Biomedical subjects

Francesco Piazza

Publications and source records attributed to Francesco Piazza.

10 recordsLinked to original sources

PubMed2006

Glasslike structure of globular proteins and the boson peak.

Vibrational spectra of proteins and topologically disordered solids display a common anomaly at low frequencies, known as boson peak. We show that such feature in globular proteins can be deciphered in terms of an energy landscape picture, as it is for glassy systems. Exploiting the tools of Euclidean random matrix theory, we clarify the physical origin of such anomaly in terms of a mechanical instability of the system. As a natural explanation, we argue that such instability is relevant for proteins in order for their molecular functions to be optimally rooted in their structures.

Animals↗

PubMed2005

Inhibition of leukocyte elastase, polymorphonuclear chemoinvasion, and inflammation-triggered pulmonary fibrosis by a 4-alkyliden-beta-lactam with a galloyl moiety.

beta-Lactams, a well known class of antibiotics, have been investigated as inhibitors of the disruptive protease released by inflammatory cells, leukocyte elastase (LE). We have synthesized a new beta-lactam with an N-linked galloyl moiety, the latter identified as strategic in conferring anti-LE properties to some flavonols. This N-galloyl-derivative beta-lactam inhibits the LE activity with a K(i) of 0.7 microM, whereas it exerts weak activity against cathepsin G and protease-3 (IC(50) > 100 microM), and matrix metalloproteinase (MMP)-2 and MMP-9. Without affecting chemotactic response and viability of polymorphonuclear (PMN) leukocytes, the compound efficiently restrains their chemoinvasion (IC(50) of 1-2 microM) blocking the LE-triggered activation of pro-MMP-9, instrumental to extravasation. Daily i.p. injection of compound enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results indicate that the new beta-lactam is a potent anti-inflammatory compound with therapeutic potential.

Animals↗

PubMed2005

Functional dynamics of PDZ binding domains: a normal-mode analysis.

Postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domains are relatively small (80-120 residues) protein binding modules central in the organization of receptor clusters and in the association of cellular proteins. Their main function is to bind C-terminals of selected proteins that are recognized through specific amino acids in their carboxyl end. Binding is associated with a deformation of the PDZ native structure and is responsible for dynamical changes in regions not in direct contact with the target. We investigate how this deformation is related to the harmonic dynamics of the PDZ structure and show that one low-frequency collective normal mode, characterized by the concerted movements of different secondary structures, is involved in the binding process. Our results suggest that even minimal structural changes are responsible for communication between distant regions of the protein, in agreement with recent NMR experiments. Thus, PDZ domains are a very clear example of how collective normal modes are able to characterize the relation between function and dynamics of proteins, and to provide indications on the precursors of binding/unbinding events.

Adenosine Triphosphate↗

PubMed2005

The anti-FPU problem.

We present a detailed analysis of the modulational instability of the zone-boundary mode for one and higher-dimensional Fermi-Pasta-Ulam (FPU) lattices. Following this instability, a process of relaxation to equipartition takes place, which we have called the Anti-FPU problem because the energy is initially fed into the highest frequency part of the spectrum, at variance with the original FPU problem (low frequency excitations of the lattice). This process leads to the formation of chaotic breathers in both one and two dimensions. Finally, the system relaxes to energy equipartition on time scales which increase as the energy density is decreased. We show that breathers formed when cooling the lattice at the edges, starting from a random initial state, bear strong qualitative similarities with chaotic breathers.

Models, Statistical↗

PubMed2005

Cytokines, chemokines and other biomolecular markers in sarcoidosis.

In recent years our knowledge in terms of the network of interactions between immunocompetent cells that set the stage for the pathogenesis of sarcoidosis has continuously improved. Remarkable advances have been made in understanding general immunological and molecular aspects of the mechanisms leading to granuloma formation. In this manuscript we will review the current concepts on cellular interactions which define regulatory networks ultimately contributing to the granuloma formation at sites of disease activity in sarcoidosis. The biological effects of Th1 and Th2 cytokines in sarcoid lung will be taken into account and the importance of the local production of those chemokines and cytokines whose release has been recently demonstrated within the lung of patients with sarcoidosis will be emphasized.

Biomarkers↗

PubMed2004

Disruption of PLZP in mice leads to increased T-lymphocyte proliferation, cytokine production, and altered hematopoietic stem cell homeostasis.

