Regulation of autoimmunity and donor cell engraftment by recipient Lyt-2+ cells during the graft-versus-host reaction.

When lymphocytes from DBA/2 mice are transferred to (C57BL X DBA/2)F1 (BDF1) mice, the ensuing graft-vs.-host reaction (GVHR) causes an autoimmune illness resembling human SLE. To examine the role of recipient T cells in this process, BDF1 mice were depleted of L3T4+ or Lyt-2+ cells by thymectomy followed by treatment with mAbs to L3T4 or Lyt-2. This produced sustained depletion of these T cell subsets. Subsequent grafting with parental DBA/2 lymphocytes produced autoimmune disease in mice depleted of L3T4+ cells and controls but not in mice depleted of Lyt-2+ cells. Analysis of blood lymphocytes 4 wk after donor cell transfer demonstrated that BDF1 recipients depleted of Lyt-2+ cells were virtually repopulated with donor T lymphocytes, compared with less than or equal to 35% donor cell engraftment in all other groups. Thus, recipient Lyt-2+ cells influence both host cell engraftment and autoimmunity during the parent-into-F1 GVHR

Environmental stress alters genetic regulation of novelty seeking in vervet monkeys.

Considerable attention has been paid to identifying genetic influences and gene-environment interactions that increase vulnerability to environmental stressors, with promising but inconsistent results. A nonhuman primate model is presented here that allows assessment of genetic influences in response to a stressful life event for a behavioural trait with relevance for psychopathology. Genetic and environmental influences on free-choice novelty seeking behaviour were assessed in a pedigreed colony of vervet monkeys before and after relocation from a low stress to a higher stress environment. Heritability of novelty seeking scores, and genetic correlations within and between environments were conducted using variance components analysis. The results showed that novelty seeking was markedly inhibited in the higher stress environment, with effects persisting across a 2-year period for adults but not for juveniles. There were significant genetic contributions to novelty seeking scores in each year (h(2) = 0.35-0.43), with high genetic correlations within each environment (rhoG > 0.80) and a lower genetic correlation (rhoG = 0.35, non-significant) between environments. There were also significant genetic contributions to individual change scores from before to after the move (h(2) = 0.48). These results indicate that genetic regulation of novelty seeking was modified by the level of environmental stress, and they support a role for gene-environment interactions in a behavioural trait with relevance for mental health

Why did the pheasant cross the road? Long-term road mortality patterns in relation to management changes.

This is the final version of the article. Available from Royal Society via the DOI in this record.Pheasants (Phasianus colchicus) are commonly killed on UK roads, presenting a threat to motorists and a loss to the game shooting industry. Pheasants may be inherently susceptible, or the recent increase in their artificial rearing and release may have exacerbated the situation, either through population increases or because artificial rearing has altered movement behaviour. We compared intra-annual patterns of roadkill reported in the UK from the 1960s (prior to the onset of mass release programmes) with that from the 2010s (when pheasant release was well established and widespread), considering roadkill sex and locations and accounting for changes in traffic levels. Pheasants in the UK are disproportionately likely to be reported killed on roads. However, this likelihood has not changed notably over the past 50 years. Instead, the timing of roadkill has changed. Pheasants in the 2010s are no longer susceptible during their breeding season, unlike in the 1960s, perhaps because relatively few breed successfully. Instead, roadkill first peaks in September-November as pheasants disperse from release pens, females first. Roadkill declines over winter, but when supplementary feeding ceases in February, we see a second peak in roadkill. Roadkill rates are higher in regions of the UK where there is little arable farming and hence natural food supplies are scarce.J.R.M. was funded by an ERC grant no. 616474

Lung function, symptoms and inflammation during exacerbations of non-cystic fibrosis bronchiectasis: a prospective observational cohort study.

Exacerbations of non-cystic fibrosis bronchiectasis cause significant morbidity but there are few detailed data on their clinical course and associated physiological changes. The biology of an exacerbation has not been previously described

Prevalence of Illicit Use and Abuse of Prescription Stimulants, Alcohol, and Other Drugs Among College Students: Relationship with Age at Initiation of Prescription Stimulants

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90112/1/phco.27.5.666.pd

Material parameter estimation and hypothesis testing on a 1D viscoelastic stenosis model: Methodology

This is the post-print version of the final published paper that is available from the link below. Copyright @ 2013 Walter de Gruyter GmbH.Non-invasive detection, localization and characterization of an arterial stenosis (a blockage or partial blockage in the artery) continues to be an important problem in medicine. Partial blockage stenoses are known to generate disturbances in blood flow which generate shear waves in the chest cavity. We examine a one-dimensional viscoelastic model that incorporates Kelvin–Voigt damping and internal variables, and develop a proof-of-concept methodology using simulated data. We first develop an estimation procedure for the material parameters. We use this procedure to determine confidence intervals for the estimated parameters, which indicates the efficacy of finding parameter estimates in practice. Confidence intervals are computed using asymptotic error theory as well as bootstrapping. We then develop a model comparison test to be used in determining if a particular data set came from a low input amplitude or a high input amplitude; this we anticipate will aid in determining when stenosis is present. These two thrusts together will serve as the methodological basis for our continuing analysis using experimental data currently being collected.National Institute of Allergy and Infectious Diseases, Air Force Office of Scientific Research, Department of Education, and Engineering and Physical Sciences Research Council

Disentangling the roles of aneuploidy, chromosomal instability and tumour heterogeneity in developing resistance to cancer therapies.

