Protein sorting gone wrong - VPS10P domain receptors in cardiovascular and metabolic diseases

VPS10P domain receptors are a unique class of sorting receptors that direct intracellular transport of target proteins in neurons and that play central roles in neurodegenerative processes. Surprisingly, genome-wide association studies now implicate the very same receptors in cardiovascular and metabolic disturbances. In this review, we discuss current findings that uncovered some of the molecular mechanisms whereby sorting receptors, such as SORLA, sortilin, and SORCS1 control homeostasis in cardiovascular and metabolic tissues, and how they promote hypercholesterolemia, atherosclerosis, obesity, and diabetes, when being altered

SORLA/SORL1, a neuronal sorting receptor implicated in Alzheimer's disease

The proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid-beta peptides in the brain has been recognized as a major pathological pathway in Alzheimer's disease (AD). Yet, the factors that control the processing of APP and their potential contribution to the common sporadic form of AD remain poorly understood. Here, we review recent findings from studies in patients and in animal models that led to the identification of a unique sorting receptor for APP in neurons, designated SORLA/SORL1, that emerges as a key player in amyloidogenic processing and as major genetic risk factor for AD

Neutron Scattering Study of Crystal Field Energy Levels and Field Dependence of the Magnetic Order in Superconducting HoNi2B2C

Elastic and inelastic neutron scattering measurements have been carried out to investigate the magnetic properties of superconducting (Tc~8K) HoNi2B2C. The inelastic measurements reveal that the lowest two crystal field transitions out of the ground state occurat 11.28(3) and 16.00(2) meV, while the transition of 4.70(9) meV between these two levels is observed at elevated temperatures. The temperature dependence of the intensities of these transitions is consistent with both the ground state and these higher levels being magnetic doublets. The system becomes magnetically long range ordered below 8K, and since this ordering energy kTN ~ 0.69meV << 11.28meV the magnetic properties in the ordered phase are dominated by the ground-state spin dynamics only. The low temperature structure, which coexists with superconductivity, consists of ferromagnetic sheets of Ho{3+ moments in the a-b plane, with the sheets coupled antiferromagnetically along the c-axis. The magnetic state that initially forms on cooling, however, is dominated by an incommensurate spiral antiferromagnetic state along the c-axis, with wave vector qc ~0.054 A-1, in which these ferromagnetic sheets are canted from their low temperature antiparallel configuration by ~17 deg. The intensity for this spiral state reaches a maximum near the reentrant superconducting transition at ~5K; the spiral state then collapses at lower temperature in favor of the commensurate antiferromagnetic state. We have investigated the field dependence of the magnetic order at and above this reentrant superconducting transition. Initially the field rotates the powder particles to align the a-b plane along the field direction, demonstrating that the moments strongly prefer to lie within this plane due to the crystal field anisotropy. Upon subsequently increasing the field atComment: RevTex, 7 pages, 11 figures (available upon request); Physica

Dynamics and Scaling of 2D Polymers in a Dilute Solution

The breakdown of dynamical scaling for a dilute polymer solution in 2D has been suggested by Shannon and Choy [Phys. Rev. Lett. {\bf 79}, 1455 (1997)]. However, we show here both numerically and analytically that dynamical scaling holds when the finite-size dependence of the relevant dynamical quantities is properly taken into account. We carry out large-scale simulations in 2D for a polymer chain in a good solvent with full hydrodynamic interactions to verify dynamical scaling. This is achieved by novel mesoscopic simulation techniques

Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD

Quantum non-demolition (QND) modulation of quantum interference

We propose an experiment where quantum interference between two different paths is modulated by means of a QND measurement on one or both the arm of the interferometer. The QND measurement is achieved in a Kerr cell. We illustrate a scheme for the realisation of this experiment and some further developments.Comment: accepted for publicatio

Mortality and causes of death in patients with sporadic inclusion body myositis: Survey study based on the clinical experience of specialists in Australia, Europe and the USA

Background: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. Objective: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians’ views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. Methods: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus. Results: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. Conclusions: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies

Stellar structure and compact objects before 1940: Towards relativistic astrophysics

Since the mid-1920s, different strands of research used stars as "physics laboratories" for investigating the nature of matter under extreme densities and pressures, impossible to realize on Earth. To trace this process this paper is following the evolution of the concept of a dense core in stars, which was important both for an understanding of stellar evolution and as a testing ground for the fast-evolving field of nuclear physics. In spite of the divide between physicists and astrophysicists, some key actors working in the cross-fertilized soil of overlapping but different scientific cultures formulated models and tentative theories that gradually evolved into more realistic and structured astrophysical objects. These investigations culminated in the first contact with general relativity in 1939, when J. Robert Oppenheimer and his students George Volkoff and Hartland Snyder systematically applied the theory to the dense core of a collapsing neutron star. This pioneering application of Einstein's theory to an astrophysical compact object can be regarded as a milestone in the path eventually leading to the emergence of relativistic astrophysics in the early 1960s.Comment: 83 pages, 4 figures, submitted to the European Physical Journal