Deregulated function of members of the POK (POZ and Kruppel) family of transcriptional repressors, such as promyelocytic leukemia zinc finger (PLZF) and B-cell lymphoma 6 (BCL-6), plays a critical role in the pathogenesis of acute promyelocytic leukemia (APL) and non-Hodgkin's lymphoma, respectively. PLZP, also known as TZFP, FAZF, or ROG, is a novel POK protein that displays strong homology with PLZF and has been implicated in the pathogenesis of the cancer-predisposing syndrome, Fanconi's anemia, and of APL, in view of its ability to heterodimerize with the FANC-C and PLZF proteins, respectively. Here we report the generation and characterization of mice in which we have specifically inactivated the PLZP gene through in-frame insertion of a lacZ reporter and without perturbing the expression of the neighboring MLL2 gene. We show that PLZP-deficient mice display defects in cell cycle control and cytokine production in the T-cell compartment. Importantly, PLZP inactivation perturbs the homeostasis of the hematopoietic stem and/or progenitor cell. On the basis of our data, a deregulation of PLZP function in Fanconi's anemia and APL may affect the biology of the hematopoietic stem cell, in turn contributing to the pathogenesis of these disorders.

Amino Acid Sequence↗

PubMed2004

Molecular therapeutic approaches to acute myeloid leukemia: targeting aberrant chromatin dynamics and signal transduction.

Acute myeloid leukemia research and clinical management have greatly benefited from the achievements in molecular biology regarding the identification of the underlying pathogenetic mechanisms of transformation and resistance to therapy. In particular, two categories of alterations, the aberrant activity of transcription/chromatin-remodeling factors and the deregulated activation of signal transduction pathways, have been demonstrated to play a pivotal role in leukemic cell differentiation, proliferation and resistance to apoptosis. These molecular lesions have proven to be suitable therapeutic targets in acute promyelocytic leukemia and chronic myeloid leukemia and are now also seen as therapeutic targets for a wider group of leukemic disorders. The development of novel drugs such as histone deacetylase inhibitors, demethylating agents and inhibitors of receptor tyrosine kinases may potentially benefit acute myeloid leukemia patients.

Acute Disease↗

PubMed2003

Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification.

Mutations in DKC1 cause dyskeratosis congenita (DC), a disease characterized by premature aging and increased tumor susceptibility. The DKC1 protein binds to the box H + ACA small nucleolar RNAs and the RNA component of telomerase. Here we show that hypomorphic Dkc1 mutant (Dkc1m) mice recapitulate in the first and second generations (G1 and G2) the clinical features of DC. Dkc1m cells from G1 and G2 mice were impaired in ribosomal RNA pseudouridylation before the onset of disease. Reductions of telomere length in Dkc1m mice became evident only in later generations. These results suggest that deregulated ribosome function is important in the initiation of DC, whereas telomere shortening may modify and/or exacerbate DC.

Anemia↗

PubMed2003

Cooling nonlinear lattices toward energy localization.

We describe the energy relaxation process produced by surface damping on lattices of classical anharmonic oscillators. Spontaneous emergence of localized vibrations dramatically slows down dissipation and gives rise to quasistationary states where energy is trapped in the form of a gas of weakly interacting discrete breathers. In one dimension, strong enough on-site coupling may yield stretched-exponential relaxation which is reminiscent of glassy dynamics. We illustrate the mechanism generating localized structures and discuss the crucial role of the boundary conditions. For two-dimensional lattices, the existence of a gap in the breather spectrum causes the localization process to become activated. A statistical analysis of the resulting quasistationary state through the distribution of breathers' energies yield information on their effective interactions.

Journal Article↗

PubMedDate not supplied

Using computer systems as microswitches for vocal utterances of persons with multiple disabilities.

We assessed the effects of two computer systems used as microswitches for the vocal utterances of an adolescent and a young adult with multiple disabilities. The systems were to respond to three one-syllable utterances of the first participant and nine word-like utterances of the second participant by presenting favorite stimuli linked to those utterances. The computer system used for the first participant relied on a software program developed specifically for this study. The computer system used for the second participant combined a new software program with a commercially available speech recognition program. Results showed that both participants increased the frequencies of their target utterances and obtained high levels of stimulation. Positive performance was maintained at post-intervention checks. Technical and practical implications of the data are discussed.

Abnormalities, Multiple↗