Aneuploidy is defined as the cellular state of having a number of chromosomes that deviates from a multiple of the normal haploid chromosome number of a given organism. Aneuploidy can be present in a static state: Down syndrome individuals stably maintain an extra copy of chromosome 21 in their cells. In cancer cells, however, aneuploidy is usually present in combination with chromosomal instability (CIN) which leads to a continual generation of new chromosomal alterations and the development of intratumour heterogeneity (ITH). The prevalence of cells with specific chromosomal alterations is further shaped by evolutionary selection, for example, during the administration of cancer therapies. Aneuploidy, CIN and ITH have each been individually associated with poor prognosis in cancer, and a wealth of evidence suggests they contribute, either alone or in combination, to cancer therapy resistance by providing a reservoir of potential resistant states, or the ability to rapidly evolve resistance. A full understanding of the contribution and interplay between aneuploidy, CIN and ITH is required to tackle therapy resistance in cancer patients. However, these characteristics often co-occur and are intrinsically linked, presenting a major challenge to defining their individual contributions. Moreover, their accurate measurement in both experimental and clinical settings is a technical hurdle. Here, we attempt to deconstruct the contribution of the individual and combined roles of aneuploidy, CIN and ITH to therapy resistance in cancer, and outline emerging approaches to measure and disentangle their roles as a step towards integrating these principles into cancer therapeutic strategy

High-order space-time finite element schemes for acoustic and viscodynamic wave equations with temporal decoupling

Copyright @ 2014 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.We revisit a method originally introduced by Werder et al. (in Comput. Methods Appl. Mech. Engrg., 190:6685–6708, 2001) for temporally discontinuous Galerkin FEMs applied to a parabolic partial differential equation. In that approach, block systems arise because of the coupling of the spatial systems through inner products of the temporal basis functions. If the spatial finite element space is of dimension D and polynomials of degree r are used in time, the block system has dimension (r + 1)D and is usually regarded as being too large when r > 1. Werder et al. found that the space-time coupling matrices are diagonalizable over inline image for r ⩽100, and this means that the time-coupled computations within a time step can actually be decoupled. By using either continuous Galerkin or spectral element methods in space, we apply this DG-in-time methodology, for the first time, to second-order wave equations including elastodynamics with and without Kelvin–Voigt and Maxwell–Zener viscoelasticity. An example set of numerical results is given to demonstrate the favourable effect on error and computational work of the moderately high-order (up to degree 7) temporal and spatio-temporal approximations, and we also touch on an application of this method to an ambitious problem related to the diagnosis of coronary artery disease

Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors

Active normal faults and coupled landscape response: bedrock variability in the southern Gulf of Corinth, central Greece

Fluvial erosion processes control landscape response to climatic and tectonic signals and its propagation into sedimentary basins. Considerable effort has gone into quantifying and modelling the effect of changes in uplift rates on fluvial erosion in bedrock rivers. However, current landscape models, based on stream power, tend to ignore the effects bedrock variability. The lack of available data relating rock strength to bedrock erodibility in fluvial settings has limited our ability to explore this question. Recent attempts at modelling to resolve this issue rely on indirect or theoretical rock strength properties. An alternative approach requires field measurements of rock strength together with geomorphological and tectonic constraints to quantify the effect of rock strength on river evolution. The Gulf of Corinth, central Greece, is one of the fastest extending rifts in the world and tectonic boundary conditions are well constrained. We (1) review published constraints on uplift along the active normal faults on the southern coast of the Gulf, and project uplift away from the faults into three catchments using a viscoelastic dislocation model; (2) test how channel width and slope vary in these rivers upstream of the active faults, and we use this data to estimate the distribution of stream power down-system; (3) systematically measure rock strength, using a Schmidt hammer, to constrain its effect on river response to uplift. All the rivers have knickpoints upstream of the active faults and we show they are responding transiently to active faulting. By assuming that our derived uplift rate equals stream power-driven erosion rate we calculate the erodibility, k, of bedrock. We demonstrate that stream powers in rivers crossing faults in the southern Gulf of Corinth correlate with rock strength and derive a non-linear power relationship between bedrock erodibility k and Schmidt hammer rebound. These findings highlight the need to incorporate bedrock variability into stream power erosion models