Showing papers by "University of Geneva published in 1990"

Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis

Abstract: THE deposition of silica particles in the lung of man or experimental animals leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction1. It has long been suspected that the phagocytosis of silica by pulmonary macrophages induces the secretion of fibrogenic factors2. Several potentially fibrogenic cytokines released by macrophages have been identified, including interleukin-1 (IL-1) (ref. 3), tumour necrosis factor-α (TNF) (ref. 4), platelet-derived growth factor5, basic fibroblast growth factor6 and transforming growth factor-β (TGF-β) (ref. 7). Here we show that TNF plays an important part in silica-induced pulmonary fibrosis in mice in that (1) a single instillation of silica leads to a marked increase in the level of lung TNF messenger RNA which lasts for >70 days, while there are no obvious changes in the amounts of IL-lα or TGF-β mRNAs; and (2) silica-induced collagen deposition is almost completely prevented by anti-TNF antibody, but is significantly increased by continuous infusion of mouse recombinant TNF.

LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein.

Abstract: A gene, encoding a liver-enriched transcriptional activator protein (LAP) has been isolated. LAP is a 32-kD protein that stimulates the transcription of chimeric genes containing albumin D-promoter elements both in vivo and in vitro. LAP shares extensive sequence homology (71%) in its DNA-binding and leucine zipper domains with C/EBP. As a consequence, these two proteins show an indistinguishable DNA-binding specificity and readily heterodimerize. In addition, both genes, lap and cebp, are devoid of intervening sequences. Although correctly initiated transcripts from the LAP gene accumulate in the six examined tissues--liver, lung, spleen, kidney, brain, and testis--LAP protein is highly enriched in liver nuclei. Thus, the preferential accumulation of LAP protein in liver appears to be regulated post-transcriptionally.

The construction of the L3 experiment

Abstract: The L3 experiment is one of the six large detectors designed for the new generation of electron-positron accelerators. It is the only detector that concentrates its efforts on limited goals of measuring electrons, muons and photons. By not attempting to identify hadrons, L3 has been able to provide an order of magnitude better resolution for electrons, muons and photons. Vertices and hadron jets are also studied. The construction of L3 has involved much state of the art technology in new principles of vertex detection and in new crystals for large scale electromagnetic shower detection and ultraprecise muon detection. This paper presents a summary of the construction of L3.

The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes.

Abstract: Receptor-bound urokinase-type plasminogen activator (uPA) remains associated to the surface of human monocytes for many hours. Monocytes induced to migrate in a chemotactic gradient of f-Met-Leu-Phe rapidly polarize their uPA receptors to the leading front of the cells. Receptor-bound enzyme can be inhibited by plasminogen activator inhibitor 2 (PAI-2), with a kinetics comparable to that determined for the free enzyme, and uPA/PAI-2 complexes can bind to the uPA receptor. In contrast to the active enzyme, the uPA/PAI-2 complex is rapidly cleared from the monocyte cell surface; this involves an initial cleavage of the complex at the cell surface, followed by endocytosis and degradation. These results indicate that the uPA receptor can function both to focus plasmin-mediated extracellular matrix degradation in front of migrating cells, and to target uPA/PAI-2 enzyme/inhibitor complexes for degradation; they suggest that this receptor is a key determinant in the control of uPA-catalyzed extracellular proteolysis.

Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cells in vitro.

Abstract: Tightly controlled proteolytic degradation of the extracellular matrix by invading microvascular endothelial cells is believed to be a necessary component of the angiogenic process. We have previously demonstrated the induction of plasminogen activators (PAs) in bovine microvascular endothelial (BME) cells by three agents that induce angiogenesis in vitro: basic FGF (bFGF), PMA, and sodium orthovanadate. Surprisingly, we find that these agents also induce plasminogen activator inhibitor-1 (PAI-1) activity and mRNA in BME cells. We also find that transforming growth factor-beta 1 (TGF-beta 1), which in vitro modulates a number of endothelial cell functions relevant to angiogenesis, also increases both PAI-1 and urokinase-type PA (u-PA) mRNA. Thus, production of both proteases and protease inhibitors is increased by angiogenic agents and TGF-beta 1. However, the kinetics and amplitude of PAI-1 and u-PA mRNA induction by these agents are strikingly different. We have used the ratio of u-PA:PAI-1 mRNA levels as an indicator of proteolytic balance. This ratio is tilted towards enhanced proteolysis in response to bFGF, towards antiproteolysis in response to TGF-beta 1, and is similar to that in untreated cultures when the two agents are added simultaneously. Using an in vitro angiogenesis assay in three-dimensional fibrin gels, we find that TGF-beta 1 inhibits the bFGF-induced formation of tube-like structures, resulting in the formation of solid endothelial cell cords within the superficial parts of the gel. These results suggest that a net positive proteolytic balance is required for capillary lumen formation. A novel perspective is provided on the relationship between extracellular matrix invasion, lumen formation, and net proteolytic balance, thereby reflecting the interplay between angiogenesis-modulating cytokines such as bFGF and TGF-beta 1.

Relative survival and the estimation of net survival: elements for further discussion.

Abstract: The methods of calculation of survival corrected for independent cause of death are discussed, and a maximum likelihood method is proposed and illustrated by survival of colon cancer patients in Geneva. The methods which are at present favoured for doing such calculations are subject to various biases when estimating net survival if the populations are heterogeneous for life expectancy. The proposed maximum likelihood approach would eliminate these biases by enabling relevant adjustment for covariates which influence survival. The routine use of such methods would permit better comparison of survival within and between populations.

YBa2CU3O7/PrBa2Cu3O7 superlattices: Properties of Ultrathin superconducting layers separated by insulating layers.

Abstract: We have artificially varied the coupling between ultrathin ${\mathrm{YBa}}_{2}$${\mathrm{Cu}}_{3}$${\mathrm{O}}_{7}$ layers by interposing insulating planes of ${\mathrm{PrBa}}_{2}$${\mathrm{Cu}}_{3}$${\mathrm{O}}_{7}$ in multilayers and studied the consequences of decoupling 12-A\r{} ${\mathrm{YBa}}_{2}$${\mathrm{Cu}}_{3}$${\mathrm{O}}_{7}$ unit cells on the superconducting properties. We find that the ${\mathrm{T}}_{\mathrm{c}}$ (midpoint) of a 12-A\r{}/12-A\r{} multilayer is 55 K, twice that of the corresponding alloy. ${\mathrm{T}}_{\mathrm{c}}$ decreases linearly with further separation of the ${\mathrm{YBa}}_{2}$${\mathrm{Cu}}_{3}$${\mathrm{O}}_{7}$ unit cells, the transition width increases and shows evidence of 2D fluctuations, and the influence of a magnetic field parallel to the layers is markedly reduced.

Manufacturing flow control and preventing maintenance: a stochastic control approach

Abstract: A stochastic control model for simultaneously planning production and maintenance in a flexible manufacturing system (FMS) is proposed, and an efficient technique for computing the optimal control policy is developed. The model extends previous formulations by including an age-dependent machine failure rate and by allowing the control to influence some jump rates (namely the preventive maintenance activities). By using an adaptation to the case of piecewise-deterministic systems of the approximation technique initially proposed by H.J. Kushner (1977) in the realm of the optimal control of diffusions, one shows how it is possible to computer the optimal control for a two-machine system. >

Optical-fiber temperature sensor based on upconversion-excited fluorescence.

Abstract: The codoping of a heavy-metal fluoride glass by two rare-earth ions, erbium and ytterbium, permits the semiconductor laser infrared excitation of two visible neighboring fluorescence lines of erbium by upconversion, the intensity ratio of which is a single variable function of temperature.

Single islet beta-cell stimulation by nutrients: relationship between pyridine nucleotides, cytosolic Ca2+ and secretion.

Abstract: It is generally believed that the initiation of insulin secretion by nutrient stimuli necessitates the generation of metabolic coupling factors, leading to membrane depolarization and the gating of voltage-sensitive Ca2+ channels. To establish this sequence of events, the kinetics of endogenous fluorescence of reduced pyridine nucleotides [NAD(P)H], reflecting nutrient metabolism, were compared to those of cytosolic calcium ([Ca2+]i) rises in single cultured rat islet beta-cells. In preliminary experiments, the loss of quinacrine fluorescence from prelabelled cells was used as an indicator of secretion. This dye is concentrated in the acidic insulin-containing secretory granules. Both glucose and 2-ketoisocaproate (KIC) raised [Ca2+]i in a dose-dependent manner. There was marked cellular heterogeneity in the [Ca2+]i response patterns. The two nutrient stimuli also increased NAD(P)H fluorescence, again showing cell-to-cell variations. In combined experiments, where the two parameters were measured in the same cell, the elevation of the NAD(P)H fluorescence preceded the rise in [Ca2+]i, confirming the statistical evaluation performed on separate cells. The application of two consecutive glucose challenges revealed coordinated changes in [Ca2+]i and NAD(P)H fluorescence. Finally, quinacrine secretion was stimulated by two nutrients with onset times similar to those recorded for [Ca2+]i elevations. These results clearly demonstrate that increased metabolism occurs during the lag period preceding Ca2+ influx via voltage-sensitive Ca2+ channels, a prerequisite for the triggering of insulin secretion by nutrient stimuli.

Cytokine‐related syndrome following injection of anti‐CD3 monoclonal antibody: Further evidence for transient in vivo T cell activation

Abstract: In vivo injection of the hamster anti-murine CD3 monoclonal antibody 145 2C11 into BALB/c mice induces a massive systemic release of several cytokines. Very high circulating levels of tumor necrosis factor are detected both by enzyme-linked immunosorbent assay and L-929 bioassay 90 min following a single injection of 10 micrograms/mouse 145 2C11. Peak circulating levels of exclusively T cell-derived products such as interferon-gamma, interleukin 2 and interleukin 3 are also detected 90 min to 8 h post-injection. Importantly, this cytokine release is transient since none of these cytokines are still present 12 to 24 h post-injection. In parallel to cytokine release, 145 2C11-treated mice (10 micrograms/mouse) exhibit somnolence, hypomotility (quantified by actimetry), hypothermia, diarrhea and piloerection. At this dosage, the physical reaction is not lethal and reverses in all mice by 48 h post-injection. Severe but again reversible anatomopathological changes are also observed: massive cellular depletion, necrosis and edema of lymphoid organs, leakage syndrome and inflammatory cell infiltrates of the lung, cell vacuolization, necrosis and vascular congestion of the liver. All these data are similar to the clinical and immunological manifestations of the OKT3-induced reaction in patients and, thus, provide an invaluable experimental tool to study its mechanisms and explore its prevention.

Formation of an anisotropic energy gap in the valence-fluctuating system of CeNiSn.

Abstract: Measurements of susceptibility \ensuremath{\chi}, resistivity \ensuremath{\rho}, and thermoelectric power S have been performed on single-crystal CeNiSn. Only along the a axis of the orthorhombic structure do \ensuremath{\chi}(T) and \ensuremath{\rho}(T) exhibit pronounced peaks at 12 K, whereas no anomaly was found in the specific heat. The gap energies estimated from \ensuremath{\rho}(T) are 2.4, 5.5, and 5.0 K along the a, b, and c axes, respectively. Near 3 K, ${\mathit{S}}_{\mathit{a}}$(T) and ${\mathit{S}}_{\mathit{c}}$(T) exhibit extremely sharp peaks, which indicate the presence of a density of states within the gap. The magnetic contribution to the specific heat divided by temperature, ${\mathit{C}}_{\mathit{m}}$/T versus T reveals a maximum of 0.19 J/${\mathrm{K}}^{2}$ mol near 6.7 K. These results suggest that an antiferromagnetic correlation develops near 12 K, which induces the formation of the pseudogap in the narrow band of heavy quasiparticles.

abdA expression in Drosophila embryos.

Abstract: The abdominal A (abdA) gene is one of three transcription units in the Bithorax Complex of Drosophila encoding a homeo box protein; it is flanked by Ultrabithorax (Ubx) and Abdominal B (AbdB). The abdA gene is required for segmental identity of the second through eighth abdominal segments. The transcription unit of abdA is approximately 20 kb long and encodes a protein of 330 amino acids. The abdA homeo box is almost identical to the homeo box of Ubx but is quite different from the AbdB homeo box. A polyclonal antibody to abdA protein stains embryonic nuclei in segments A1-A7 (parasegments 7-13). The iab-2, 3, and 4 mutant classes define positive cis-regulatory elements that induce expression of abdA in segments A2-A4 (parasegments 7-9), respectively. Once a pattern of abdA expression is turned on in a given parasegment, it remains on in the more posterior parasegments, so that the complex pattern of expression is built up in the successive parasegments. The abdA product appears to repress expression of Ubx whenever they appear in the same cell, but abdA is repressed by AbdB only in the eighth and ninth abdominal segments.

Differentiating emotion elicited and deliberate emotional facial expressions

Abstract: Recent research suggests the potential importance of dynamic aspects (e.g. speed of onset and ofset and degree of irregularity) of facial movement for the encoding of spontaneous versus deliberate emotional facial expressions. The present studies were conducted to investigate whether emotion elicited and deliberate facial expressions of happiness and disgust difer regarding their dynamic features. Two experiments were designed to elicit spontaneous and deliberate facial expressions of happiness and disgust. The experiments difered regarding the deliberate facial expressions, which were either poses (Experiment I) or masking deceptions (Experiment 2). Experiment 2 confirmed Ekman and Friesen S (1982) notion, that spontaneous expressions have slower onsets and ofsets than do deliberate expressions. The data show that dynamic aspects of the facial expressions diferentiate between elicitation conditions. However, the evidence was more consistently found for the degree of irregularity of the expression than for the speed of onset and ofset.

