Failure of Local Realism Revealed by Extremely-Coarse-Grained Measurements

We show that failure of local realism can be revealed to observers for whom only extremely-coarse-grained measurements are available. In our instances, Bell's inequality is violated even up to the maximum limit while both the local measurements and the initial local states under scrutiny approach the classical limit. Furthermore, we can observe failure of local realism when an inequality enforced by nonlocal realistic theories is satisfied. This suggests that locality alone may be violated while realism cannot be excluded for specific observables and states. Small-scale experimental demonstration of our examples may be possible in the foreseeable future.

Developing critical social work in theory and in practice: child protection and communicative reason

This paper argues that a critical analysis of the ideologies that inform contemporary child care has been missing from the ‘re-focusing debate’. Such an analysis points up the necessity of reasserting a critical social work position in order to provide a basis for reconstructing practice and engaging with other social actors and their ideologies in an open and creative fashion compatible with Habermas’ aspiration of ‘communicative reason’.

Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline.

Abstract A classic physiologic response to hypoxia in humans is the up-regulation of the ERYTHROPOIETIN (EPO) gene, which is the central regulator of red blood cell mass. The EPO gene, in turn, is activated by hypoxia inducible factor (HIF). HIF is a transcription factor consisting of an alpha subunit (HIF-alpha) and a beta subunit (HIF-beta). Under normoxic conditions, prolyl hydroxylase domain protein (PHD, also known as HIF prolyl hydroxylase and egg laying-defective nine protein) site specifically hydroxylates HIF-alpha in a conserved LXXLAP motif (where underlining indicates the hydroxylacceptor proline). This provides a recognition motif for the von Hippel Lindau protein, a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF-alpha for degradation. Under hypoxic conditions, this inherently oxygen-dependent modification is arrested, thereby stabilizing HIF-alpha and allowing it to activate the EPO gene. We previously identified and characterized an erythrocytosis-associated HIF2A mutation, G537W. More recently, we reported two additional erythrocytosis-associated HIF2A mutations, G537R and M535V. Here, we describe the functional characterization of these two mutants as well as a third novel erythrocytosis-associated mutation, P534L. These mutations affect residues C-terminal to the LXXLAP motif. We find that all result in impaired degradation and thus aberrant stabilization of HIF-2alpha. However, each exhibits a distinct profile with respect to their effects on PHD2 binding and von Hippel Lindau interaction. These findings reinforce the importance of HIF-2alpha in human EPO regulation, demonstrate heterogeneity of functional defects arising from these mutations, and point to a critical role for residues C-terminal to the LXXLAP motif in HIF-alpha.