Computational approaches to complex biological networks

The need of understanding and modeling the biological networks is one of the raisons d'\ueatre and of the driving forces behind the emergence of Systems Biology. Because of its holistic approach and because of the widely different level of complexity of the networks, different mathematical methods have been developed during the years. Some of these computational methods are used in this thesis in order to investigate various properties of different biological systems. The first part deals with the prediction of the perturbation of cellular metabolism induced by drugs. Using Flux Balance Analysis to describe the reconstructed genome-wide metabolic networks, we consider the problem of identifying the most selective drug synergisms for given therapeutic targets. The second part of this thesis considers gene regulatory and large social networks as signed graphs (activation/deactivation or friendship/hostility are rephrased as positive/negative coupling between spins). Using the analogy with an Ising spin glass an analysis of the energy landscape and of the content of \u201cdisorder\u201d 'is carried out. Finally, the last part concerns the study of the spatial heterogeneity of the signaling pathway of rod photoreceptors. The electrophysiological data produced by our collaborators in the Neurobiology laboratory have been analyzed with various dynamical systems giving an insight into the process of ageing of photoreceptors and into the role diffusion in the pathway

Cutting edge: differential chemokine production by myeloid and plasmacytoid dendritic cells.

Abstract To examine the different roles of myeloid dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) in the induction and regulation of immune response, we have studied chemokine secretion by freshly isolated DC subsets in response to bacterial, viral, and T cell-derived stimuli. M-DCs selectively produced very high levels of the homeostatic chemokines CC chemokine ligand (CCL)17 and CCL22, while P-DCs produced very little if any. In contrast, the proinflammatory chemokine CCL3 was secreted mostly by P-DCs, whereas CCL4 and CXC chemokine ligand 8 were produced by both subsets. The selective production of CCL17 and CCL22 by M-DCs but not P-DCs was confirmed in vivo by immunohistology on human reactive lymph node sections. The high production of CCR4 ligands by M-DCs suggests their capacity to selectively recruit at sites of inflammation T cells with regulatory properties or with a Th2 phenotype, whereas P-DCs, by preferentially secreting CCR1/CCR5 ligands, would mostly recruit effector T cells and, in particular, Th1-type cells

Common dynamical features of sensory adaptation in photoreceptors and olfactory sensory neurons

Sensory systems adapt, i.e., they adjust their sensitivity to external stimuli according to the ambient level. In this paper we show that single cell electrophysiological responses of vertebrate olfactory receptors and of photoreceptors to different input protocols exhibit several common features related to adaptation, and that these features can be used to investigate the dynamical structure of the feedback regulation responsible for the adaptation. In particular, we point out that two different forms of adaptation can be observed, in response to steps and to pairs of pulses. These two forms of adaptation appear to be in a dynamical trade-off: the more adaptation to a step is close to perfect, the slower is the recovery in adaptation to pulse pairs and viceversa. Neither of the two forms is explained by the dynamical models currently used to describe adaptation, such as the integral feedback model

PENGARUH CAMPURAN ABU AMPAS KAYU PADA TANAH DESA COT SEUNONG DENGAN PENGUJIAN CALIFORNIA BEARING RATIO

Tanah yang tersedia di alam sering tidak dapat langsung digunakan karena secara alamiah tanah memiliki sifat-sifat fisis dan mekanis tertentu yang terbatas. Oleh karena itu diperlukan penelitian tentang tanah untuk mengetahui sifat-sifatnya dengan teliti sehingga dapat menyesuaikan dengan kebutuhan konstruksi sehingga menjamin stabilitas suatu konstruksi. Penelitian ini bertujuan untuk mengetahui pengaruh penambahan abu ampas kayu yang digunakan sebagai bahan stabilisasi terhadap nilai CBR (California Bearing Ratio). Tanah yang digunakan dalam penelitian ini berasal dari Desa Cot Seunong Kecamatan Montasik Kabupaten Aceh Besar. Abu ampas kayu yang diperoleh diambil dari sisa-sisa limbah perabot pembuatan kayu yang berada di daerah Desa Kajhu Aceh Besar. Tanah tersebut menurut klasifikasi AASHTO tergolong A-7-6 (tanah berlempung). Menurut USCS tanah Desa Cot Seunong termasuk golongan tanah lempung tak organik dengan plastisitas tinggi yang disimbolkan CH (Clay High) dengan indeks plastisitasnya adalah 33,69%. Persentase penambahan abu ampas kayu yaitu 0%, 5%, 10%, 15% dan 20% terhadap berat kering tanah. Hasil pengujian Standart Proctor tanpa campuran didapat nilai OMC (Optimim Moisture Content) 23,60% dengan berat isi kering maksimum (?dmax) 1,595 gr/cm3. Hasil pengujian CBR memperlihatkan bahwa nilai CBR pada persentase 0% sebesar 1,67%, pada persentase 5% sebesar 2,45%, pada persentase 10% sebesar 2,62%, pada persentase 15% sebesar 2,73%, dan pada persentase 20% sebesar 3,03%. Nilai CBR tertinggi terdapat pada persentase 20% dengan nilai CBR 3,03%, dengan demikian penggunaan abu ampas kayu pada tanah lempung Desa Cot Seunong sangat efektif karena semakin banyak campuran abu ampas kayu yang mengisi pori-pori kosong pada tanah, sehingga tanah menjadi padat dan dapat meningkatkan daya dukung tanah menjadi lebih baik.Banda Ace

