Showing papers by "University of Florence published in 1994"

Learning long-term dependencies with gradient descent is difficult

Abstract: Recurrent neural networks can be used to map input sequences to output sequences, such as for recognition, production or prediction problems. However, practical difficulties have been reported in training recurrent neural networks to perform tasks in which the temporal contingencies present in the input/output sequences span long intervals. We show why gradient based learning algorithms face an increasingly difficult problem as the duration of the dependencies to be captured increases. These results expose a trade-off between efficient learning by gradient descent and latching on information for long periods. Based on an understanding of this problem, alternatives to standard gradient descent are considered. >

Lymphokine Production by Human T Cells in Disease States

Abstract: A large body of evidence suggests the existence of polarized human T cell responses, reminiscent of Th1 and Th2 subsets described for mouse T cells. Human Th1-like cells preferentially develop during infections by intracellular bacteria, protozoa, and viruses, whereas Th2-like cells predominate during helminthic infestations and in response to common environmental allergens. The cytokine profile of "natural immunity" evoked by different offending agents in the context of different host genetic backgrounds appears to be a critical factor in determining the phenotype of the subsequent specific response. Strongly polarized human Th1-type and Th2-type responses not only play different roles in protection, they can also promote different immunopathological reactions. Th1-type responses appear to be involved in organ specific autoimmunity, in contact dermatitis, and in some chronic inflammatory disorders of unknown etiology. In contrast, in genetically predisposed hosts, Th2-type responses against common environmental allergens are responsible for triggering of allergic atopic disorders. Altered profiles of lymphokine production may account for immune dysfunctions in some primary or acquired immunodeficiency syndromes. The role of lymphokines produced by T cells in the pathogenesis of systemic autoimmune disorders is less clear. Further work is also required to better clarify the role of T cell-derived lymphokines in protecting against tumors or in favoring their development.

Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P.

Abstract: We evaluated the effects of nitric oxide (NO) generators and endogenous production of NO elicited by substance P (SP) in the angiogenesis process. Angiogenesis was monitored in the rabbit cornea in vivo and in vitro by measuring the growth and migration of endothelial cells isolated from coronary postcapillary venules. The angiogenesis promoted in the rabbit cornea by [Sar9]-SP-sulfone, a stable and selective agonist for the tachykinin NK1 receptor, and by prostaglandin E1 (PGE1), was potentiated by sodium nitroprusside (SNP). Conversely, the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), given systemically, inhibited angiogenesis elicited by [Sar9]-SP-sulfone and by PGE1. Endothelial cells exposed to SNP exhibited an increase in thymidine incorporation and in total cell number. Exposure of the cells to NO generating drugs, such as SNP, isosorbide dinitrate, and glyceryl trinitrate, produced a dose-dependent increase in endothelial cell migration. Capillary endothelial cell proliferation and migration produced by SP were abolished by pretreatment with the NO synthase inhibitors N omega-mono-methyl-L-arginine (L-NMMA), N omega-nitro-L-arginine (L-NNA), and L-NAME. Exposure of the cells to SP activated the calcium-dependent NO synthase. Angiogenesis and endothelial cell growth and migration induced by basic fibroblast growth factor were not affected by NO synthase inhibitors. These data indicate that NO production induced by vasoactive agents, such as SP, functions as an autocrine regulator of the microvascular events necessary for neovascularization and mediates angiogenesis.

Large clusters of metal ions: The transition from molecular to bulk magnets

Abstract: Clusters of metal ions are a class of compounds actively investigated for their magnetic properties, which should gradually change from those of simple paramagnets to those of bulk magnets. However, their interest lies in a number of different disciplines: chemistry, which seeks new synthetic strategies to make larger and larger clusters in a controlled manner; physics, which can test the validity of quantum mechanical approaches at the nanometer scale; and biology, which can use them as models of biomineralization of magnetic particles.

Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells

Abstract: IT has been suggested that mutations within immunodominant cytotoxic T-lymphocyte (CTL) epitopes may be exploited by viruses to evade protective immune responses critical for clearance1–4. Viral escape could originate from passive mechanisms, such as mutations within crucial CTL epitopes, either affecting major histocompatibility complex binding or T-cell antigen receptor (TCR) recognition. Additionally, it has recently been shown that substitutions of TCR contact sites can yield analogue peptides that can still interact with the T-cell receptor but be unable to deliver a full stimulatory signal, thus inducing anergy5 or acting as an antagonist for the TCR6–8. We report here that hepatitis B virus isolates derived from two chronically infected patients display variant epitopes that act as natural TCR antagonists with the capacity to inhibit the CTL response to the wild-type epitope. During natural infection, TCR antagonist mutations of CTL epitopes could contribute to the development of viral persistence, especially if the antiviral CTL response is monospecific or the epitope is strongly immunodominant.

