Control of asymmetric Hopfield networks and application to cancer attractors

The asymmetric Hopfield model is used to simulate signaling dynamics in gene/transcription factor networks. The model allows for a direct mapping of a gene expression pattern into attractor states. We analyze different control strategies aiming at disrupting attractor patterns using selective local fields representing therapeutic interventions. The control strategies are based on the identification of signaling $bottlenecks$, which are single nodes or strongly connected clusters of nodes that have a large impact on the signaling. We provide a theorem with bounds on the minimum number of nodes that guarantee controllability of bottlenecks consisting of strongly connected components. The control strategies are applied to the identification of sets of proteins that, when inhibited, selectively disrupt the signaling of cancer cells while preserving the signaling of normal cells. We use an experimentally validated non-specific network and a specific B cell interactome reconstructed from gene expression data to model cancer signaling in lung and B cells, respectively. This model could help in the rational design of novel robust therapeutic interventions based on our increasing knowledge of complex gene signaling networks

Ultra-cold Single-Atom Quantum Heat Engines

We propose a scheme for a single-atom quantum heat engine based on ultra-cold atom technologies. Building on the high degree of control typical of cold atom systems, we demonstrate that three paradigmatic heat engines -- Carnot, Otto and Diesel -- are within reach of state-of-the-art technology, and their performances can be benchmarked experimentally. We discuss the implementation of these engines using realistic parameters and considering the friction effects that limit the maximum obtainable performances in real-life experiments. We further consider the use of super-adiabatic transformations that allow to extract a finite amount of power keeping maximum (real) efficiency, and consider the energetic cost of running such protocols

Metabolomics of the Tumor Microenvironment in Pediatric Acute Lymphoblastic Leukemia

Stefano Tiziani, Yunyi Kang, Ricky Harjanto, Joshua Axelrod, Giovanni Paternostro, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of AmericaCarlo Piermarocchi, Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan, United States of AmericaWilliam Roberts, Rady Children’s Hospital, Department of Pediatrics, University of California San Diego, San Diego, California, United States of AmericaStefano Tiziani, Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, United States of AmericaThe tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p less than 0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p less than 9.2×10-10). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.This work was funded by the National Science Foundation (Grant No. 0829891). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Nutritional SciencesDell Pediatric Research InstituteEmail: [email protected] (GP), Email: [email protected] (ST

Biological control networks suggest the use of biomimetic sets for combinatorial therapies

Cells are regulated by networks of controllers having many targets, and targets affected by many controllers, but these "many-to-many" combinatorial control systems are poorly understood. Here we analyze distinct cellular networks (transcription factors, microRNAs, and protein kinases) and a drug-target network. Certain network properties seem universal across systems and species, suggesting the existence of common control strategies in biology. The number of controllers is ~8% of targets and the density of links is 2.5% \pm 1.2%. Links per node are predominantly exponentially distributed, implying conservation of the average, which we explain using a mathematical model of robustness in control networks. These findings suggest that optimal pharmacological strategies may benefit from a similar, many-to-many combinatorial structure, and molecular tools are available to test this approach.Comment: 33 page

Anatomy and anatomists in Tuscany in the 17th century

The 17th century was characterized by a real revolution in the field of scientific research due to the introduction of the experimental method, promoted by Galileo Galilei who was the most representative scientist of this period. Therefore, medical disciplines, particularly Anatomy, underwent innovative and deep changes shattering traditional culture and representing the background for the modern science. In this fermenting period, Tuscany played a significant role since numerous distinguished scientists were gathered by Medici Grand Dukes (especially Ferdinando the 2nd and Cosimo the 3rd) at Pisa University and at their court in Florence. Among them, it must be mentioned Giovanni Alfonso Borelli, creator of iathromechanics, Marcello Malpighi, founder of microscopic Anatomy, Francesco Redi, who denied the insect spontaneous generation, Nils Steensen who continued in Florence his anatomical studies on lymph nodes and salivary glands while setting also the bases of modern geology. Moreover, at the end of the 17th century, the anatomical wax modelling techniques arose and developed in Florence thanks to the work of Gaetano Zumbo (or Zummo), capable of creating some real masterpieces, still very well preserved and collected in the Museum of Natural Sciences “La Specola”

The anatomical representation of the human body: From epistemological examples deriving from medical history to morphometric imaging performed with the laser scanner technique

The anatomical illustration of the human body is a topic rich in epistemological elements in the course of medical history. Since ancient times concerns about the real correspondence of the scientific and/or artistic representation of human anatomy with the original one arose. First of all, a static two-dimensional representation, the one typical of drawings, was not able to get the depth and complexity of dynamic three-dimensional anatomical morphology. In addition, the epistemic issue that a post-mortem illustration could not somehow correspond to living structures was present even in the past. For a long time the anatomical representation of the human body has been attracting the interest of medical doctors, artists, scholars and philosophers as a fact-finding technique of dissection of corpses preparatory to curative surgical practice in the living body. With regard to that, in the Western world the sixteenth century is often seen as the golden age of normal and macroscopic human anatomy. Major steps in the evolution of the anatomical discipline are the switch from the “normal” to the “pathological” area during the seventeenth century and the transition from the macroscopic to the microscopic level in the eighteenth century; that is true also from an illustrative and iconographic point of view. The tradition of setting up three-dimensional models for the study of the human body dates back to the eighteenth century too. Today’s research techniques in the field of anatomical images are so advanced that they allow the full conformity of human representation, the continuous availability of preserved images, the complete multi-dimensionality of the rendering and the complete dynamism of the whole view. In this context, laser scanner could be the ideal tool to create a new Atlas of Human Anatomy composed of models which are rotatable, observable from every perspective, absolutely faithful to reality, analysable as in a real dissection and carefully measurable