PrPCWD lymphoid cell targets in early and advanced chronic wasting disease of mule deer

Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt¿Jakob disease in which the abnormal prion protein isoform, PrPCWD, accumulates in lymphoid tissue. Experimental scrapie studies have indicated that this early lymphoid phase is an important constituent of prion replication interposed between mucosal entry and central nervous system accumulation. To identify the lymphoid target cells associated with PrPCWD, we used triple-label immunofluorescence and high-resolution confocal microscopy on tonsils from naturally infected deer in advanced disease. We detected PrPCWD primarily extracellularly in association with follicular dendritic and B cell membranes as determined by frequent co-localization with antibodies against membrane bound immunoglobulin and CD21. There was minimal co-localization with cytoplasmic labels for follicular dendritic cells (FDC). This finding could indicate FDC capture of PrPCWD, potentially in association with immunoglobulin or complement, or PrPC conversion on FDC. In addition, scattered tingible body macrophages in the germinal centre contained coarse intracytoplasmic aggregates of PrPCWD, reflecting either phagocytosis of PrPCWD on FDC processes, apoptotic FDC or B cells, or actual PrPCWD replication within tingible body macrophages. To compare lymphoid cell targets in early and advanced disease, we also examined: (i) PrPCWD distribution in lymphoid cells of fawns within 3 months of oral CWD exposure and (ii) tonsil biopsies from preclinical deer with naturally acquired CWD. These studies revealed that the early lymphoid cellular distribution of PrPCWD was similar to that in advanced disease, i.e. in a pattern suggesting FDC association. We conclude that in deer, PrPCWD accumulates primarily extracellularly and associated with FDCs and possibly B cells ¿ a finding which raises questions as to the cells responsible for pathological prion productio

More light and less heat Mirowski on economics and the energy metaphor

I initially approached More Heat than Light with some apprehension. This is not because I suspected that I would disagree with its main thesis but because I feared that I would find the book anticlimactic. Over the past few years, Phil Mirowski has served us a number of delightful appetizers’-so many in fact that I suspected I might tire of the taste before the main entrée appeared. These concerns were wholly unfounded. The main entrée has finally arrived and is of such depth and complexity that it makes the appetizers, well, just appetizers. Mirowski’s central thesis is that neoclassical economics-initially developed during the 1870s and currently the dominant paradigm in economic theory-amounts to little more than a &dquo;brazen daylight robbery&dquo; (p. 4)2 of nineteenth-century energy physics. Motivated by the desire to achieve the status and prestige of the physical sciences, early neoclassical economists created their &dquo;revolution&dquo; by simply substituting &dquo;utility&dquo; for &dquo;energy&dquo; in the physics of their day. In a limited respect, this project was successful-the mathematical formalism of energy physics did (and does) contribute to the scientific respectability of the neoclassical research program-but this status was achieved at substantial cost. Mirowski argues that there were (and are) deep problems associated with the economic appropriation of the energy metaphor; physical systems have properties that make the mathematics appropriate, but these properties are not shared by economic systems. For example, the physical requirement that potential energy and kinetic energy sum to a constant translates into the economic requirement that utility and income sum to a constant. This is a problem because utility and income are measured in entirely different units. Mirowski argues that such difficulties were exacerbated by the scientific naivete of the early neoclassical economists who were trained in science and engineering-they had been exposed to the basic ideas of energy physics-but their knowledge was relatively rudimentary (p. 250). The result was energy physics appropriated in a &dquo;shoddy and slipshod manner&dquo; (p. 108). Mirowski provides a detailed discussion of how this misappropriation of the energy metaphor has surreptitiously influenced the development of modern economic thought. He reconstructs and explains certain generally accepted facts of theoretical life in economics (such as the problems of neoclassical production theory) and exposes some of the fundamental weaknesses of neoclassical theory (such as its inability to explain preference changes). Mirowski also argues that the dominance of the energy metaphor from nineteenth-century physics has prevented economists from taking advantage of more recent developments in physical theory, such as quantum mechanics and the theory of relativity. The result, according to Mirowski, is a tale reminiscent of Dorian Gray .... Neoclassicals, by imbibing some mystical elixir of modern mathematical techniques, have maintained the figure of vibrant youth, while hidden away somewhere in the attic is the real portrait, the original metaphor of a conserved preference field in an independently constituted commodity space, growing progressively desiccated and decrepit. (p. 374) My overall evaluation of Mirowski’s thesis is quite positive. I believe that he is entirely correct about the role of the energy metaphor in early neoclassical economics (probably reaching an apogee in Irving Fisher), and he is also correct that the metaphor has been lurking ever since in the background of neoclassical economics. The energy metaphor and its mathematics have been actively influential in the development of modem neoclassical theory, although I would probably weaken its impact from Mirowski’s story by saying &dquo;influenced&dquo; whereas Mirowski would say &dquo;dominated.&dquo; Where I mainly differ from Mirowski is on the implications of his thesis. For Mirowski, uncovering this hidden influence amounts to a scathing critique of modern neoclassical economics (and given the neoclassical dominance of the profession, this means most of modem economics). For him, the metaphor and its mathematics have been both dominant and pernicious. I disagree. While I am convinced that Mirowski has uncovered something important that can be used to further our understanding of the development of modem economic theory, I am not convinced that his thesis entails the kind of critical bite that he would like it to have. Given this overall evaluation of More Heat than Light, I will divide my comments into two sections. The first-more light-lends additional support to Mirowski’s general historical thesis by using it to illuminate two areas of modem neoclassical economics that Mirowski does not emphasize. The second-less heat-offers some arguments against Mirowski’s critical interpretation of his general thesis

Ab initio and finite-temperature molecular dynamics studies of lattice resistance in tantalum

This manuscript explores the apparent discrepancy between experimental data and theoretical calculations of the lattice resistance of bcc tantalum. We present the first results for the temperature dependence of the Peierls stress in this system and the first ab initio calculation of the zero-temperature Peierls stress to employ periodic boundary conditions, which are those best suited to the study of metallic systems at the electron-structure level. Our ab initio value for the Peierls stress is over five times larger than current extrapolations of experimental lattice resistance to zero-temperature. Although we do find that the common techniques for such extrapolation indeed tend to underestimate the zero-temperature limit, the amount of the underestimation which we observe is only 10-20%, leaving open the possibility that mechanisms other than the simple Peierls stress are important in controlling the process of low temperature slip.Comment: 12 pages and 9 figure

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

BACKGROUND: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. METHODS: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. RESULTS: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. CONCLUSIONS: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer