Posttranslational modifications of the retinoblastoma tumor suppressor protein as determinants of function

The retinoblastoma tumor suppressor protein (pRB) plays an integral role in G1-S checkpoint control and consequently is a frequent target for inactivation in cancer. The RB protein can function as an adaptor, nucleating components such as E2Fs and chromatin regulating enzymes into the same complex. For this reason, pRB\u27s regulation by posttranslational modifications is thought to be critical. pRB is phosphorylated by a number of different kinases such as cyclin dependent kinases (Cdks), p38 MAP kinase, Chk1/2, Abl, and Aurora b. Although phosphorylation of pRB by Cdks has been extensively studied, activities regulated through phosphorylation by other kinases are just starting to be understood. As well as being phosphorylated, pRB is acetylated, methylated, ubiquitylated, and SUMOylated. Acetylation, methylation, and SUMOylation play roles in pRB mediated gene silencing. Ubiquitinylation of pRB promotes its degradation and may be used to regulate apoptosis. Recent proteomic data have revealed that pRB is posttranslationally modified to a much greater extent than previously thought. This new information suggests that many unknown pathways affect pRB regulation. This review focuses on posttranslational modifications of pRB and how they influence its function. The final part of the review summarizes new phosphorylation sites from accumulated proteomic data and discusses the possibilities that might arise from this data. © The Author(s) 2013

A computational investigation of seasonally forced disease dynamics

In recent years there has been a great increase in work on epidemiological modelling, driven partly by the increase in the availability and power of computers, but also by the desire to improve standards of public and animal health. Through modelling, understanding of the mechanisms of previous epidemics can be gained, and the lessons learnt applied to make predictions about future epidemics, or emerging diseases. The standard SIR model is in some sense quite a simplistic model, and can lack realism. One solution to this problem is to increase the complexity of the model, or to perform full scale simulation—an experiment in silico. This thesis, however, takes a different approach and makes an in depth analysis of one small improvement to the model: the replacement of a constant birth rate with a birth pulse. This more accurately describes the seasonal birth patterns observed in many animal populations. The combination of the nonlinearities of the SIR model and the strong seasonal forcing provided by the birth pulse necessitate the use of numerical methods. The model shows complex multi annual cycles of epidemics and even chaos for shorter infectious periods. The robustness of these results are proven with respect to a wide range or perturbations: in phase space, in the shape and temporal extent of the birth pulse and in the underlying model to which the pulsing is applied. To complement the numerics, analytic methods are used to gain further understanding of the dynamics in particular areas of the chosen parameter space where the numerics can be challenging. Three approximations are presented, one to investigate very small levels of forcing, and two covering short infectious periods

A computational investigation of seasonally forced disease dynamics

In recent years there has been a great increase in work on epidemiological modelling, driven partly by the increase in the availability and power of computers, but also by the desire to improve standards of public and animal health. Through modelling, understanding of the mechanisms of previous epidemics can be gained, and the lessons learnt applied to make predictions about future epidemics, or emerging diseases. The standard SIR model is in some sense quite a simplistic model, and can lack realism. One solution to this problem is to increase the complexity of the model, or to perform full scale simulation—an experiment in silico. This thesis, however, takes a different approach and makes an in depth analysis of one small improvement to the model: the replacement of a constant birth rate with a birth pulse. This more accurately describes the seasonal birth patterns observed in many animal populations. The combination of the nonlinearities of the SIR model and the strong seasonal forcing provided by the birth pulse necessitate the use of numerical methods. The model shows complex multi annual cycles of epidemics and even chaos for shorter infectious periods. The robustness of these results are proven with respect to a wide range or perturbations: in phase space, in the shape and temporal extent of the birth pulse and in the underlying model to which the pulsing is applied. To complement the numerics, analytic methods are used to gain further understanding of the dynamics in particular areas of the chosen parameter space where the numerics can be challenging. Three approximations are presented, one to investigate very small levels of forcing, and two covering short infectious periods.EThOS - Electronic Theses Online ServiceEngineering and Physical Sciences Research Council (EPSRC)GBUnited Kingdo

Phosphorylation of the RB C-terminus regulates condensin II release from chromatin

The retinoblastoma tumor suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate and render RB inactive in late G1/S, promoting entry into S phase. Recently, monophosphorylated RB species were described to have distinct cell-cycle-independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output. We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK and RB S838/ T841 phosphorylation. This signaling pathway disrupts RB and condensin II interaction with chromatin. Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin

Falling Incapacity Benefit claims in a former industrial city: policy impacts or labour market improvement?

This article provides an in-depth study of Incapacity Benefit (IB) claims in a major city and of the factors behind their changing level. It relates to the regime prior to the introduction of the Employment and Support Allowance (ESA) in 2008. Glasgow has had one of the highest levels of IB in Britain with a peak of almost one fifth of the working age population on IB or Severe Disablement Allowance (SDA). However, over the past decade the number of IB claimants in Glasgow, as in other high claiming areas, has fallen at a faster rate than elsewhere, and Glasgow now has twice the national proportion of working-age people on IB/SDA rather than its peak of three times. The rise in IB in Glasgow can be attributed primarily to deindustrialisation; between 1971 and 1991, over 100,000 manufacturing jobs were lost in the city. Policy response was belated. Lack of local statistics on IB led to a lengthy delay in official recognition of the scale of the issue, and targeted programmes to divert or return IB claimants to work did not begin on any scale until around 2004. Evidence presented in the article suggests that the reduction in claims, which has mainly occurred since about 2003, has been due more to a strengthening labour market than to national policy changes or local programmes. This gives strong support to the view that excess IB claims are a form of disguised unemployment. Further detailed evaluation of ongoing programmes is required to develop the evidence base for this complex area. However, the study casts some doubt on the need for the post-2006 round of IB reforms in high-claim areas, since rapid decline in the number of claimants was already occurring in these areas. The article also indicates the importance of close joint working between national and local agencies, and further development of local level statistics on IB claimants