Patellar tendon versus doubled semitendinosus and gracilis tendons for anterior cruciate ligament reconstruction

Abstract: The results of intraarticular anterior cruciate ligament reconstruction with either the patellar tendon or the semitendinosus and gracilis tendons (four strands) were prospectively compared in a consecutive series of 60 patients with chronic injuries. A single surgeon performed arthroscopically assisted reconstructions in an alternating sequence. Preoperative and operative data revealed no significant differences between the two groups. After 28 months of followup there were no significant differences in the incidence of symptoms, and recurrent giving way was present in only one knee with semitendinosus and gracilis tendon graft. Return to sport participation was more frequent in the patellar tendon group (80% versus 43%, P 5 mm at 30 pounds was present in 13% of the knees with patellar tendon grafts and in 20% of those with semitendinosus and gracilis; a patellofemoral crepitation developed in 17% and 3% of the two groups, respectively. Based on these data we routinely use patellar tendon grafts. Semitendinosus and gracilis tendons are preferred in selected cases: older patients, patients with preexisting patellofemoral problems, and those with failed patellar tendon grafts.

Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells

Abstract: Both interferon gamma (IFN-gamma) produced by T helper 1 (TH1) lymphocytes and interleukin-4 (IL-4) produced by TH2 lymphocytes were reduced in either bulk circulating mononuclear cells or mitogen-induced CD4+ T cell clones from the peripheral blood of individuals infected with human immunodeficiency virus (HIV). There was a preferential reduction in clones producing IL-4 and IL-5 in the advanced phases of infection. However, enhanced proportions of CD4+ T cell clones producing both TH1-type and TH2-type cytokines (TH0 clones) were generated from either skin-infiltrating T cells that had been activated in vivo or peripheral blood T cells stimulated by antigen in vitro when cells were isolated from HIV-infected individuals. All TH2 and most TH0 clones supported viral replication, although viral replication was not detected in any of the TH1 clones infected in vitro with HIV. These results suggest that HIV (i) does not induce a definite TH1 to TH2 switch, but can favor a shift to the TH0 phenotype in response to recall antigens, and (ii) preferentially replicates in CD4+ T cells producing TH2-type cytokines (TH2 and TH0).

Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

Abstract: Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

Hepatitis C virus infection in patients with non-Hodgkin's lymphoma.

Abstract: Hepatitis C virus (HCV), which is both a hepatotropic and a lymphotropic virus, has been proposed as a possible causative agent of mixed cryoglobulinaemia. This 'benign' lymphoproliferative disorder can switch over to a malignant B-cell non-Hodgkin's lymphoma (NHL). Therefore HCV infection has been investigated in a series of 50 unselected Italian patients with B-cell NHL. Antibodies against HCV were found in 30% of NHL and HCV viraemia in 32% of cases. HCV-related markers were detected in 34% (17/50) of our NHL patients; this prevalence is particularly significant when compared with HCV seropositivity in Hodgkin's lymphoma (3%) and healthy controls (1.3%).

An Input Output HMM Architecture

Abstract: We introduce a recurrent architecture having a modular structure and we formulate a training procedure based on the EM algorithm. The resulting model has similarities to hidden Markov models, but supports recurrent networks processing style and allows to exploit the supervised learning paradigm while using maximum likelihood estimation.

Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection.

Abstract: We analyzed at clonal level the functional profile of circulating or skin-infiltrating T lymphocytes from two individuals infected with the human immunodeficiency virus type 1 (HIV-1), suffering from a Job's-like syndrome (eczematous dermatitis, recurrent skin and sinopulmonary infections, and hypergammaglobulinemia E) and showing virtually no circulating CD4+ T cells. Most of the CD3+ T cell clones generated from both patients were CD4- CD8+ TCR alpha beta +. The others were CD4- CD8- TCR alpha beta + which exhibited reduced mRNA expression for the CD8 molecule or no mRNA expression for either CD4 or CD8 molecules. The great majority of both CD4- CD8+ and CD4- CD8- did not produce interferon (IFN) gamma and exhibited reduced cytolytic activity. Rather, most of them produced large amounts of both interleukin (IL) 4 and IL-5 and provided B cell helper function for IgE synthesis. These data suggest that a switch of cytolytic CD8+ T cells showing a Th1-like cytokine secretion profile to cells that make Th2-type cytokines, exhibit reduced cytolytic potential, and provide B cell helper function can occur in the course of HIV-1 infection. These cells may contribute to the reduced defense against viral infections and intracellular parasites and account for the elevated IgE serum levels, eosinophilia, and the allergic-like clinical manifestations seen in a proportion of HIV-1-infected individuals.

Optimal, Predictive and Adaptive Control

Abstract: 1. Introduction. I. BASIC DETERMINISTIC THEORY OF LQ AND PREDICTIVE CONTROL. 2. Deterministic LQ Regulation - I: Riccati-Based Solution. 3. I/O Descriptions and Feedback Systems. 4. Deterministic LQ Regulation - II: Solution via Polynomial Equations. 5. Deterministic Receding Horizon Control. II. STATE ESTIMATION, SYSTEM IDENTIFICATION, LQ AND PREDICTIVE STOCHASTIC CONTROL. 6. Recursive State Filtering and System Identification. 7. LQ and Predictive Stochastic Control. III. ADAPTIVE CONTROL. 8. Single-Step-Ahead Self-Tuning Control. 9. Adaptive Predictive Control. APPENDICES. A. Some Results from Linear Systems Theory. B. Some Results of Polynomial Matrix Theory. C. Some Results on Linear Diophantine Equations. D. Probability Theory and Stochastic Processes. References. Some Often Used Abbreviations. Index.

Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver.

Abstract: Altered degradation of extracellular matrix has been implicated in the pathogenesis of hepatic fibrosis. We investigated levels and cellular sites of gene expression of two major collagen-degrading enzymes, matrix-metalloproteinase (MMP)-1 (fibroblast type-interstitial collagenase) and MMP-2 (72-kd gelatinase, type IV collagenase) in five normal and 18 fibrotic human livers as well as in cultured human hepatic fat-storing cells by Northern blot analysis and in situ hybridization. Fat-storing cells expressed both MMP-1 and MMP-2 RNA in vitro. In vivo, MMP-1 was undetectable in mesenchymal and parenchymal cells of all liver specimens, whereas MMP-2 transcripts were expressed in all livers by vimentin-positive, CD68-negative mesenchymal cells. Mesenchymal cells of all fibrotic livers displayed high transcript levels of transforming growth factor-beta 1, which is known to modulate MMP expression. Along with de novo fibrogenesis and possibly influenced by transforming growth factor-beta 1, expression of MMP-2 in the absence of MMP-1 expression may be responsible for the quantitative and qualitative changes of extracellular matrix observed in chronic liver disease.

Genome renewal: A new phenomenon revealed from a genetic study of 43 strains of Saccharomyces cerevisiae derived from natural fermentation of grape musts

Abstract: We have analyzed by genetic means 43 strains of Saccharomyces that had been isolated from fermenting grape musts in Italy. Twenty eight of these strains were isolated from 28 cellars in the Region of Emilia Romagna. The other 15 strains came from 5 fermentations at four cellars near the city of Arpino, which is located south and east of Rome. We found that 20 of the 28 strains from Emilia Romagna were heterozygous at from one to seven loci. The balance were, within the limits of our detection, completely homozygous. All these strains appeared to be diploid and most were homozygous for the homothallism gene (HO/HO). Spore viability varied greatly between the different strains and showed an inverse relation with the degree of heterozygosity. Several of the strains, and in particular those from Arpino, yielded asci that came from genetically different cells. These different cells could be interpreted to have arisen from a heterozygote that had sporulated and, because of the HO gene, yielded homozygous diploid spore clones. We propose that natural wine yeast strains can undergo such changes and thereby change a multiple heterozygote into completely homozygous diploids, some of which may replace the original heterozygous diploid. We call this process ‘genome renewal’.

Cooperation and competition in the industrial district as an organization model

Abstract: Starting from the theory of the industrial district, this paper concentrates on the interplay between competition and cooperation characteristic of the industrial district as an organization model. After recalling the wide vertical and horizontal division of labour between firms in the district, it is shown how cooperation based on local custom and investments in personal reputation allows for the coordination of a large part of complementary activities carried out by local independent firms. Subsequently, we see how competition between firms and agents specialized in similar activities drives them towards allocative efficiency and innovation. Finally, the paper focuses on the reciprocal balance between cooperation and competition which is necessary for stability over time in the industrial district.

