Repeated challenge with prion disease: The risk of infection and impact on incubation period

Natural exposure to prion disease is likely to occur throughout successive challenges, yet most experiments focus on single large doses of infectious material. We analyze the results from an experiment in which rodents were exposed to multiple doses of feed contaminated with the scrapie agent. We formally define hypotheses for how the doses combine in terms of statistical models. The competing hypotheses are that only the total dose of infectivity is important (cumulative model), doses act independently, or a general alternative that interaction between successive doses occurs (to raise or lower the risk of infection). We provide sample size calculations to distinguish these hypotheses. In the experiment, a fixed total dose has a significantly reduced probability of causing infection if the material is presented as multiple challenges, and as the time between challenges lengthens. Incubation periods are shorter and less variable if all material is consumed on one occasion. We show that the probability of infection is inconsistent with the hypothesis that each dose acts as a cumulative or independent challenge. The incubation periods are inconsistent with the independence hypothesis. Thus, although a trend exists for the risk of infection with prion disease to increase with repeated doses, it does so to a lesser degree than is expected if challenges combine independently or in a cumulative manner.

Comprehension of wh-questions and declarative sentences in agrammatic aphasia: the set partition hypothesis

Problematic trace-antecedent relations between deep and surface structure have been a dominant theme in sentence comprehension in agrammatism. We challenge this view and propose that the comprehension in agrammatism in declarative sentences and wh-questions stems from impaired processing in logical form. We present new data from wh-questions and declarative sentences and advance a new hypothesis which we call the set partition hypothesis. We argue that elements that signal set partition operations influence sentence comprehension while trace-antecedent relations remain intact. (C) 2007 Elsevier Ltd. All rights reserved.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Making development simple. The genetic deterministic hypothesis for economic development

This paper discusses the dangers inherent in allempting to simplify something as complex as development. It does this by exploring the Lynn and Vanhanen theory of deterministic development which asserts that varying levels of economic development seen between countries can be explained by differences in 'national intelligence' (national IQ). Assuming that intelligence is genetically determined, and as different races have been shown to have different IQ, then they argue that economic development (measured as GDP/capita) is largely a function of race and interventions to address imbalances can only have a limited impact. The paper presents the Lynne and Vanhanen case and critically discusses the data and analyses (linear regression) upon which it is based. It also extends the cause-effect basis of Lynne and Vanhanen's theory for economic development into human development by using the Human Development Index (HDI). It is argued that while there is nothing mathematically incorrect with their calculations, there are concerns over the data they employ. Even more fundamentally it is argued that statistically significant correlations between the various components of the HDI and national IQ can occur via a host of cause-effect pathways, and hence the genetic determinism theory is far from proven. The paper ends by discussing the dangers involved in the use of over-simplistic measures of development as a means of exploring cause-effect relationships. While the creators of development indices such as the HDI have good intentions, simplistic indices can encourage simplistic explanations of under-development. (c) 2005 Elsevier B.V. All rights reserved.

The geography of tyranny and despair: development indicators and the hypothesis of genetic inevitability of national inequality

Development geography has long sought to understand why inequalities exist and the best ways to address them. Dependency theory sets out an historical rationale for under development based on colonialism and a legacy of developed core and under-developed periphery. Race is relevant in this theory only insofar that Europeans are white and the places they colonised were occupied by people with darker skin colour. There are no innate biological reasons why it happened in that order. However, a new theory for national inequalities proposed by Lynn and Vanhanen in a series of publications makes the case that poorer countries have that status because of a poorer genetic stock rather than an accident of history. They argue that IQ has a genetic basis and IQ is linked to ability. Thus races with a poorer IQ have less ability, and thus national IQ can be positively correlated with performance as measured by an indicator like GDP/capita. Their thesis is one of despair, as little can be done to improve genetic stock significantly other than a programme of eugenics. This paper summarises and critiques the Lynn and Vanhanen hypothesis and the assumptions upon which it is based, and uses this analysis to show how a human desire to simplify in order to manage can be dangerous in development geography. While the attention may naturally be focused on the 'national IQ' variables as a proxy measure of 'innate ability', the assumption of GDP per capita as an indicator of 'success' and 'achievement' is far more readily accepted without criticism. The paper makes the case that the current vogue for indicators, indices and cause-effect can be tyrannical.

Curbing agricultural exceptionalism: The EU's response to external challenge

From 1948 to 1994, the agricultural sector was afforded special treatment in the GATT. We analyse the extent to which this agricultural exceptionalism was curbed as a result of the GATT Uruguay Round Agreement on Agriculture, discuss why it was curbed and finally explore the implication of this for EU policy making. We argue that, in particular, two major changes in GATT institutions brought about restrictions on agricultural exceptionalism. First, the Uruguay Round was a 'single undertaking' in which progress on other dossiers was contingent upon an outcome on agriculture. The EU had keenly supported this new decision rule in the GATT. Within the EU this led to the MacSharry reforms of the Common Agricultural Policy (CAP) in 1992, paving the way for a trade agreement on agriculture within the GATT. Second, under the new quasi-judicial dispute settlement procedure, countries are expected to bring their policies into conformity with WTO rules or face retaliatory trade sanctions. This has brought about a greater willingness on the part of the EU to submit its farm policy to WTO disciplines.