Weight Vectors of the Basic A_1^(1)-Module and the Littlewood-Richardson Rule

The basic representation of \A is studied. The weight vectors are represented in terms of Schur functions. A suitable base of any weight space is given. Littlewood-Richardson rule appears in the linear relations among weight vectors.Comment: February 1995, 7pages, Using AMS-Te

Strong stability preserving explicit Runge-Kutta methods of maximal effective order

We apply the concept of effective order to strong stability preserving (SSP) explicit Runge-Kutta methods. Relative to classical Runge-Kutta methods, methods with an effective order of accuracy are designed to satisfy a relaxed set of order conditions, but yield higher order accuracy when composed with special starting and stopping methods. We show that this allows the construction of four-stage SSP methods with effective order four (such methods cannot have classical order four). However, we also prove that effective order five methods - like classical order five methods - require the use of non-positive weights and so cannot be SSP. By numerical optimization, we construct explicit SSP Runge-Kutta methods up to effective order four and establish the optimality of many of them. Numerical experiments demonstrate the validity of these methods in practice.Comment: 17 pages, 3 figures, 8 table

Distribution of selenium in zebrafish larvae after exposure to organic and inorganic selenium forms

Selenium is an essential micronutrient for many organisms, and in vertebrates has a variety of roles associated with protection from reactive oxygen species. Over the past two decades there have been conflicting reports upon human health benefits and detriments arising from consumption of selenium dietary supplements. Thus, early studies report a decrease in the incidence of certain types of cancer, whereas subsequent studies did not observe any anti-cancer effect, and adverse effects such as increased risks for type 2 diabetes have been reported. A possible contributing factor may be that different chemical forms of selenium were used in different studies. Using larval stage zebrafish (Danio rerio) as a model organism, we report a comparison of the toxicities and tissue selenium distributions of four different chemical forms of selenium. We find that the organic forms of selenium tested (Se-methyl-l-selenocysteine and l-selenomethionine) show considerably more toxicity than inorganic forms (selenite and selenate), and that this appears to be correlated with the level of bioaccumulation. Despite differences in concentrations, the tissue specific pattern of selenium accumulation was similar for the chemical forms tested; selenium was found to be highly concentrated in pigment (melanin) containing tissues especially for the organic selenium treatments, with lower concentrations in eye lens, yolk sac and heart. These results suggest that pigmented tissues might serve as a storage reservoir for selenium. © 2016 The Royal Society of Chemistry

Information Symmetries in Irreversible Processes

We study dynamical reversibility in stationary stochastic processes from an information theoretic perspective. Extending earlier work on the reversibility of Markov chains, we focus on finitary processes with arbitrarily long conditional correlations. In particular, we examine stationary processes represented or generated by edge-emitting, finite-state hidden Markov models. Surprisingly, we find pervasive temporal asymmetries in the statistics of such stationary processes with the consequence that the computational resources necessary to generate a process in the forward and reverse temporal directions are generally not the same. In fact, an exhaustive survey indicates that most stationary processes are irreversible. We study the ensuing relations between model topology in different representations, the process's statistical properties, and its reversibility in detail. A process's temporal asymmetry is efficiently captured using two canonical unifilar representations of the generating model, the forward-time and reverse-time epsilon-machines. We analyze example irreversible processes whose epsilon-machine presentations change size under time reversal, including one which has a finite number of recurrent causal states in one direction, but an infinite number in the opposite. From the forward-time and reverse-time epsilon-machines, we are able to construct a symmetrized, but nonunifilar, generator of a process---the bidirectional machine. Using the bidirectional machine, we show how to directly calculate a process's fundamental information properties, many of which are otherwise only poorly approximated via process samples. The tools we introduce and the insights we offer provide a better understanding of the many facets of reversibility and irreversibility in stochastic processes.Comment: 32 pages, 17 figures, 2 tables; http://csc.ucdavis.edu/~cmg/compmech/pubs/pratisp2.ht

Analytic Markovian Rates for Generalized Protein Structure Evolution

A general understanding of the complex phenomenon of protein evolution requires the accurate description of the constraints that define the sub-space of proteins with mutations that do not appreciably reduce the fitness of the organism. Such constraints can have multiple origins, in this work we present a model for constrained evolutionary trajectories represented by a Markovian process throughout a set of protein-like structures artificially constructed to be topological intermediates between the structure of two natural occurring proteins. The number and type of intermediate steps defines how constrained the total evolutionary process is. By using a coarse-grained representation for the protein structures, we derive an analytic formulation of the transition rates between each of the intermediate structures. The results indicate that compact structures with a high number of hydrogen bonds are more probable and have a higher likelihood to arise during evolution. Knowledge of the transition rates allows for the study of complex evolutionary pathways represented by trajectories through a set of intermediate structures