Driven lattice gases: models for intracellular transport

Intracellular transport phenomena, such as kinesins and myosins moving along cytoskeletal filaments or ribosomes along messenger RNA, can be modeled by one-dimensional driven lattice gases. Among these, the Totally Asymmetric Simple Exclusion Process (TASEP), has been extensively used. It describes a system of particles hopping in a preferred direction with hard core interaction. The goal of this thesis is to explore the relevance of some features that are missed by this simple model, such as the exchange of particles between molecular track and the cytoplasm, the extended molecular structure of each motor, and the interaction of motors with imperfections on the track acting as road blocks for intracellular traffic. Recent studies have taken into account particle exchange between the track and bulk solution (Langmuir kinetics). It was found that this violation of current conservation along the track leads to phase coexistence regions in the phase diagram not present in the TASEP. We have extended these studies in two ways. First, motivated by the fact that many molecular motors are dimers, we study how the stationary properties of the system (density profile and phase behavior) change upon replacing monomers with extended particles. Analytical refined and generalized mean field theory, supported by numerical Monte Carlo simulations, give a detailed description of the phase diagram. Our study proves that the extension gives quantitative but not qualitative changes in the phase diagram, showing that the picture obtained in the case of monomers is robust upon considering extended particles. Second, motivated by the presence of structural imperfections of the track that act as road blocks, we study the influence of an isolated defect characterized by a reduced hopping rate on the non-equilibrium steady state. We explore the phase behavior in the full parameter range and find that the phase diagram changes qualitatively as compared to the case without defects, showing new phase coexistence regions. In particular above a certain threshold strength of the defect, its presence induces a macroscopic change in the density profile. The regions where the defect is relevant (called bottleneck phases) are identified and studied. In the second part of the thesis we investigate the dynamical features of these models. First we concentrate on the dynamics of the simple TASEP, for which a complete analysis was missing. We use a technique borrowed from solid state physics, the Boltzmann-Langevin method, to give a full description of the correlation function in the whole parameter space. Finally we study the dynamics of a tracer particle in a TASEP with on-off kinetics. We observe that it is possible to reconstruct the density profile from the velocity of the tracer particle and we propose to perform single molecule experiments with fluorescently labelled molecular motors to explore the density profile and ultimately test the phase behavior predicted in this thesis

Tell Barri / Kahat. La campagna del 2003

In the undulating plains of north-eastern Syria is the site of Tell Barri, identified with the city of Kahat. The archaeological sequence which has been brought to light stretches without interruption from the start of the third millennium up to the fourteenth century AD. This report illustrates the results of the twentieth excavation campaign, carried out by the group from the University of Florence and from the "Federico II" University of Naples. In Area G, the excavation of the chapel dating to the third millennium proceeded along with that of the palace of the Mid Assyrian King Adadnirari I; three coeval tombs were discovered, two with lavish furnishings. In Area J, the exploration of the Assyrian palace of Tukulti-Ninurta II was continued. As regards the Parthian phase, investigation has proceeded on the Great Defensive Wall in Area E and of the residential section in Area H. The text, prepared for printing in July 2005, was published following the tragic death of Paolo Emilio Pecorella, which took place on 29 August in Tell Barri in the course of the excavation campaign

Tell Barri / Kahat. La campagna del 2004

In the undulating plains of north-eastern Syria is the site of Tell Barri, identified with the city of Kahat. The archaeological sequence which has been brought to light stretches without interruption from the start of the third millennium up to the fourteenth century AD. This report illustrates the results of the twentieth excavation campaign, carried out by the group from the University of Florence and from the "Federico II" University of Naples. In Area G the levels of the first half of the III millennium BC and a sequence of strata of the Mitanni epoch were investigated, while on the western border of the site another section of the palace of Adad-nirari I was brought to light. In Area J the operations exposed the eastward extension of the palace structure resulting from transformations in the Neo-Babylonian period; in the northern section another courtyard of the palace of Tukulti Ninurta II was brought to light. The text, prepared for printing in July 2005, was published following the tragic death of Paolo Emilio Pecorella, which took place on 29 August in Tell Barri in the course of the excavation campaign

Dynamic correlation functions and Boltzmann Langevin approach for driven one dimensional lattice gas

We study the dynamics of the totally asymmetric exclusion process with open boundaries by phenomenological theories complemented by extensive Monte-Carlo simulations. Upon combining domain wall theory with a kinetic approach known as Boltzmann-Langevin theory we are able to give a complete qualitative picture of the dynamics in the low and high density regime and at the corresponding phase boundary. At the coexistence line between high and low density phases we observe a time scale separation between local density fluctuations and collective domain wall motion, which are well accounted for by the Boltzmann-Langevin and domain wall theory, respectively. We present Monte-Carlo data for the correlation functions and power spectra in the full parameter range of the model.Comment: 10 pages, 9 figure

