Generation of prions in vitro and the protein-only hypothesis

Prions are self-propagating proteinaceous infectious agents capable of transmitting disease in the absence of nucleic acids. The nature of the infectious agent in prion diseases has been at the center of passionate debate for the past 30 years. However, recent reports on the in vitro generation of prions have settled all doubts that the misfolded prion protein (PrP^Sc) is the key component in propagating infectivity. However, we still do not understand completely the mechanism of prion replication and whether or not other cellular factors besides PrP^Sc are required for infectivity. In this article, we discuss these recent reports under the context of the protein-only hypothesis and their implications.     

Generation of prions in vitro and the protein-only hypothesis

Prions are self-propagating proteinaceous infectious agents capable of transmitting disease in the absence of nucleic acids. The nature of the infectious agent in prion diseases has been at the center of passionate debate for the past 30 years. However, recent reports on the in vitro generation of prions have settled all doubts that the misfolded prion protein (PrP^Sc) is the key component in propagating infectivity. However, we still do not understand completely the mechanism of prion replication and whether or not other cellular factors besides PrP^Sc are required for infectivity. In this article, we discuss these recent reports under the context of the protein-only hypothesis and their implications.Key words: prions, infectivity, protein-only hypothesis, protein misfolding cyclic amplification, synthetic prion     

Are Patents Impeding Medical Care and Innovation?

Background to the debate: Pharmaceutical and medical device manufacturers argue that the current patent system is crucial for stimulating research and development (R&D), leading to new products that improve medical care. The financial return on their investments that is afforded by patent protection, they claim, is an incentive toward innovation and reinvestment into further R&D. But this view has been challenged in recent years. Many commentators argue that patents are stifling biomedical research, for example by preventing researchers from accessing patented materials or methods they need for their studies. Patents have also been blamed for impeding medical care by raising prices of essential medicines, such as antiretroviral drugs, in poor countries. This debate examines whether and how patents are impeding health care and innovation.     

An assessment of the geological evidence for previous Acanthaster outbreaks

Much debate has surrounded the notion that outbreaks of the crown-of-thorns starfish (Acanthaster planci) have occurred in the geological past and hence are natural phenomena. As this debate has recently been renewed, we have reassessed statistically data presented by Frankel (1977, 1978) as evidence for the occurrence of past outbreaks. This was done using Frankel's data as well as those from extensive starfish surveys conducted prior to the commencement of his research. Our analysis of these data indicates that the occurrence of A. planci remains in recent sediments is independent of whether or not the reef from which the sample was collected had experienced a recent outbreak. Based on this premise, it is not possible to infer from Frankel's data the occurrence of past outbreaks from similar material in much older sediments. Thus while the data presented by Frankel (1977, 1978) may show that A. planci has existed within the Great Barrier Reef for at least several thousand years it does not demonstrate that outbreaks of this starfish have occurred in the geological past.     

Patenting of university and non-university public research organisations in Germany: evidence from patent applications for medical research results

Background

Patents are one of the most important forms of intellectual property. They grant a time-limited exclusivity on the use of an invention allowing the recuperation of research costs. The use of patents is fiercely debated for medical innovation and especially controversial for publicly funded research, where the patent holder is an institution accountable to public interest. Despite this controversy, for the situation in Germany almost no empirical information exists. The purpose of this study is to examine the amount, types and trends of patent applications for health products submitted by German public research organisations.

Methods/Principal Findings

We conducted a systematic search for patent documents using the publicly accessible database search interface of the German Patent and Trademark Office. We defined keywords and search criteria and developed search patterns for the database request. We retrieved documents with application date between 1988 and 2006 and processed the collected data stepwise to compile the most relevant documents in patent families for further analysis. We developed a rationale and present individual steps of a systematic method to request and process patent data from a publicly accessible database. We retrieved and processed 10194 patent documents. Out of these, we identified 1772 relevant patent families, applied for by 193 different universities and non-university public research organisations. 827 (47%) of these patent families contained granted patents. The number of patent applications submitted by universities and university-affiliated institutions more than tripled since the introduction of legal reforms in 2002, constituting almost half of all patent applications and accounting for most of the post-reform increase. Patenting of most non-university public research organisations remained stable.

Conclusions

We search, process and analyse patent applications from publicly accessible databases. Internationally mounting evidence questions the viability of policies to increase commercial exploitation of publicly funded research results. To evaluate the outcome of research policies a transparent evidence base for public debate is needed in Germany.     

Patenting nonassociated polymeric structures (NAPS): implications for structural genomic data release

The intellectual property laws that govern patent rights should provide a reasonable balance between the competing concerns of open access and exclusivity. Open access can facilitate knowledge dissemination and collaboration in furthering science. On the other hand, exclusivity can ensure interest and financial investment in scientific research and development.In recent days, the appropriate balance between open access and exclusivity has been a focus of public debate, particularly with regard to genomic inventions and their applications. In seeking to reconcile the timing of structural genomic data release with certain efforts to secure intellectual property rights, the International Structural Genomics Organisation joins others confronting this controversy.This paper seeks to inform the discussion with an overview of the U.S. standards for patenting nonassociated polymeric structures (NAPS), which include polynucleotides or polypeptides of unknown biological significance, and their corresponding structural data. In the United States, the present ability to obtain patent rights to these discoveries appears problematic given the requirement of specific, substantial and credible utility, among other things. Without demonstrable utility, NAPS and NAPS-related data likely will not be entitled to patent protection, whether the U.S. Patent & Trademark Office rejects NAPS claims as unpatentable in the first instance, or the U.S. federal courts invalidate NAPS claims in later patent litigation. As such, the improbability of obtaining enforceable patent rights to NAPS might undermine the rationale for delaying structural genomic data release to allow for the filing of patent applications in this regard.Abbreviations: ESTs, expressed sequence tags; ISGO, International Structural Genomics Organisation; NAPS, nonassociated polymeric structures; SNPs, single nucleotide polymorphisms; USPTO, U.S. Patent & Trademark Office     

Language and values in the human cloning debate: a web-based survey of scientists and christian fundamentalist pastors

Over the last seven years, a major debate has arisen over whether human cloning should remain legal in the United States. Given that this may be the ‘first real global and simultaneous news story on biotechnology’ (Einsiedel et al., 2002, p. 313), nations around the world have struggled with the implications of this newly viable scientific technology, which is often also referred to as somatic cell nuclear transfer. Since the successful cloning of Dolly the sheep in 1997, and with increasing media attention paid to the likelihood of a successful human reproductive clone coupled with research suggesting the medical potential of therapeutic cloning in humans, members of the scientific community and Christian fundamentalist leaders have become increasingly vocal in the debate over U.S. policy decisions regarding human cloning (Wilmut, 2000). Yet despite a surfeit of public opinion polls and widespread opining in the news media on the topic of human cloning, there have been no empirical studies comparing the views of scientists and Christian fundamentalists in this debate (see Evans, 2002a for a recent study of opinion polls assessing religion and attitudes toward cloning).

In order to further investigate the values that underlie scientists' and Christian fundamentalist leader's understanding of human cloning, as well as their differential use of language in communicating about this issue, we conducted an open-ended, exploratory survey of practicing scientists in the field of molecular biology and Christian fundamentalist pastors. We then analyzed the responses from this survey using qualitative discourse analysis. While this was not necessarily a representative sample (in quantitative terms, see Gaskell & Bauer, 2000) of each of the groups and the response rate was limited, this approach was informative in identifying both commonalities between the two groups, such as a focus on ethical concerns about reproductive cloning and the use of scientific terminology, as well as significant differences including concerns over ‘playing God’ for the Christian pastors, focus on therapeutic cloning by scientists, and subtle but informative differences between the two groups in their use of scientific terminology and their interpretations of human cloning as scientific progress.     

The rationing agenda in the NHS. Rationing Agenda Group.

The Rationing Agenda Group has been founded to deepen the British debate on rationing health care. It believes that rationing in health care is inevitable and that the public must be involved in the debate about issues relating to rationing. The group comprises people from all parts of health care, none of whom represent either their group or their institutions. RAG has begun by producing this document, which attempts to set an agenda of all the issues that need to be considered when debating the rationing of health care. We hope for responses to the document. The next stage will be to incorporate the responses into the agenda. Then RAG will divide the agenda into manageable chunks and commission expert, detailed commentaries. From this material a final paper will be published and used to prompt public debate. This stage should be reached early in 1997. While these papers are being prepared RAG is developing ways to involve the public in the debate and evaluate the whole process. We present as neutrally as possible all the issues related to rationing and priority setting in the NHS. We focus on the NHS for two reasons. Firstly, for those of us resident in the United Kingdom the NHS is the health care system with which we are most familiar and most concerned. Secondly, focusing on one system alone allows more coherent analysis than would be possible if issues in other systems were included as well. Our concern is with the delivery of health care, not its finance, though we discuss the possible effects of changing the financing system of the NHS. Finally, though our position is neutral, we hold two substantive views--namely, that rationing is unavoidable and that there should be more explicit debate about the principles and issues concerned. We consider the issues under four headings: preliminaries, ethics, democracy, and empirical questions. Preliminaries deal with the semantics of rationing, whether rationing is necessary, and with the range of services to which rationing relates. Under ethics and democracy are the substantive issues of principle and theory. The final section deals with empirical questions and those relating to the practicality of various strategies.     

Rethinking Informed Consent in Research on Heroin‐Assisted Treatment

Can heroin addicts give consent to research on trials in which heroin is prescribed to them? Analyses of addicts and informed consent have been objects of debate in several articles. Informed consent requires the agent not only to be competent but also to give consent voluntarily. This has been questioned because of alleged features of heroin addiction. Until recently the discussion has focused on heroin addicts' desires for heroin, whether these are irresistible and thus pose a problem for giving consent. Still, in light of empirical evidence, there seems to be a consensus more or less that the problem is not whether the addicts can resist their desire for heroin. A recent article concentrates specifically on heroin addicts' false assumptions of options and voluntariness. We argue that the prevailing framing of the options in this discussion in terms of heroin and access to it is problematic. The way in which the options are typically laid out suggests an assumption that participation in the research is allegedly based on the addicts' views on using the drug. We argue that this way of presenting the options is, first, a mismatch to the studies carried out and, second, symptomatic of potential misconceptions about heroin addiction and addicts. Furthermore, we also suggest that the account of voluntariness needs to be realistic in order for subjects to be able to give consent voluntarily in actual situations, and for medical research to carry out studies on improving outcomes in addiction treatment in an ethical way.     

Timing and mechanism of ancient vertebrate genome duplications -- the adventure of a hypothesis

Complete genome doubling has long-term consequences for the genome structure and the subsequent evolution of an organism. It has been suggested that two genome duplications occurred at the origin of vertebrates (known as the 2R hypothesis). However, there has been considerable debate as to whether these were two successive duplications, or whether a single duplication occurred, followed by large-scale segmental duplications. In this article, we review and compare the evidence for the 2R duplications from vertebrate genomes with similar data from other more recent polyploids.     

Exposure to MTBE and Acute Human Health Effects: A Critical Literature Review

Whether use of oxygen-rich gasoline additives to reduce air pollution is a cause of acute adverse health effects is an ongoing concern in the United States. Attention has focused in particular on use of methyl tert-butyl ether (MTBE, CAS #1634-04-4) and, despite considerable published research, debate persists regarding its potential for adverse health effects. To better understand the debate, we critically reviewed published and unpublished reports to assess whether differences in methodological approach or quality could explain the variable results reported. We considered studies on acute human health effects of inhalation exposure to MTBE either alone or in gasoline (19 reports) as well as clinical use of parenteral MTBE to dissolve cholesterol gall stones (12 reports). Each study was reviewed from three perspectives (epidemiology, industrial hygiene, and, clinical diagnostics), judged satisfactory, limited adequacy, or unsatisfactory for each criterion, and grouped into one of three categories from most to least adequate in overall methodology. The studies judged most adequate on individual criteria and those with highest overall adequacy found no significant association between MTBE exposure and symptoms. We propose that the persistent debate has been fueled by the findings of methodologically weak hypothesis-generating studies.     

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

BackgroundCell stiffness is a crucial mechanical property that is closely related to cell motility. AFM is the most prevalent method used to determine cell stiffness by the quantitative parameter designated as Young's modulus. Young's modulus is regarded as a biomarker of cell motility, especially in estimating the metastasis of cancer cells, because in recent years, it has been repeatedly shown that cancerous cells are softer than their benign counterparts. However, some conflicting evidence has shown that cells with higher motility are sometimes stiffer than their counterparts. Thus, the correlation between cell stiffness and motility remains a matter of debate.Scope of reviewIn this review, we first summarize the reports on correlations between cell motility and stiffness determined by AFM and then discuss the major determinants of AFM-determined cell stiffness with a focus on the cytoskeleton, nuclear stiffness and methodological issues. Last, we propose a possible correlation between cell stiffness and motility and the possible explanations for the conflicting evidence.Major conclusionsThe AFM-determined Young's modulus is greatly affected by the characteristics of the cytoskeleton, as well as the procedures and parameters used in detection. Young's modulus is a reliable biomarker for the characterization of metastasis; however, reliability is questioned in the evaluation of pharmacologically or genetically modified motility.General significanceThis review provides an overview of the current understanding of the correlation between AFM-determined cell stiffness and motility, the determinants of this detecting method, as well as clues to optimize detecting parameters.     

Isolation of Candida in the blood cultures of patients admitted to the Emergency Room in a tertiary care hospital

BackgroundIn Spain, data of candidemia are limited to surveys conducted in specific areas or tertiary care centers. Also, in recent years, attention has shifted toward episodes of candidemia in non-ICU wards.AimsWe reviewed the cases of Candida isolates recovered from the blood of patients admitted to the Emergency Room (ER) in our tertiary care hospital.MethodsThe patients selected for this study had an isolation of Candida in the blood culture. All data were collected retrospectively from the clinical records of a 11-year period.ResultsCandida albicans and other species of the genus were present in 10 and 18 patients, respectively. The patients did not present different clinical features in comparison with other reports of hospitalized patients. All patients had several risk factors for candidemia. Only two patients had received previous antifungal therapy before admission. All the isolates of C. albicans, Candida glabrata and the only isolate of Candida tropicalis were susceptible to all the antifungal agents tested. Only one isolate of Candida parapsilosis was susceptible dose-dependent to fluconazole, and the only isolate of Candida metapsilosis was resistant to fluconazole.ConclusionsIt is essential to evaluate the risk factors, underlying conditions and clinical features in non-hospitalized patients in order to determine whether an empirical treatment for candidemia is appropriate.     

Barley landraces are characterized by geographically heterogeneous genomic origins

BackgroundThe genetic provenance of domesticated plants and the routes along which they were disseminated in prehistory have been a long-standing source of debate. Much of this debate has focused on identifying centers of origins for individual crops. However, many important crops show clear genetic signatures of multiple domestications, inconsistent with geographically circumscribed centers of origin. To better understand the genetic contributions of wild populations to domesticated barley, we compare single nucleotide polymorphism frequencies from 803 barley landraces to 277 accessions from wild populations.ResultsWe find that the genetic contribution of individual wild populations differs across the genome. Despite extensive human movement and admixture of barley landraces since domestication, individual landrace genomes indicate a pattern of shared ancestry with geographically proximate wild barley populations. This results in landraces with a mosaic of ancestry from multiple source populations rather than discrete centers of origin. We rule out recent introgression, suggesting that these contributions are ancient. The over-representation in landraces of genomic segments from local wild populations suggests that wild populations contributed locally adaptive variation to primitive varieties.ConclusionsThis study increases our understanding of the evolutionary process associated with the transition from wild to domesticated barley. Our findings indicate that cultivated barley is comprised of multiple source populations with unequal contributions traceable across the genome. We detect putative adaptive variants and identify the wild progenitor conferring those variants.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0712-3) contains supplementary material, which is available to authorized users.     

Heterogeneity of KRAS Mutation Status in Rectal Cancer

IntroductionAnti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy. However, at which occasions this should be performed is still under debate. We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy (CRT), and if there are any changes in KRAS mutation status due to this intervention.ResultsFor 20 (43%) out of the 47 patients, a KRAS mutation was detected. With 12 out of 20, the majority of these mutations affected codon 35. We did not obtained evidence that CRT results in changes of the KRAS mutation pattern. In addition, no intratumoral heterogeneity in the KRAS mutational status could be proven. This was true for both the biopsies prior to CRT and the resection specimens thereafter. The discrepancy observed in some samples when using the SNaPshot™ assay was due to insufficient sensitivity of this technique upon massive tumor regression by CRT as application of the therascreen® KRAS test revealed concordant results.ConclusionOur results indicate that the KRAS mutation status at the primary tumor site of rectal cancer is homogenous. Its assessment for therapeutic decisions is feasible in pre-therapeutic biopsies as well as in post-therapeutic resected specimens. The amount of viable tumor cells seems to be an important determinant for assay sensitivity and should thus be considered for selection of the analytical method.     

Highly incomplete taxa can rescue phylogenetic analyses from the negative impacts of limited taxon sampling

Background

Phylogenies are essential to many areas of biology, but phylogenetic methods may give incorrect estimates under some conditions. A potentially common scenario of this type is when few taxa are sampled and terminal branches for the sampled taxa are relatively long. However, the best solution in such cases (i.e., sampling more taxa versus more characters) has been highly controversial. A widespread assumption in this debate is that added taxa must be complete (no missing data) in order to save analyses from the negative impacts of limited taxon sampling. Here, we evaluate whether incomplete taxa can also rescue analyses under these conditions (empirically testing predictions from an earlier simulation study).

Methodology/Principal Findings

We utilize DNA sequence data from 16 vertebrate species with well-established phylogenetic relationships. In each replicate, we randomly sample 4 species, estimate their phylogeny (using Bayesian, likelihood, and parsimony methods), and then evaluate whether adding in the remaining 12 species (which have 50, 75, or 90% of their data replaced with missing data cells) can improve phylogenetic accuracy relative to analyzing the 4 complete taxa alone. We find that in those cases where sampling few taxa yields an incorrect estimate, adding taxa with 50% or 75% missing data can frequently (>75% of relevant replicates) rescue Bayesian and likelihood analyses, recovering accurate phylogenies for the original 4 taxa. Even taxa with 90% missing data can sometimes be beneficial.

Conclusions

We show that adding taxa that are highly incomplete can improve phylogenetic accuracy in cases where analyses are misled by limited taxon sampling. These surprising empirical results confirm those from simulations, and show that the benefits of adding taxa may be obtained with unexpectedly small amounts of data. These findings have important implications for the debate on sampling taxa versus characters, and for studies attempting to resolve difficult phylogenetic problems.     

Graying of the hair and mortality

Abstract

Since the early 1970s, considerable attention has been given to U. S. trends in childlessness. Studies have shown that childlessness rates have been increasing in recent years; many believe that the bulk of the increase has been due to increases in voluntary childlessness. However, there have been few methodological and empirical analyses of trends in voluntary and involuntary childlessness. This paper has two objectives: to develop two procedures for measuring voluntary and involuntary childlessness with fertility survey data; and to apply empirically these approaches to five fertility surveys conducted between 1955 and 1973.     

Do we expect natural selection to produce rational behaviour?

We expect that natural selection should result in behavioural rules which perform well; however, animals (including humans) sometimes make bad decisions. Researchers account for these with a variety of explanations; we concentrate on two of them. One explanation is that the outcome is a side effect; what matters is how a rule performs (in terms of reproductive success). Several rules may perform well in the environment in which they have evolved, but their performance may differ in a 'new' environment (e.g. the laboratory). Some rules may perform very badly in this environment. We use the debate about whether animals follow the matching law rather than maximizing their gains as an illustration. Another possibility is that we were wrong about what is optimal. Here, the general idea is that the setting in which optimal decisions are investigated is too simple and may not include elements that add extra degrees of freedom to the situation.     

生态系统稳定性及其与生物多样性的关系

在全球变化背景下, 生态系统能否长期有效地维持功能并提供服务, 有赖于其稳定性。生态系统稳定性及其与生物多样性的关系, 是生态学研究的核心问题, 生物多样性能否促进生态系统稳定性曾引起很多争论。该文在前期国内外综述和研究的基础上, 重点从以下三个方面对近期进展做了总结。第一, 介绍了近期理论研究在生态系统稳定性的内涵及不同稳定性指标间的内在关联方面取得的新认识。第二, 梳理了最近基于生物多样性实验开展的多项整合分析研究和理论探索, 以及在多维度框架下开展的多样性-稳定性关系研究。第三, 详细介绍了最近发展起来的多尺度稳定性理论框架, 对稳定性的尺度依赖、多样性-稳定性的多尺度关系等新议题做了探讨。最后, 提出了本领域有待进一步研究的关键问题和方向建议。     

Evolution of the mitochondrial DNA control region in the mbuna (Cichlidae) species flock of lake Malawi, East Africa

Considerable controversy has surrounded the application of mitochondrial DNA data to reconstruction of evolutionary relationships among the endemic cichlids of Lake Malawi. Central to this debate has been the issue of whether lineage sorting is complete, and thus whether these data actually reflect species phylogeny, or simply gene genealogy. Review of all mtDNA control region sequences available for members of one monophyletic subset of this species flock, the Malawi rockfishes, or mbuna, strongly indicates that lineage sorting is incomplete: Character-based analyses of these sequences reconstruct gene, not species, interrelationships. Analysis of the pattern of nucleotide substitutions differentiating these mtDNA alleles suggests that pyrimidine residues undergo transition substitutions more often than do purines. Estimation of the magnitude of derived sequence differentiation in light of the reconstructed gene genealogy suggests that the mbuna may be of considerably more recent vintage than previous molecular characterizations have indicated. Received: 6 April 1996 / Accepted: 3 March 1997