Necessary and sufficient condition for absolute stability of neural networks

Abstract: The main result in this paper is that for a neural circuit of the Hopfield type with a symmetric connection matrix T, the negative semidefiniteness of T is a necessary and sufficient condition for Absolute Stability. The most significant theoretical implication is that the class of neural circuits with a negative semidefinite T is the largest class of circuits that can be employed for embedding and solving optimization problems without the risk of spurious responses. >

The L3 silicon microvertex detector

Abstract: The design and construction of the silicon strip microvertex detector (SMD) of the L3 experiment at LEP are described. We present the sensors, readout electronics, data acquisition system, mechanical assembly and support, displacement monitoring systems and radiation monitoring system of the recently installed double-sided, double-layered SMD. This detector utilizes novel and sophisticated techniques for its readout.

The crystal structure of a low-molecular-weight phosphotyrosine protein phosphatase

Abstract: PROTEIN tyrosine phosphorylation and dephosphorylation are central reactions for control of cellular division, differentiation and development1. Here we describe the crystal structure of a low-molecular-weight phosphotyrosine protein phosphatase (PTPase)2, a cytosolic phosphatase present in many mammalian cells. The enzyme catalyses the dephosphorylation of phosphotyrosine-containing substrates3–6, and overexpression of the protein in normal and transformed cells inhibits cell proliferation7,8. The structure of the low-molecular-weight PTPase reveals an α/β protein containing a phosphate-binding loop motif at the amino end of helix αl. This motif includes the essential active-site residues Cys 12 and Arg 18 and bears striking similarities to the active-site motif recently described in the structure of human PTP1B9. The structure of the low-molecular-weight PTPase supports a reaction mechanism involving the conserved Cys 12 as an attacking nucleophile in an in-line associative mechanism. The structure also suggests a catalytic role for Asp 129 in the reaction cycle.

Relationships between biochemical markers for residual sperm cytoplasm, reactive oxygen species generation, and the presence of leukocytes and precursor germ cells in human sperm suspensions.

Abstract: In this study, we have examined the relationship between creatine phosphokinase (CPK), a biochemical measure of human sperm quality (Huszar et al., 1988a,b, 1990; Huszar and Vigue, 1994), and a marker for the presence of residual cytoplasm in human spermatozoa, glucose-6-phosphate dehydrogenase (G6PDH). We then determined whether the diagnostic potential of these enzymes was related to the capacity of the sperm suspensions to generate reactive oxygen species (ROS) and/or the presence of leukocytes and precursor germ cells. Across the data set as a whole, G6PDH and CPK were highly correlated with each other and, to a lesser extent, with the generation of ROS. Contamination of the sperm suspensions with leukocytes might have contributed to these associations, since the presence of such cells was also significantly correlated with CPK, G6PDH, and ROS. However, even after the leukocytes had been carefully removed, G6PDH was still highly correlated with CPK (r = 0.794), indicating that both criteria were providing similar information of the cytosolic component of human sperm suspensions. In the absence of leukocyte contamination, CPK and G6PDH activities were also correlated with the presence of precursor germ cells, and this association may, in part, explain the diagnostic value of these criteria. An additional component of their prognostic value may be reflected in the statistically significant association observed between G6PDH activity and ROS generation. A possible mechanism for such an association is suggested, which should be amenable to experimental verification.

Magnetic Relaxation in Big Magnetic Molecules

Abstract: The relaxation time of the magnetization of a big magnetic molecule is evaluated. Isotropic exchange is assumed to be dominant, resulting in a fixed spin modulus s (equal to 20 in the case of interest). A perturbation of the form ASz2 results from spin-orbit coupling and produces an energy barrier As2 which separates positive and negative values of Sz. Spin-phonon interactions are treated by second-order perturbation theory. An upper limit of the pre-exponential factor in the Arrhenius law is obtained, which is consistent with the very large experimental value.

Hyaluronic acid in cutaneous intrinsic aging

Abstract: Background. In elderly individuals all components of the skin and subcutaneous tissue undergo histologic and ultra-structural changes. The turgidity of the dermis appears decreased, presumably due to altered patterns and levels of glycosaminoglycans (GAGS), especially hyaluronic acid and dermatan sulfate that are the most common. A linear, age-related decrease in the content of GAGS (mainly hyaluronic acid) has been hypothesized in human aged skin. Methods. We used the cationic dye Alcian Blue to selectively stain hyaluronic acid within the dermis in old and young subjects to compare ultrastructurally its topography and variations with age. Results. We demonstrated a progressive reduction in the number of electron-dense granules of hyaluronic acid and of their filaments until they were completely absent in subjects aged 60. Conclusions. We propose that the variations of the levels of hyaluronic acid in the dermis in aging could account for some of the most striking alterations of the aged skin, including decreased turgidity, less support for microvessles, wrinkling, and altered elasticity.