The natural history of property : natural law theories from Grotius to Hume

This essay examines the development of the major themes in the natural law account of property, and of the conceptions of social life and moral action on which they rely, from Hugo Grotius to David Hume. In the opening two chapters, the two main variants of modern n a tu ra l law theory, those of Grotius and Pufendorf, are explained in some detail. Their understanding of natural law, as a science of morals grounded in human nature, is spelled out, and it is shown how this results in an understanding of property relations as a natural response to the changes in human circumstances wrought by increasing sophistication in human social life. It is a natural response because it reflects the requirements of human nature, such reflection being shown by the fact th a t it arises necessarily, through peaceful processes, from the recognition of the elemental moral realm of what is “one’s own” . In this sense property has a natural history; but it is also shown th a t, for these theories, the division between natural history and actual history is not sufficiently clearly drawn, an inadequacy which is well illustrated by problems in the account of the place of slavery in the account of property. But Pufendorf, at least, recognizes th a t the problem of slavery can be reduced if the principal incentive to voluntary enslavement, material necessity, can itself be overcome. In this way the problem of slavery can have an economic solution. By carefully examining the implications of the basic notion of “one’s own” , which, following English practice, he calls property in one’s person, Locke concludes both that slavery is always unacceptable (is unnatural) and th a t the origin of property in no way depends on consent. Rather, property is shown to be the inevitable consequence of human self-preserving action in a world given to us by God. Neither does material necessity provide a reason for enslavement: on the one hand, the right of charity of the poor against the surplus of the wealthy makes enslavement an avoidable option for the individual; and on the other, the productive power of improving labour is so great th a t, where a system of private property is established which secures the fruits of their industry to the industrious, necessity itself (and thereby slavery also) becomes avoidable for a whole society, by making even the worst off wealthier than the richest in a primitive economy. Thus the question of property undergoes a significant shift. The concern of Locke’s successors with political economy, and the manner in which this concern modifies their interest in slavery and necessity as serious problems for society shows the extent to which Locke’s conclusions win the day. The question of what it is to have a social theory which is grounded in human nature becomes very pressing, however, because of difficulties perceived to be generated by Lockean (and, more generally, all “self-love” ) theories of human motivation. Such theories were perceived as compromising the natural law stress on the naturalness of human social life. The issue hinges on the nature of obligation. Hutcheson (and, following him, Hume) defends an account of human motivation which allocates a central role to impartial benevolence, and which thereby offers an understanding of moral obligation independent of theological commitments. Hutcheson’s programme runs into difficulties in its account of property, however, stressing the necessity of strict rule-following while at the same time providing general principles which threaten it. Hume’s account of the source of our obligation to respect the rules of property (the cornerstone of justice) is explained as an attempt to overcome this tension, by adapting some Pufendorfian distinctions to account for different types of moral obligation, grounded in different aspects of human sociability. So, despite some well established assumptions to the contrary, Hume can be recognized to be an important contributor to the natural law tradition. Together, he and Hutcheson pave the way for the more complete critical natural history of Adam Smith

PFD: a database for the investigation of protein folding kinetics and stability

We have developed a new database that collects all protein folding data into a single, easily accessible public resource. The Protein Folding Database (PFD) contains annotated structural, methodological, kinetic and thermodynamic data for more than 50 proteins, from 39 families. A user-friendly web interface has been developed that allows powerful searching, browsing and information retrieval, whilst providing links to other protein databases. The database structure allows visualization of folding data in a useful and novel way, with a long-term aim of facilitating data mining and bioinformatics approaches. PFD can be accessed freely at http://pfd.med.monash.edu.au

The REFOLD database: a tool for the optimization of protein expression and refolding

A large proportion of proteins expressed in Escherichia coli form inclusion bodies and thus require renaturation to attain a functional conformation for analysis. In this process, identifying and optimizing the refolding conditions and methodology is often rate limiting. In order to address this problem, we have developed REFOLD, a web-accessible relational database containing the published methods employed in the refolding of recombinant proteins. Currently, REFOLD contains >300 entries, which are heavily annotated such that the database can be searched via multiple parameters. We anticipate that REFOLD will continue to grow and eventually become a powerful tool for the optimization of protein renaturation. REFOLD is freely available at