Comparing rice production systems: A challenge for agronomic research and for the dissemination of knowledge-intensive farming practices

This article is a commentary on several research studies conducted on the prospects for aerobic rice production systems that aim at reducing the demand for irrigation water which in certain major rice producing areas of the world is becoming increasingly scarce. The research studies considered, as reported in published articles mainly under the aegis of the International Rice Research Institute (IRRI), have a narrow scope in that they test only 3 or 4 rice varieties under different soil moisture treatments obtained with controlled irrigation, but with other agronomic factors of production held as constant. Consequently, these studies do not permit an assessment of the interactions among agronomic factors that will be of critical significance to the performance of any production system. Varying the production factor of "water" will seriously affect also the levels of the other factors required to optimise the performance of a production system. The major weakness in the studies analysed in this article originates from not taking account of the interactions between experimental and non-experimental factors involved in the comparisons between different production systems. This applies to the experimental field design used for the research studies as well as to the subsequent statistical analyses of the results. The existence of such interactions is a serious complicating element that makes meaningful comparisons between different crop production systems difficult. Consequently, the data and conclusions drawn from such research readily become biased towards proposing standardised solutions for possible introduction to farmers through a linear technology transfer process. Yet, the variability and diversity encountered in the real-world farming environment demand more flexible solutions and approaches in the dissemination of knowledge-intensive production practices through "experiential learning" types of processes, such as those employed by farmer field schools. This article illustrates, based on expertise of the 'system of rice intensification' (SRI), that several cost-effective and environment-friendly agronomic solutions to reduce the demand for irrigation water, other than the asserted need for the introduction of new cultivars, are feasible. Further, these agronomic Solutions can offer immediate benefits of reduced water requirements and increased net returns that Would be readily accessible to a wide range of rice producers, particularly the resource poor smallholders. (C) 2009 Elsevier B.V. All rights reserved.

Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge

A major problem in hepatitis C virus (HCV) immunotherapy or vaccine design is the extreme variability of the virus. We identified human monoclonal antibodies (mAbs) that neutralize genetically diverse HCV isolates and protect against heterologous HCV quasispecies challenge in a human liver-chimeric mouse model. The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable.

Adventitious root formation in anacardium occidentale L. in response to phytohormones and removal of roots

Despite advances in tissue culture techniques, propagation by leafy, softwood cuttings is the preferred, practical system for vegetative reproduction of many tree and shrub species. Species are frequently defined as 'difficult'- or 'easy-to-root' when propagated by conventional cuttings. Speed of rooting is often linked with ease of propagation, and slow-to-root species may be 'difficult' precisely because tissues deteriorate prior to the formation of adventitious roots. Even when roots form, limited development of these may impair the establishment of a cutting. In this study we used softwood cuttings of cashew (Anacardium occidentale), a species considered as 'difficult-to-root'. We aimed to test the hypothesis that speed, and extent of early rooting, is critical in determining success with this species; and that the potential to form adventitious roots will decrease with time in the propagation environment. Using two genotypes, initial rooting rates were examined in the presence or absence of exogenous auxin. In cuttings that formed adventitious roots, either entire roots or root tips were removed, to determine if further root formation/development was feasible. To investigate if subsequent root responses were linked to phytohormone action, a number of cuttings were also treated with either exogenous auxin (indole-3-butyric acid-IBA) or cytokinin (zeatin). Despite the reputation of Anacardium as being 'difficult-to-root', we found high rooting rates in two genotypes (AC 10 and CCP 1001). Removing adventitious roots from cuttings and returning them to the propagation environment, resulted in subsequent re-rooting. Indeed, individual cuttings could develop new adventitious roots on four to five separate occasions over a 9 week period. Data showed that rooting potential increased, not decreased with time in the propagation environment and that cutting viability was unaffected. Root expression was faster (8-15 days) after the removal of previous roots compared to when the cuttings were first stuck (21 days). Exposing cuttings to IBA at the time of preparation, improved initial rooting in AC 10, but not in CCP 1001. Application of IBA once roots had formed had little effect on subsequent development, but zeatin reduced root length and promoted root number and dry matter accumulation. These results challenge our hypothesis, and indicate that rooting potential remains high in Anacardium. The precise mechanisms that regulate the number of adventitious roots expressed, remain to be determined. Nevertheless, results indicate that rooting potential can be high in 'difficult-to-root' species, and suggest that providing supportive environments is the key to expressing this potential. (c) 2006 Elsevier B.V. All rights reserved.

A test of the master gene hypothesis for interspersed repetitive DNA sequences

Many families of interspersed repetitive DNA elements, including human Alu and LINE (Long Interspersed Element) elements, have been proposed to have accumulated through repeated copying from a single source locus: the "master gene." The extent to which a master gene model is applicable has implications for the origin, evolution, and function of such sequences. One repetitive element family for which a convincing case for a master gene has been made is the rodent ID (identifier) elements. Here we devise a new test of the master gene model and use it to show that mouse ID element sequences are not compatible with a strict master gene model. We suggest that a single master gene is rarely, if ever, likely to be responsible for the accumulation of any repeat family.