The Law of Society: Governance Through Contract

This paper focuses on contract law as a central field in contemporary regulatory practice. In recent years, governance by contract has emerged as the central concept in the context of domestic privatization, domestic and transnational commercial relations and law-and-development projects. Meanwhile, as a result of the neo-formalist attack on contract law, governance of contract through contract adjudication, consumer protection law and judicial intervention into private law relations has come under severe pressure. Building on early historical critique of the formalist foundations of an allegedly private law of the market, the paper assesses the current justifications for contractual governance and posits that only an expanded legal realist perspective can adequately explain the complex nature of contractual agreements in contemporary practice. The paper argues for an understanding of contracts as complex societal arrangements that visibilize and negotiate conflicting rationalities and interests. Institutionally, contractual governance has been unfolding in a complex, historically grown and ideologically continually contested regulatory field. Governance through contract, then, denotes a wide field of conflicting concepts, ideas and symbols, that are themselves deeply entrenched in theories of society, market and the state. From this perspective, we are well advised to study contracts in their socio-economic, historical and cultural context. A careful reading of scholars such as Henry Sumner Maine, Morris Cohen, Robert Hale, Karl Llewellyn, Stewart Macaulay and Ian Macneil offers a deeper understanding of the institutional and normative dimensions of contractual governance. Their analysis is particularly helpful in assessing currently ongoing shifts away from a welfare state based regulation (governance) of contractual relations. Such shifts are occurring on two levels. First, they take place against the backdrop of a neo-liberal critique of government interference into allegedly private relations. Secondly, the increasingly influential return to formalism in contract law, which privileges a functionalist, purportedly technical and autonomous design and execution of contractual agreements over the view of regulated contracts, is linked to a particular concept of sovereignty. The ensuing revival of freedom of contract occurs in remarkable neglect of the experiences of welfare state adjudication of private law adjudication and a continuing contestation of the political in private relationships. The paper takes up the Legal Realists\u27 search for the \u27basis of contract\u27, but seeks to redirect the focus from the traditional perspective on state vs. market to a disembedded understanding of contractual governance as delineating multipolar and multirational regulatory regimes. Where Globalization has led to a fragmentation, disembeddedness and transnationalization of contexts and, thus, has been challenging traditional understanding of embeddedness, the task should no longer be to try applying a largely nation-state oriented Legal Realist perspective and critique to the sphere of contemporary contractual governance, but - rather - to translate its aims into a more reflexive set of instruments of legal critique. Even if Globalization has led to a dramatic denationalization of many regulatory fields and functions, it is still not clear, whether and how Globalization replaces, complements or aggravates transformations of societal governance, with and through contract

Effective Treatment of Respiratory Alphaherpesvirus Infection Using RNA Interference

BACKGROUND: Equine herpesvirus type 1 (EHV-1), a member of the Alphaherpesvirinae, is spread via nasal secretions and causes respiratory disease, neurological disorders and abortions. The virus is a significant equine pathogen, but current EHV-1 vaccines are only partially protective and effective metaphylactic and therapeutic agents are not available. Small interfering RNAs (siRNA's), delivered intranasally, could prove a valuable alternative for infection control. siRNA's against two essential EHV-1 genes, encoding the viral helicase (Ori) and glycoprotein B, were evaluated for their potential to decrease EHV-1 infection in a mouse model. METHODOLOGY/PRINCIPAL FNDINGS: siRNA therapy in vitro significantly reduced virus production and plaque size. Viral titers were reduced 80-fold with 37.5 pmol of a single siRNA or with as little as 6.25 pmol of each siRNA when used in combination. siRNA therapy in vivo significantly reduced viral replication and clinical signs. Intranasal treatment did not require a transport vehicle and proved effective when given up to 12 h before or after infection. CONCLUSIONS/SIGNIFICANCE: siRNA treatment has potential for both prevention and early treatment of EHV-1 infections

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions

Mammalian prions are unusual infectious agents, as they are thought to consist solely of aggregates of misfolded prion protein (PrP). Generation of synthetic prions, composed of recombinant PrP (recPrP) refolded into fibrils, has been utilised to address whether PrP aggregates are, indeed, infectious prions. In several reports, neurological disease similar to transmissible spongiform encephalopathy (TSE) has been described following inoculation and passage of various forms of fibrils in transgenic mice and hamsters. However, in studies described here, we show that inoculation of recPrP fibrils does not cause TSE disease, but, instead, seeds the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). Importantly, both WT-recPrP fibrils and 101L-recPrP fibrils can seed plaque formation, indicating that the fibrillar conformation, and not the primary sequence of PrP in the inoculum, is important in initiating seeding. No replication of infectious prions or TSE disease was observed following both primary inoculation and subsequent subpassage. These data, therefore, argue against recPrP fibrils being infectious prions and, instead, indicate that these pre-formed seeds are acting to accelerate the formation of PrP amyloid plaques in 101LL Tg mice. In addition, these data reproduce a phenotype which was previously observed in 101LL mice following inoculation with brain extract containing in vivo-generated PrP amyloid fibrils, which has not been shown for other synthetic prion models. These data are reminiscent of the “prion-like” spread of aggregated forms of the beta-amyloid peptide (Aβ), α-synuclein and tau observed following inoculation of transgenic mice with pre-formed seeds of each misfolded protein. Hence, even when the protein is PrP, misfolding and aggregation do not reproduce the full clinicopathological phenotype of disease. The initiation and spread of protein aggregation in transgenic mouse lines following inoculation with pre-formed fibrils may, therefore, more closely resemble a seeded proteinopathy than an infectious TSE disease