Autoimmune destruction of pericytes as the cause of diabetic retinopathy

In diabetic retinopathy, collapse of the retinal vasculature is associated with loss of the pericytes. These are contractile cells that together with endothelial cells form the terminal arterioles of the retina. The cause of the loss of pericytes is not known. Recently, it has been discovered that type 1 diabetes is caused by forbidden clones of cytotoxic T lymphocytes, which destroy the insulin-making cells with exquisite specificity. In the light of this, I postulate that an antigenically-related forbidden clone of cytotoxic T lymphocytes selectively destroys the pericytes and that this is the cause of the vascular collapse of diabetic retinopathy. If this is so, the therapeutic implications are immense, involving a switch from ineffectual tight glycemic control to immunotherapy. This is already used as immunosuppression to prevent organ transplant rejection, and as the immune ablation and autologous bone marrow cell reconstitution that has saved the lives of patients with lethally-severe scleroderma. Once the pericyte surface auto-antigen for the T lymphocytes has been isolated, selective destruction of the pathogenic T lymphocytes would be possible by manufacture and use of cytotoxic auto-antigen complexes, which arrests progression of the retinopathy

Transverse Momentum Correlations in Relativistic Nuclear Collisions

From the correlation structure of transverse momentum $p_t$ in relativistic nuclear collisions we observe for the first time temperature/velocity structure resulting from low-$Q^2$ partons. Our novel analysis technique does not invoke an {\em a priori} jet hypothesis. $p_t$ autocorrelations derived from the scale dependence of $$ fluctuations reveal a complex parton dissipation process in RHIC heavy ion collisions. We also observe structure which may result from collective bulk-medium recoil in response to parton stopping.Comment: 10 pages, 10 figures, proceedings, MIT workshop on fluctuations and correlations in relativistic nuclear collision

Public geographies II: being organic

This second report on ‘public geographies' considers the diverse, emergent and shifting spaces of engaging with and in public/s. Taking as its focus the more ‘organic’ rather than ‘traditional’ approach to doing public geography, as discussed in the first report, it explores the multiple and unorthodox ways in which engagements across academic-public spheres play out, and what such engagements may mean for geography/ers. The report first explores the role of the internet in ‘enabling conversations', generating a range of opportunities for public geography through websites, wikis, blogs, file-sharing sites, discussion forums and more, thinking critically about how technologies may enable/disable certain kinds of publically engaged activities. It then considers issues of process and praxis: how collaborations with groups/communities/organizations beyond academia are often unplanned, serendipitous encounters that evolve organically into research/learning/teaching endeavours; but also that personal politics/positionality bring an agency to bear upon whether we, as academics, follow the leads we may stumble upon. The report concludes with a provocative question – given that many non-academics appear to be doing some amazing and inspiring projects and activities, thoughtful, critical and (arguably) examples of organic public geographies, what then is academia’s role

General Solutions for Tunneling of Scalar Fields with Quartic Potentials

For the theory of a single scalar field $\varphi$ with a quartic potential $V(\varphi)$, we find semi-analytic expressions for the Euclidean action in both four and three dimensions. The action in four dimensions determines the quantum tunneling rate at zero temperature from a false vacuum state to the true vacuum state; similarly, the action in three dimensions determines the thermal tunneling rate for a finite temperature theory. We show that for all quartic potentials, the action can be obtained from a one parameter family of instanton solutions corresponding to a one parameter family of differential equations. We find the solutions numerically and use polynomial fitting formulae to obtain expressions for the Euclidean action. These results allow one to calculate tunneling rates for the entire possible range of quartic potentials, from the thin-wall (nearly degenerate) limit to the opposite limit of vanishing barrier height. We also present a similar calculation for potentials containing $\varphi^4 \ln \varphi^2$ terms, which arise in the one-loop approximation to the effective potential in electroweak theory.Comment: 17 pages, 6 figures not included but available upon request, UM AC 93-

Is socioeconomic status associated with biological aging as measured by telomere length?

It has been hypothesized that one way in which lower socioeconomic status (SES) affects health is by increasing the rate of biological aging. A widely used marker of biological aging is telomere length. Telomeres are structures at the ends of chromosomes that erode with increasing cell proliferation and genetic damage. We aimed to identify, through systematic review and meta-analysis, whether lower SES (greater deprivation) is associated with shorter telomeres. Thirty-one articles, including 29 study populations, were identified. We conducted 3 meta-analyses to compare the telomere lengths of persons of high and low SES with regard to contemporaneous SES (12 study populations from 10 individual articles), education (15 study populations from 14 articles), and childhood SES (2 study populations from 2 articles). For education, there was a significant difference in telomere length between persons of high and low SES in a random-effects model (standardized mean difference (SMD) = 0.060, 95% confidence interval (CI): 0.002, 0.118; P = 0.042), although a range of sensitivity analyses weakened this association. There was no evidence for an association between telomere length and contemporaneous SES (SMD = 0.104, 95% CI: −0.027, 0.236; P = 0.119) or childhood SES (SMD = −0.037, 95% CI: −0.143, 0.069; P = 0.491). These results suggest weak evidence for an association between SES (as measured by education) and biological aging (as measured by telomere length), although there was a lack of consistent findings across the SES measures investigated here