A rate-distortion theory for gene regulatory networks and its application to logic gate consistency

ABSTRACT Motivation: A gene regulatory network in which the modes (activation/ inhibition) of the transcriptional regulations are known and in which gene expression assumes boolean values can be treated as a system of linear equations over a binary field, i.e. as a constraint satisfaction problem for an information code. Results: For currently available gene networks, we show in this article that the distortion associated with the corresponding information code is much lower than expected from null models, and that it is close to (when not lower than) the Shannon bound determined by the ratedistortion theorem. This corresponds to saying that the distribution of regulatory modes is highly atypical in the networks, and that this atypicality greatly helps in avoiding contradictory transcriptional actions. Choosing a boolean formalism to represent the gene networks, we also show how to formulate criteria for the selection of gates that maximize the compatibility with the empirical information available on the transcriptional regulatory modes. Proceeding in this way, we obtain in particular that non-canalizing gates are upper-bounded by the distortion, and hence that the boolean gene networks are more canalizing than expected from null models

Impact of blood glucose variability on carotid artery intima media thickness and distensibility in type 1 diabetes mellitus

Aims. Diabetes mellitus is characterized by structural and functional alterations of the large- and medium-size arteries. Whether blood glucose variability, i.e. the glycemic oscillations occurring during the 24-h period, represents a risk factor for vascular alterations additional to and independent on HbA1c in type 1 diabetes mellitus is still undefined. The present study was carried out with the aim at investigating the impact of different measures of blood glucose variability on arterial structure and function. We studied 17 non-complicated type 1 diabetic patients (11 males, six females) with an age of 40.8 ± 7.6 years (mean ± SD). In each patient, 24-h glucose profile was obtained by continuous glucose monitoring system and glucose variability was expressed as mean ± SD of 24-h blood glucose levels, mean amplitude of glycemic excursions and postprandial hyperglycemic spikes. Arterial structure and function was measured as carotid IMT and stiffness. Major findings. The different approaches to assessing blood glucose variability well correlated between and with HbA1c. Carotid IMT and stiffness showed significant correlations with age, blood pressure, heart rate and daily insulin intake but a non- significant correlation with blood glucose variability. Principal conclusion. Thus, in type 1 diabetes mellitus, measures of glycemic variability are useful in predicting both actual and long-lasting glycemic control. In absence of diabetes-related complications and of any intima-media thickness alterations, the major predictors of arterial distensibility are represented by traditional risk factors beside glycemic 24-h control. © 2013 Scandinavian Foundation for Cardiovascular Researc

Partial inhibition and bilevel optimization in flux balance analysis

Motivation: Within Flux Balance Analysis, the investigation of complex subtasks, such as finding the optimal perturbation of the network or finding an optimal combination of drugs, often requires to set up a bilevel optimization problem. In order to keep the linearity and convexity of these nested optimization problems, an ON/OFF description of the effect of the perturbation (i.e. Boolean variable) is normally used. This restriction may not be realistic when one wants, for instance, to describe the partial inhibition of a reaction induced by a drug.Results: In this paper we present a formulation of the bilevel optimization which overcomes the oversimplified ON/OFF modeling while preserving the linear nature of the problem. A case study is considered: the search of the best multi-drug treatment which modulates an objective reaction and has the minimal perturbation on the whole network. The drug inhibition is described and modulated through a convex combination of a fixed number of Boolean variables. The results obtained from the application of the algorithm to the core metabolism of E.coli highlight the possibility of finding a broader spectrum of drug combinations compared to a simple ON/OFF modeling.Conclusions: The method we have presented is capable of treating partial inhibition inside a bilevel optimization, without loosing the linearity property, and with reasonable computational performances also on large metabolic networks. The more fine-graded representation of the perturbation allows to enlarge the repertoire of synergistic combination of drugs for tasks such as selective perturbation of cellular metabolism. This may encourage the use of the approach also for other cases in which a more realistic modeling is required. \ua9 2013 Facchetti and Altafini; licensee BioMed Central Ltd

Management of the corpse with suspect, probable or confirmed COVID-19 respiratory infection \u2013 Italian interim recommendations for personnel potentially exposed to material from corpses, including body fluids, in morgue structures and during autopsy practice.

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