Global gene expression analysis of human erythroid progenitors

This article is available open access through the publisher’s website. Copyright @ 2011 American Society of Hematology. This article has an erratum: http://bloodjournal.hematologylibrary.org/content/118/26/6993.3.Understanding the pattern of gene expression during erythropoiesis is crucial for a synthesis of erythroid developmental biology. Here, we isolated 4 distinct populations at successive erythropoietin-dependent stages of erythropoiesis, including the terminal, pyknotic stage. The transcriptome was determined using Affymetrix arrays. First, we demonstrated the importance of using defined cell populations to identify lineage and temporally specific patterns of gene expression. Cells sorted by surface expression profile not only express significantly fewer genes than unsorted cells but also demonstrate significantly greater differences in the expression levels of particular genes between stages than unsorted cells. Second, using standard software, we identified more than 1000 transcripts not previously observed to be differentially expressed during erythroid maturation, 13 of which are highly significantly terminally regulated, including RFXAP and SMARCA4. Third, using matched filtering, we identified 12 transcripts not previously reported to be continuously up-regulated in maturing human primary erythroblasts. Finally, using transcription factor binding site analysis, we identified potential transcription factors that may regulate gene expression during terminal erythropoiesis. Our stringent lists of differentially regulated and continuously expressed transcripts containing many genes with undiscovered functions in erythroblasts are a resource for future functional studies of erythropoiesis. Our Human Erythroid Maturation database is available at https://cellline.molbiol.ox.ac.uk/eryth/index.html.National Health Service Blood and Transplant, National Institute for Health Research Biomedical Research Center Program, and National Institute for Health Research

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder

BACKGROUND: Autism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ∼70-80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints. METHODS: The rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC). RESULTS: IMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD. CONCLUSIONS: TCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith-Magenis and Potocki-Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD

Risk factors for the development of severe typhoid fever in Vietnam

Background Typhoid fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi. Age, sex, prolonged duration of illness, and infection with an antimicrobial resistant organism have been proposed risk factors for the development of severe disease or fatality in typhoid fever. Methods We analysed clinical data from 581 patients consecutively admitted with culture confirmed typhoid fever to two hospitals in Vietnam during two periods in 1993–1995 and 1997–1999. These periods spanned a change in the antimicrobial resistance phenotypes of the infecting organisms i.e. fully susceptible to standard antimicrobials, resistance to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole (multidrug resistant, MDR), and intermediate susceptibility to ciprofloxacin (nalidixic acid resistant). Age, sex, duration of illness prior to admission, hospital location and the presence of MDR or intermediate ciprofloxacin susceptibility in the infecting organism were examined by logistic regression analysis to identify factors independently associated with severe typhoid at the time of hospital admission. Results The prevalence of severe typhoid was 15.5% (90/581) and included: gastrointestinal bleeding (43; 7.4%); hepatitis (29; 5.0%); encephalopathy (16; 2.8%); myocarditis (12; 2.1%); intestinal perforation (6; 1.0%); haemodynamic shock (5; 0.9%), and death (3; 0.5%). Severe disease was more common with increasing age, in those with a longer duration of illness and in patients infected with an organism exhibiting intermediate susceptibility to ciprofloxacin. Notably an MDR phenotype was not associated with severe disease. Severe disease was independently associated with infection with an organism with an intermediate susceptibility to ciprofloxacin (AOR 1.90; 95% CI 1.18-3.07; p = 0.009) and male sex (AOR 1.61 (1.00-2.57; p = 0.035). Conclusions In this group of patients hospitalised with typhoid fever infection with an organism with intermediate susceptibility to ciprofloxacin was independently associated with disease severity. During this period many patients were being treated with fluoroquinolones prior to hospital admission. Ciprofloxacin and ofloxacin should be used with caution in patients infected with S. Typhi that have intermediate susceptibility to ciprofloxacin

Blood culture-PCR to optimise typhoid fever diagnosis after controlled human infection identifies frequent asymptomatic cases and evidence of primary bacteraemia.

BACKGROUND: Improved diagnostics for typhoid are needed; a typhoid controlled human infection model may accelerate their development and translation. Here, we evaluated a blood culture-PCR assay for detecting infection after controlled human infection with S. Typhi and compared test performance with optimally performed blood cultures. METHODOLOGY/PRINCIPAL FINDINGS: Culture-PCR amplification of blood samples was performed alongside daily blood culture in 41 participants undergoing typhoid challenge. Study endpoints for typhoid diagnosis (TD) were fever and/or bacteraemia. Overall, 24/41 (59%) participants reached TD, of whom 21/24 (86%) had ≥1 positive blood culture (53/674, 7.9% of all cultures) or 18/24 (75%) had ≥1 positive culture-PCR assay result (57/684, 8.3%). A further five non-bacteraemic participants produced culture-PCR amplicons indicating infection; overall sensitivity/specificity of the assay compared to the study endpoints were 70%/65%. We found no significant difference between blood culture and culture-PCR methods in ability to identify cases (12 mismatching pairs, p = 0.77, binomial test). Clinical and stool culture metadata demonstrated that additional culture-PCR amplification positive individuals likely represented true cases missed by blood culture, suggesting the overall attack rate may be 30/41 (73%) rather than 24/41 (59%). Several participants had positive culture-PCR results soon after ingesting challenge providing new evidence for occurrence of an early primary bacteraemia. CONCLUSIONS/SIGNIFICANCE: Overall the culture-PCR assay performed well, identifying extra typhoid cases compared with routine blood culture alone. Despite limitations to widespread field-use, the benefits of increased diagnostic yield, reduced blood volume and faster turn-around-time, suggest that this assay could enhance laboratory typhoid diagnostics in research applications and high-incidence settings