A Polyphasic Approach for Phenotypic and Genetic Characterization of the Fastidious Aquatic Pathogen Francisella noatunensis subsp. orientalis

Francisella noatunensis subsp. orientalis (Fno) is the causative agent of piscine francisellosis, an emerging infectious disease in Asia and Latin America. In this study two outbreaks of francisellosis were diagnosed in the UK on the basis of histopathology, electron microscopy, PCR, bacterial isolation and fulfilment of Koch’s postulates. Furthermore, a phenotypic fingerprint based on biochemical analyses, metabolic activity, chemotaxonomic composition and antimicrobial assays was generated for the novel isolates, the Fno type strain Ehime-1 from Asia and other Fno from Latin America. The genetic relatedness between the novel Fno and other Francisellaceae species was investigated by sequencing and comparing 8 housekeeping genes and the 16S rRNA-ITS-23S rRNA sequence. The phenotypic profiling indicated a high degree of similarity between the Fno taxon as all were able to metabolise dextrin, N-acetyl-D glucosamine, D-fructose, α-D-glucose, D-mannose, methyl pyruvate, acetic acid, α-keto butyric acid, L-alaninamide, L-alanine, L-alanylglycine, L-asparagine, L-glutamic acid, L-proline, L-serine, L-threonine, inosine, uridine, glycerol, D L-α-glycerol phosphate, glucose-1-phosphate and glucose-6-phosphate. The chemotaxonomic analyses indicated that 24:1 (20.3%), 18:1n-9 (16.9%), 24:0 (13.1%) 14:0 (10.9%), 22:0 (7.8%), 16:0 (7.6%) and 18:0 (5.5%) were the predominant structural fatty acids in Fno. The antimicrobial assays showed little variation between the isolates and high susceptibility to enrofloxacin, gentamicin, neomycin, streptomycin, amikacin, ciprofloxacin, gatifloxacin, nitrofurantoin, tobramycin, kanamycin, tetracycline, oxytetracycline, florfenicol, oxolinic acid and streptomycin in all the Fno analysed. In all the phylogenetic trees the Fno strains clustered together in independent branches confirming a high degree of homogeneity. Interestingly in five of the individual trees i.e mutS, putA, rpoB, the concatenated sequence and 16S rRNA-ITS-23S rRNA genes the two Francisella noatunensis ssp. diverged more from each other than from the closely related human pathogen Francisella philomiragia (Fp). The phenotypic and genetic characterisation confirmed the Fno isolates represent a solid phylo-phenetic taxon that in the current context of the genus seems to be misplaced within the species Fn. We propose the use of the present polyphasic approach in future studies to characterise strains of Fnn and Fp and verify their current taxonomic rank of Fno

On the Migration of Jupiter and Saturn: Constraints from Linear Models of Secular Resonant Coupling with the Terrestrial Planets

We examine how the late divergent migration of Jupiter and Saturn may have perturbed the terrestrial planets. We identify six secular resonances between the nu_5 apsidal eigenfrequency of Jupiter and Saturn and the four eigenfrequencies of the terrestrial planets (g_{1-4}). We derive analytic upper limits on the eccentricity and orbital migration timescale of Jupiter and Saturn when these resonances were encountered to avoid perturbing the eccentricities of the terrestrial planets to values larger than the observed ones. If Jupiter and Saturn migrated with eccentricities comparable to their present day values, smooth migration with exponential timescales characteristic of planetesimal-driven migration (\tau~5-10 Myr) would have perturbed the eccentricities of the terrestrial planets to values greatly exceeding the observed ones. This excitation may be mitigated if the eccentricity of Jupiter was small during the migration epoch, migration was very rapid (e.g. \tau<~ 0.5 Myr perhaps via planet-planet scattering or instability-driven migration) or the observed small eccentricity amplitudes of the j=2,3 terrestrial modes result from low probability cancellation of several large amplitude contributions. Further, results of orbital integrations show that very short migration timescales (\tau<0.5 Myr), characteristic of instability-driven migration, may also perturb the terrestrial planets' eccentricities by amounts comparable to their observed values. We discuss the implications of these constraints for the relative timing of terrestrial planet formation, giant planet migration, and the origin of the so-called Late Heavy Bombardment of the Moon 3.9+/-0.1 Ga ago. We suggest that the simplest way to satisfy these dynamical constraints may be for the bulk of any giant planet migration to be complete in the first 30-100 Myr of solar system history.Comment: Accepted for publication in The Astrophysical Journa

European Union enlargement, post-accession migration and imaginative geographies of the ‘New Europe’: media discourses in Romania and the United Kingdom.

This paper is concerned with re-imaginings of ‘Europe’ following the accession to the European Union (EU) of former ‘Eastern European’ countries. In particular it explores media representations of post-EU accession migration from Romania to the United Kingdom in the UK and Romanian newspaper press. Todorova’s (1997) notion of Balkanism is deployed as a theoretical construct to facilitate the analysis of these representations as first, the continuation of long-standing and deeply embedded imaginings of the ‘East’ of Europe and, second, as a means of contesting these discourses. The paper explores the way in which the UK press construct Balkanist discourses about Romania and Romanian migrants, and then analyses how the Romanian press has contested such discourses. The paper argues that the idea of the ‘East’ remains important in constructing notions of ‘Europe’ within popular media geographies

Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials