting, and deposition of microfibrils within the increased basement membrane substance. Detailed light- and electron microscopic findings were non-specific but the overall morphologic picture was characteristic and even diagnostic in conjunction with the clinical presentation.A recurrence of nephronophthisis in transplanted kidneys has not been observed.The pathogenesis of nephronophthisis is obscure but with respect to the morphologic findings a primary or secondary tubular basement membrane defect seems very likely.Our experience suggests that nephronophthisis is a frequent cause of chronic renal failure in children and commonly associated with non-renal abnormalities. To avoid the separation of different syndromes presenting with a uniform renal disease but various non-renal manifestations, we suggest that the term nephronopthisis complex be used.Presented in part at the 63th Annual Meeting of the German Society of Pathology, Stuttgart 1979     

Bestimmung der enteralen Resorption hoher Calciumdosen mittels stabiler Isotope

Zusammenfassung Bei 8 gesunden Versuchspersonen (Durchschnittsalter 25,6 Jahre) wurde nach oraler Applikation von 500 mg und 1000 mg Calcium die Calcium-Resorption bestimmt. Hierzu wurde ein Doppelisotopenverfahren mit angereicherten stabilen Calciumisotopen verwendet, das, da im Gegensatz zu Radiotracermethoden jegliche Strahlenbelastung vermieden wird, uneingeschränkt anwendbar ist. Die oral verabreichten Calciumsalze wurden mit⁴⁸Ca, das intravenös injizierte CaCl₂ mit⁴⁶Ca markiert. Die Bestimmung der beiden Isotope in Serum- und Urinproben erfolgte mit Hilfe der Neutronenaktivierungsanalyse. Für die Resorptionsquote wurde, unabhängig von der Calcium-Dosis, ein Wert von 30% gefunden. Aus dem⁴⁶Ca-Gehalt im Serum wurde für das in 24 h ausgetauschte Körper-Calcium ein mittlerer Wert von 6,4±1,0 g Calcium oder 98,8±15,4 mg Ca/kg Körpergewicht berechnet.