Tumour angiogenesis: The gap between theory and experiment

A common experimental technique for viewing in vivo angiogenesis utilises tumours implanted into a test animal cornea. The cornea is avascular but the tumour promotes vascularisation from the limbus and the new blood vessels can be readily observed through the transparent cornea. Many of the early mathematical models for tumour angiogenesis used this scenario as their experimental template and as such assumed that there is a large gap, of the order of 2 mm, between the tumour and neighbouring vasculature at the onset of angiogenesis. In this work we consider whether the assumption that there is a significant gap between the tumour and neighbouring vasculature is unique to intra-cornea tumour implants, or whether this characterises avascular tumour growth more generally. To do this we utilise a simple scaling argument, derive a multi-compartment model for tumour growth, and consider in vivo images. This analysis demonstrates that the corneal implant experiments and the corresponding mathematical models cannot generally be applied to a clinical setting

Analysis of the Dynamics of Liquid Aluminium: Recurrent Relation Approach

By use of the recurrent relation approach (RRA) we study the microscopic dynamics of liquid aluminium at T=973 K and develop a theoretical model which satisfies all the corresponding sum rules. The investigation covers the inelastic features as well as the crossover of our theory into the hydrodynamical and the free-particle regimes. A comparison between our theoretical results with those following from a generalized hydrodynamical approach is also presented. In addition to this we report the results of our molecular dynamics simulations for liquid aluminium, which are also discussed and compared to experimental data. The received results reveal that (i) the microscopical dynamics of density fluctuations is defined mainly by the first four even frequency moments of the dynamic structure factor, and (ii) the inherent relation of the high-frequency collective excitations observed in experimental spectra of dynamic structure factor $S(k,\omega)$ with the two-, three- and four-particle correlations.Comment: 11 pages, 4 figure

Coleridge, Sara

An encylopaedia article on the life and writings of Sara Coleridge (1802-1852), for an online work of reference and scholarshi

The surface accessibility of the glycine receptor M2-M3 loop is increased in the channel open state

Mutations in the extracellular M2-M3 loop of the glycine receptor (GlyR) alpha1 subunit have been shown previously to affect channel gating. In this study, the substituted cysteine accessibility method was used to investigate whether a structural rearrangement of the M2-M3 loop accompanies GlyR activation. All residues from R271C to V277C were covalently modified by both positively charged methanethiosulfonate ethyltrimethylammonium (MTSET) and negatively charged methanethiosulfonate ethylsulfonate (MTSES), implying that these residues form an irregular surface loop. The MTSET modification rate of all residues from R271C to K276C was faster in the glycine-bound state than in the unliganded state. MTSES modification of A272C, L274C, and V277C was also faster in the glycine-bound state. These results demonstrate that the surface accessibility of the M2-M3 loop is increased as the channel transitions from the closed to the open state, implying that either the loop itself or an overlying domain moves during channel activation

Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

Germline mutations in the von Hippel–Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma(RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-a subunits (and hence expression of the HIF-a transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (nZ82) and inherited RCC (nZ64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC

Quantum free energy differences from non-equilibrium path integrals: I. Methods and numerical application

The imaginary-time path integral representation of the canonical partition function of a quantum system and non-equilibrium work fluctuation relations are combined to yield methods for computing free energy differences in quantum systems using non-equilibrium processes. The path integral representation is isomorphic to the configurational partition function of a classical field theory, to which a natural but fictitious Hamiltonian dynamics is associated. It is shown that if this system is prepared in an equilibrium state, after which a control parameter in the fictitious Hamiltonian is changed in a finite time, then formally the Jarzynski non-equilibrium work relation and the Crooks fluctuation relation are shown to hold, where work is defined as the change in the energy as given by the fictitious Hamiltonian. Since the energy diverges for the classical field theory in canonical equilibrium, two regularization methods are introduced which limit the number of degrees of freedom to be finite. The numerical applicability of the methods is demonstrated for a quartic double-well potential with varying asymmetry. A general parameter-free smoothing procedure for the work distribution functions is useful in this context.Comment: 20 pages, 4 figures. Added clarifying remarks and fixed typo

Multi-nutrient, multi-group model of present and future oceanic phytoplankton communities

International audiencePhytoplankton community composition profoundly affects patterns of nutrient cycling and the dynamics of marine food webs; therefore predicting present and future phytoplankton community structure is crucial to understand how ocean ecosystems respond to physical forcing and nutrient limitations. We develop a mechanistic model of phytoplankton communities that includes multiple taxonomic groups (diatoms, coccolithophores and prasinophytes), nutrients (nitrate, ammonium, phosphate, silicate and iron), light, and a generalist zooplankton grazer. Each taxonomic group was parameterized based on an extensive literature survey. We test the model at two contrasting sites in the modern ocean, the North Atlantic (North Atlantic Bloom Experiment, NABE) and subarctic North Pacific (ocean station Papa, OSP). The model successfully predicts general patterns of community composition and succession at both sites: In the North Atlantic, the model predicts a spring diatom bloom, followed by coccolithophore and prasinophyte blooms later in the season. In the North Pacific, the model reproduces the low chlorophyll community dominated by prasinophytes and coccolithophores, with low total biomass variability and high nutrient concentrations throughout the year. Sensitivity analysis revealed that the identity of the most sensitive parameters and the range of acceptable parameters differed between the two sites. We then use the model to predict community reorganization under different global change scenarios: a later onset and extended duration of stratification, with shallower mixed layer depths due to increased greenhouse gas concentrations; increase in deep water nitrogen; decrease in deep water phosphorus and increase or decrease in iron concentration. To estimate uncertainty in our predictions, we used a Monte Carlo sampling of the parameter space where future scenarios were run using parameter combinations that produced acceptable modern day outcomes and the robustness of the predictions was determined. Change in the onset and duration of stratification altered the timing and the magnitude of the spring diatom bloom in the North Atlantic and increased total phytoplankton and zooplankton biomass in the North Pacific. Changes in nutrient concentrations in some cases changed dominance patterns of major groups, as well as total chlorophyll and zooplankton biomass. Based on these scenarios, our model suggests that global environmental change will inevitably alter phytoplankton community structure and potentially impact global biogeochemical cycles

Differences in experiences of care between patients diagnosed with metastatic cancer of known and unknown primaries: mixed-method findings from the 2013 cancer patient experience survey in England.

OBJECTIVES: To explore differences in experiences of care reported in the Cancer Patient Experience Survey (CPES) between patients with cancer of unknown primary (CUP) and those with metastatic disease of known primary (non-CUP); to determine insights pertaining to the experiences of care for CUP respondents from free-text comments. DESIGN: Two separate, but related, studies, involving secondary analysis of existing data. Using frequency matching of CUP and non-CUP patients, statistical comparisons of responses to CPES questions were conducted. Free-text comments from CUP respondents were analysed thematically. SETTING AND PARTICIPANTS: The CPES questionnaire comprises 63 closed questions measuring 8 areas that relate to experience of care and 3 free-text questions. Questionnaires were mailed to all adult patients (aged ≥16 years) in England with cancer admitted to hospital between 1 September 2013 and 30 November 2013. RESULTS: Matched analysis of closed response items from 2992 patients found significant differences between CUP (n=1496) and non-CUP patients (n=1496): CUP patients were more likely to want more written information about their type of cancer and tests received, to receive their diagnosis from a general practitioner (GP) and have seen allied health professionals, but less likely to have understood explanations of their condition or had surgery. Freetext responses (n=3055) were coded into 17 categories and provided deeper insight regarding patient information and interactions with GPs. CPES data may include a preponderance of patients with favourable CUP subtypes and patients initially identified as CUP but whose primary was subsequently identified. CONCLUSIONS: These are the first large-scale studies to explore the experiences of care of CUP patients. The significant differences identified between the experiences of CUP and non-CUP patients suggest CUP patients require more psychosocial support and specific interventions to manage diagnostic uncertainty and the multiple investigations many CUP patients face. Substantial limitations were identified with the CPES data, emphasising the need for prospective studies

Mode-coupling theory for multiple-time correlation functions of tagged particle densities and dynamical filters designed for glassy systems

The theoretical framework for higher-order correlation functions involving multiple times and multiple points in a classical, many-body system developed by Van Zon and Schofield [Phys. Rev. E 65, 011106 (2002)] is extended here to include tagged particle densities. Such densities have found an intriguing application as proposed measures of dynamical heterogeneities in structural glasses. The theoretical formalism is based upon projection operator techniques which are used to isolate the slow time evolution of dynamical variables by expanding the slowly-evolving component of arbitrary variables in an infinite basis composed of the products of slow variables of the system. The resulting formally exact mode-coupling expressions for multiple-point and multiple-time correlation functions are made tractable by applying the so-called N-ordering method. This theory is used to derive for moderate densities the leading mode coupling expressions for indicators of relaxation type and domain relaxation, which use dynamical filters that lead to multiple-time correlations of a tagged particle density. The mode coupling expressions for higher order correlation functions are also succesfully tested against simulations of a hard sphere fluid at relatively low density.Comment: 15 pages, 2 figure

OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation

2-Oxoglutarate (2OG) and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1) is predicted to be a conserved 2OG oxygenase, the catalytic domain of which is related to hypoxia-inducible factor prolyl hydroxylases. OGFOD1 homologs in yeast are implicated in diverse cellular functions ranging from oxygen-dependent regulation of sterol response genes (Ofd1, Schizosaccharomyces pombe) to translation termination/mRNA polyadenylation (Tpa1p, Saccharomyces cerevisiae). However, neither the biochemical activity of OGFOD1 nor the identity of its substrate has been defined. Here we show that OGFOD1 is a prolyl hydroxylase that catalyzes the posttranslational hydroxylation of a highly conserved residue (Pro-62) in the small ribosomal protein S23 (RPS23). Unusually OGFOD1 retained a high affinity for, and forms a stable complex with, the hydroxylated RPS23 substrate. Knockdown or inactivation of OGFOD1 caused a cell type-dependent induction of stress granules, translational arrest, and growth impairment in a manner complemented by wild-type but not inactive OGFOD1. The work identifies a human prolyl hydroxylase with a role in translational regulation