Bottleneck-induced transitions in a minimal model for intracellular transport

We consider the influence of disorder on the non-equilibrium steady state of a minimal model for intracellular transport. In this model particles move unidirectionally according to the \emph{totally asymmetric exclusion process} (TASEP) and are coupled to a bulk reservoir by \emph{Langmuir kinetics}. Our discussion focuses on localized point defects acting as a bottleneck for the particle transport. Combining analytic methods and numerical simulations, we identify a rich phase behavior as a function of the defect strength. Our analytical approach relies on an effective mean-field theory obtained by splitting the lattice into two subsystems, which are effectively connected exploiting the local current conservation. Introducing the key concept of a carrying capacity, the maximal current which can flow through the bulk of the system (including the defect), we discriminate between the cases where the defect is irrelevant and those where it acts as a bottleneck and induces various novel phases (called {\it bottleneck phases}). Contrary to the simple TASEP in the presence of inhomogeneities, many scenarios emerge and translate into rich underlying phase-diagrams, the topological properties of which are discussed.Comment: 14 pages, 15 figures, 1 tabl

Role of axillary sentinel lymph node biopsy in patients with pure ductal carcinoma in situ of the breast

BACKGROUND: Sentinel lymph node (SLN) biopsy is an effective tool for axillary staging in patients with invasive breast cancer. This procedure has been recently proposed as part of the treatment for patients with ductal carcinoma in situ (DCIS), because cases of undetected invasive foci and nodal metastases occasionally occur. However, the indications for SLN biopsy in DCIS patients are controversial. The aim of the present study was therefore to assess the incidence of SLN metastases in a series of patients with a diagnosis of pure DCIS. METHODS: A retrospective evaluation was made of a series of 102 patients who underwent SLN biopsy, and had a final histologic diagnosis of pure DCIS. Patients with microinvasion were excluded from the analysis. The patients were operated on in five Institutions between 1999 and 2004. Subdermal or subareolar injection of 30–50 MBq of 99 m-Tc colloidal albumin was used for SLN identification. All sentinel nodes were evaluated with serial sectioning, haematoxylin and eosin staining, and immunohistochemical analysis for cytocheratin. RESULTS: Only one patient (0.98%) was SLN positive. The primary tumour was a small micropapillary intermediate-grade DCIS and the SLN harboured a micrometastasis. At pathologic revision of the specimen, no detectable focus of microinvasion was found. CONCLUSION: Our findings indicate that SLN metastases in pure DCIS are a very rare occurrence. SLN biopsy should not therefore be routinely performed in patients who undergo resection for DCIS. SLN mapping can be performed, as a second operation, in cases in which an invasive component is identified in the specimen. Only DCIS patients who require a mastectomy should have SLN biopsy performed at the time of breast operation, since in these cases subsequent node mapping is not feasible

EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription

Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. Here we show that under mechanical stress, the EHD2 ATPase is rapidly released from caveolae, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents. We also found that EHD2 is required to maintain the caveolae reservoir at the plasma membrane during the variations of membrane tension induced by mechanical stress. Metal-replica electron microscopy of breast cancer cells lacking EHD2 revealed a complete absence of caveolae and a lack of gene regulation under mechanical stress. Expressing EHD2 was sufficient to restore both functions in these cells. Our findings therefore define EHD2 as a central player in mechanotransduction connecting the disassembly of the caveolae reservoir with the regulation of gene transcription under mechanical stress

Cdc42 controls the dilation of the exocytotic fusion pore by regulating membrane tension.

Membrane fusion underlies multiple processes, including exocytosis of hormones and neurotransmitters. Membrane fusion starts with the formation of a narrow fusion pore. Radial expansion of this pore completes the process and allows fast release of secretory compounds, but this step remains poorly understood. Here we show that inhibiting the expression of the small GTPase Cdc42 or preventing its activation with a dominant negative Cdc42 construct in human neuroendocrine cells impaired the release process by compromising fusion pore enlargement. Consequently the mode of vesicle exocytosis was shifted from full-collapse fusion to kiss-and-run. Remarkably, Cdc42-knockdown cells showed reduced membrane tension, and the artificial increase of membrane tension restored fusion pore enlargement. Moreover, inhibiting the motor protein myosin II by blebbistatin decreased membrane tension, as well as fusion pore dilation. We conclude that membrane tension is the driving force for fusion pore dilation and that Cdc42 is a key regulator of this force.journal articleresearch support, non-u.s. gov't2014 Oct 152014 08 20importe