Folding and cytoplasm viscoelasticity contribute jointly to chromosome dynamics

The chromosome is a key player of cell physiology, and its dynamics provides valuable information about its physical organization. In both prokaryotes and eukaryotes, the short-time motion of chromosomal loci has been described as a Rouse model in a simple or viscoelastic medium. However, little emphasis has been put on the role played by the folded organization of chromosomes on the local dynamics. Clearly, stress-propagation, and thus dynamics, must be affected by such organization, but a theory allowing to extract such information from data, e.g.\ of two-point correlations, is lacking. Here, we describe a theoretical framework able to answer this general polymer dynamics question, and we provide a general scaling analysis of the stress-propagation time between two loci at a given arclength distance along the chromosomal coordinate. The results suggest a precise way to detect folding information from the dynamical coupling of chromosome segments. Additionally, we realize this framework in a specific theoretical model of a polymer with variable-range interactions in a viscoelastic medium characterized by a tunable scaling exponent, where we derive analytical estimates of the correlation functions.Comment: 14 pages including supplementary material

Hydrodynamic induced deformation and orientation of a microscopic elastic filament

We describe simulations of a microscopic elastic filament immersed in a fluid and subject to a uniform external force. Our method accounts for the hydrodynamic coupling between the flow generated by the filament and the friction force it experiences. While models that neglect this coupling predict a drift in a straight configuration, our findings are very different. Notably, a force with a component perpendicular to the filament axis induces bending and perpendicular alignment. Moreover, with increasing force we observe four shape regimes, ranging from slight distortion to a state of tumbling motion that lacks a steady state. We also identify the appearance of marginally stable structures. Both the instability of these shapes and the observed alignment can be explained by the combined action of induced bending and non-local hydrodynamic interactions. Most of these effects should be experimentally relevant for stiff micro-filaments, such as microtubules.Comment: three figures. To appear in Phys Rev Let

Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumors. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in G1 supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies

Physical descriptions of the bacterial nucleoid at large scales, and their biological implications.

Recent experimental and theoretical approaches have attempted to quantify the physical organization (compaction and geometry) of the bacterial chromosome with its complement of proteins (the nucleoid). The genomic DNA exists in a complex and dynamic protein-rich state, which is highly organized at various length scales. This has implications for modulating (when not directly enabling) the core biological processes of replication, transcription and segregation. We overview the progress in this area, driven in the last few years by new scientific ideas and new interdisciplinary experimental techniques, ranging from high space- and time-resolution microscopy to high-throughput genomics employing sequencing to map different aspects of the nucleoid-related interactome. The aim of this review is to present the wide spectrum of experimental and theoretical findings coherently, from a physics viewpoint. In particular, we highlight the role that statistical and soft condensed matter physics play in describing this system of fundamental biological importance, specifically reviewing classic and more modern tools from the theory of polymers. We also discuss some attempts toward unifying interpretations of the current results, pointing to possible directions for future investigation

Statistical Mechanics of the Chinese Restaurant Process: lack of self-averaging, anomalous finite-size effects and condensation

The Pitman-Yor, or Chinese Restaurant Process, is a stochastic process that generates distributions following a power-law with exponents lower than two, as found in a numerous physical, biological, technological and social systems. We discuss its rich behavior with the tools and viewpoint of statistical mechanics. We show that this process invariably gives rise to a condensation, i.e. a distribution dominated by a finite number of classes. We also evaluate thoroughly the finite-size effects, finding that the lack of stationary state and self-averaging of the process creates realization-dependent cutoffs and behavior of the distributions with no equivalent in other statistical mechanical models.Comment: (5pages, 1 figure

External validation of the Surgical Outcome Risk Tool (SORT) in 3305 abdominal surgery patients in the independent sector in the UK

BACKGROUND: Assessing the risk of post-surgical mortality is a key component of pre-surgical planning. The Surgical Outcome Risk Tool (SORT) uses pre-operative variables to predict 30-day mortality. The aim of this study was to externally validate SORT in patients undergoing major abdominal surgery. METHODS: Data were collected from patients treated in five independent hospitals in the UK. Individualised SORT scores were calculated, and area under the receiver operating characteristic (AUROC) and precision-recall curves (PRC) plus 95% confidence intervals (CI) were drawn to test the ability of SORT to identify in-hospital death. Outcomes of patients with a SORT predicted risk of mortality of ≥ 5% (high risk) were compared to those with a predicted risk of < 5% (standard risk). RESULTS: The study population comprised 3305 patients, mean age 51 years, 2783 (84.2%) underwent elective surgery most frequently involving the colon (24.6%), or liver, pancreas or gallbladder (18.2%). Overall, 1551 (46.9%) patients were admitted to ICU and 29 (0.88%) died. The AUROC of SORT for discriminating patients at risk of death in hospital was 0.899 (95% CI 0.849 to 0.949) and the PRC 0.247. In total, 72 (2.18%) patients were stratified as high risk. There were more unplanned ICU admissions and deaths in this group compared to the standard risk group (25.0% and 3.3%, versus 3.1% and 0.5%, respectively). CONCLUSION: We externally validated SORT in a large population of abdominal surgery patients. SORT performed well in patients with lower risk profiles, but underpredicted adverse outcomes in the higher risk group

X-48B Flight Test Progress Overview

The results of a series of 39 flight tests of the X-48B Low Speed Vehicle (LSV) performed at the NASA Dryden Flight Research Center from July 2007 through December 2008 are reported here. The goal of these tests is to evaluate the aerodynamic and controls and dynamics performance of the subscale LSV aircraft, eventually leading to the development of a control system for a full-scale vehicle. The X-48B LSV is an 8.5%-scale aircraft of a potential, full-scale Blended Wing Body (BWB) type aircraft and is flown remotely from a ground control station using a computerized flight control system located onboard the aircraft. The flight tests were the first two phases of a planned three-phase research program aimed at ascertaining the flying characteristics of this type of aircraft. The two test phases reported here are: 1) envelope expansion, during which the basic flying characteristics of the airplane were examined, and 2) parameter identification, stalls, and engine-out testing, during which further information on the aircraft performance was obtained and the airplane was tested to the limits of controlled flight. The third phase, departure limiter assaults, has yet to be performed. Flight tests in two different wing leading edge configurations (slats extended and slats retracted) as well as three weight and three center of gravity positions were conducted during each phase. Data gathered in the test program included measured airplane performance parameters such as speed, acceleration, and control surface deflections along with qualitative flying evaluations obtained from pilot and crew observations. Flight tests performed to-date indicate the aircraft exhibits good handling qualities and performance, consistent with pre-flight simulations