Nomenclature for factors of the HLA system, 1989

Abstract: Since diarrhoea and weight loss are so characteristic of acquired immune deficiency syndrome (AIDS), it is per- haps ::,urprising that only recently has there been careful investigation of the gastrointestinal tract of affected patienLs. Human immunodeficiency virus (HIV) infection of human intesti- nal mononuclear cells (C. Fiocchi, Cleveland) and of intestinal epi- thelium (M.F. Kagnoff, San Diego) have been demonstrated and it is clear that the changes in the intestinal epithelium are subtly differ- ent from those of other infectious and inflammatory diseases of the gut (M. Zeitz0 Berlin; A.G. Cummins, Adela!de). This report has concentrated al- most entirely on the gastrointestinal tract since that is mv ,~wn interest, but paoers relevant to other mucosal surfaces including the eye, the nose, the genital tract, the urinary tract and respiratory system were abundant; two interesting papers demonstrated possible effects of cigarette smoking on mucosal immunology (G.F. Cope, Leeds; J.R. Barton, Edinburgh). J. Holmgren and A.M. Svennerhoim (Gothenburg) separately presented details of progress in the develop- ment and application oral vac- cines; the oral cholera vaccine containing cholera B sub-unit cross- reacts immunologically with E. coil heat labile enterotoxin (LT) and has been shown to afford significant pro- tection against diarrhoea caused by LT producing enterotoxigenic E. coil (ETEC) in humans. Anne Ferguson is at the Department of Medi- cine, Western General Hospital, Edinbu~h EH4 2XU, UK. The WHO Nomenclature Committee for Factors of the HLA System t met during the Seventh Intematin. nal Congress of Im- munology to consider additions to pre- vious reports. Here new data on DNA sequences of alleles and of three new loci are presented and names of new a/le!~s and led defined by nucleotide or inferred amino acid sequences are given.

Role of TNF and IL-1 in infections with Toxoplasma gondii.

Abstract: Mice lethally infected with the C56 strain of Toxoplasma gondii and treated with purified recombinant murine tumour necrosis factor (TNF, 1 microgram/day/mouse for 8 days), recombinant human interleukin-1 (IL-1 alpha or IL-1 beta, 100 ng/day/mouse for 5 days) or a single dose of a combination of TNF (1 microgram/mouse) and IL-1 alpha or IL-1 beta (100 ng/mouse) were significantly protected against death (P less than 0.05-0.001, as compared with untreated infected controls). Mice infected with 100,000 tachyzoites of the highly virulent RH strain of T. gondii released serum TNF in relation to the time after infection and were primed to secrete an enhanced level of serum TNF upon stimulation with bacterial lipopolysaccharide (LPS). In vitro studies showed that interferon-gamma (IFN-gamma) increased the antimicrobial activity of murine peritoneal macrophages whereas TNF, IL-1 alpha and IL-1 beta did not. TNF, however, synergized with the anti-toxoplasmic effect provided by IFN-gamma and this activity was blocked by anti-TNF antibodies. IFN-gamma induced the production of TNF and the anti-toxoplasmic effect provided by IFN-gamma seemed to be dependent partly on the production of TNF. We conclude that TNF and IL-1 may play a significant role in modulating the host's immune defence against T. gondii infection.

Editing of the Sendai virus P/C mRNA by G insertion occurs during mRNA synthesis via a virus-encoded activity.

Abstract: Two forms of the Sendai virus P/C mRNA have been predicted: one an exact copy of the viral genome, and the other with a single G insertion within a run of three G's. We directly cloned the mRNA or portions of it containing the insertion site and screened the resulting colonies with oligonucleotides that could distinguish the presence of three or four G's at this position. We found that 31% of the mRNAs did in fact contain the predicted insertion, whereas the viral genomes contained no heterogeneity at this position. A smaller fraction (7%) of the mRNA contained two to eight G's inserted at this position. The insertions also took place during RNA synthesis in vitro with purified virions but were not detected when the mRNA was expressed in vivo via a vaccinia virus recombinant. When the Sendai virus- and vaccinia virus-derived P/C mRNAs were coexpressed in the same cells under conditions in which each could be distinguished, those from the Sendai genome were altered as before, but those from the vaccinia virus genome remained unaltered. The activity that alters the mRNA is therefore likely to be coded for by the virus and cannot function in trans.