Contracts for Interacting Two-Party Systems

This article deals with the interrelation of deontic operators in contracts -- an aspect often neglected when considering only one of the involved parties. On top of an automata-based semantics we formalise the onuses that obligations, permissions and prohibitions on one party impose on the other. Such formalisation allows for a clean notion of contract strictness and a derived notion of contract conflict that is enriched with issues arising from party interdependence.Comment: In Proceedings FLACOS 2012, arXiv:1209.169

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states

On a clear day you can see forever : integrating values and skills in sex offender treatment

The topic of sex offender rehabilitation frequently evokes fierce reactions, ranging from strident demands for harsher sentences contrasted with calls for more imaginative and compassionate sentencing options. There seems to be a polarization of positions centred on the question of offenders\u27 moral standing: are they moral strangers or fellow travellers? This fundamental disagreement about offenders\u27 moral status is at the core of a number of independent, although related current practice and research issues confronting the field, namely: (1) risk management versus strength-based treatment approaches; (2) the utility of utilizing individually tailored versus manual-based programmes for offenders; (3) focusing on the technical aspects or therapy as opposed to relationship and therapist factors (what has been called process issues); and (4) the conflict between protecting the community versus promoting the interests of offenders. In this paper I suggest that an approach to sex offender treatment based on a combination of human rights theory (an ethical resource) and strengths-based approaches can help us navigate our way through the above dilemmas in a way that addressees both the needs of offenders and those of the community

Safety, fairness, and inclusion: transgender athletes and the essence of Rugby

In this paper, I link philosophical discussion of policies for trans inclusion or exclusion, to a method of policy making. I address the relationship between concerns about safety, fairness, and inclusion in policy making about the inclusion of transwomen athletes into women’s sport. I argue for an approach based on lexical priority rather than simple ‘balancing’, considering the different values in a specific order. I present justifying reasons for this approach and this lexical order, based on the special obligations of International Federations such as World Rugby. As a result, I provide a justificatory framework for the WR Guidelines that exclude transwomen from the women’s game in WR competitions. Finally, I give an account of a maximally safe, maximally fair and maximally inclusive form of sex categorisation in sport

My body and other objects : the internal limits of self‐ownership

Common practices such as donating blood or selling hair assume rights of disposal over oneself that are similar to, if not indistinguishable from, property rights. However, a simple view of self‐ownership fails to capture relevant moral differences between parts of a person and other objects. In light of this, we require some account of the continuity in the form of ownership rights a person has over herself and other objects, which also acknowledges the normative differences between constitutive parts of a person, on the one hand, and external objects, on the other. This paper provides such an account by arguing that there are reasons internal to a general justification of property rights to limit the extent of powers included in ownership of different kinds of object, depending on how the person is situated in relation to them. Rejecting a typical Hohfeldian view of property as a univocal, gradable concept allows us to make space for a new approach to property and self‐ownership: one which can make sense of various uses of the body as property without entailing that our relation to those parts is exhaustively characterised by an ordinary property right

Haploinsufficiency of the E3 Ubiquitin Ligase C-Terminus of Heat Shock Cognate 70 Interacting Protein (CHIP) Produces Specific Behavioral Impairments

The multifunctional E3 ubiquitin ligase CHIP is an essential interacting partner of HSP70, which together promote the proteasomal degradation of client proteins. Acute CHIP overexpression provides neuroprotection against neurotoxic mitochondrial stress, glucocorticoids, and accumulation of toxic amyloid fragments, as well as genetic mutations in other E3 ligases, which have been shown to result in familial Parkinson's disease. These studies have created a great deal of interest in understanding CHIP activity, expression and modulation. While CHIP knockout mice have the potential to provide essential insights into the molecular control of cell fate and survival, the animals have been difficult to characterize in vivo due to severe phenotypic and behavioral dysfunction, which have thus far been poorly characterized. Therefore, in the present study we conducted a battery of neurobehavioral and physiological assays of adult CHIP heterozygotic (HET) mutant mice to provide a better understanding of the functional consequence of CHIP deficiency. We found that CHIP HET mice had normal body and brain weight, body temperature, muscle tone and breathing patterns, but do have a significant elevation in baseline heart rate. Meanwhile basic behavioral screens of sensory, motor, emotional and cognitive functions were normative. We observed no alterations in performance in the elevated plus maze, light-dark preference and tail suspension assays, or two simple cognitive tasks: novel object recognition and spontaneous alternation in a Y maze. Significant deficits were found, however, when CHIP HET mice performed wire hang, inverted screen, wire maneuver, and open field tasks. Taken together, our data indicate a clear subset of behaviors that are altered at baseline in CHIP deficient animals, which will further guide whole animal studies of the effects of CHIP dysregulation on cardiac function, brain circuitry and function, and responsiveness to environmental and cellular stress

High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers

Sensitivity to oestrogens and apoptosis are critical determinants of the development and progression of breast cancer and reflect closely linked pathways in breast epithelial cells. For example, induction of BCL-2 oncoprotein expression by oestrogen contributes to suppression of apoptosis and BCL-2 and oestrogen receptor (ER) are frequently co-expressed in tumours. BAG-1/HAP is a multifunctional protein which complexes with BCL-2 and steroid hormone receptors (including the ER), and can suppress apoptosis and influence steroid hormone-dependent transcription. Therefore, analysis of expression of BAG-1 in human breast cancer is of considerable interest. BAG-1 was readily detected by immunostaining in normal breast epithelial cells and most ER-positive tumours, but was undetectable or weakly expressed in ER-negative tumours. BAG-1 positive cells showed a predominantly cytoplasmic or cytoplasmic plus nuclear distribution of staining. A correlation between ER and BAG-1 was also evident in breast cancer derived cell lines, as all lines examined with functional ER expression also expressed high levels of BAG-1. In addition to the prototypical 36 kDa BAG-1 isoform, breast cancer cells expressed higher molecular weight isoforms and, in contrast to BCL-2, BAG-1 expression was independent of oestrogens. BAG-1 isoforms were differentially localized to the nucleus or cytoplasm and this was also independent of oestrogens. These results demonstrate a close association between BAG-1 and functional ER expression and suggest BAG-1 may be useful as a therapeutic target or prognostic marker in breast cancer. © 1999 Cancer Research Campaig

The Lid Domain of Caenorhabditis elegans Hsc70 Influences ATP Turnover, Cofactor Binding and Protein Folding Activity

Hsc70 is a conserved ATP-dependent molecular chaperone, which utilizes the energy of ATP hydrolysis to alter the folding state of its client proteins. In contrast to the Hsc70 systems of bacteria, yeast and humans, the Hsc70 system of C. elegans (CeHsc70) has not been studied to date