Optical Tolerance Analysis of the Multi-Beam Limb Viewing Instrument STEAMR

In this paper, we report on an optical tolerance analysis of the submillimeter atmospheric multi-beam limb sounder, STEAMR. Physical optics and ray-tracing methods were used to quantify and separate errors in beam pointing and distortion due to reflector misalignment and primary reflector surface deformations. Simulations were performed concurrently with the manufacturing of a multi-beam demonstrator of the relay optical system which shapes and images the beams to their corresponding receiver feed horns. Results from Monte Carlo simulations show that the inserts used for reflector mounting should be positioned with an overall accuracy better than 100 μm (~ 1/10 wavelength). Analyses of primary reflector surface deformations show that a deviation of magnitude 100 μm can be tolerable before deployment, whereas the corresponding variations should be less than 30 μm during operation. The most sensitive optical elements in terms of misalignments are found near the focal plane. This localized sensitivity is attributed to the off-axis nature of the beams at this location. Post-assembly mechanical measurements of the reflectors in the demonstrator show that alignment better than 50 μm could be obtained.

Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates.

Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1) linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt) induces p62 phosphorylation at its ubiquitin-association (UBA) domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington's disease.

Religion as Culture? How European and American High Courts Endorse Majority Religion

This paper examines a trend in European and American High Courts to endorse majority religion by transforming it into “culture”, and thus by secularizing it. To dissociate religion and state is the hallmark of the liberal state. However, no state has ever managed a perfect separation, not even the American. Under conditions of mounting religious pluralism and ongoing secularization, there is pressure on the state to live up to its “neutrality”. A main strategy to square the circle of neutrality and incomplete dissociation from religion is to declare it “culture”, which gives the state the license to associate or even identify with it (as guardian of nationhood). The paper compares recent American and European High Court rules on religious symbols (especially crucifixes) that exhibits this strategy, addressing similarities and differences as well as the limits and pitfalls of “culturalizing” religion.

Dysfunction of respiratory muscles in critically ill patients on the intensive care unit.

Muscular weakness and muscle wasting may often be observed in critically ill patients on intensive care units (ICUs) and may present as failure to wean from mechanical ventilation. Importantly, mounting data demonstrate that mechanical ventilation itself may induce progressive dysfunction of the main respiratory muscle, i.e. the diaphragm. The respective condition was termed 'ventilator-induced diaphragmatic dysfunction' (VIDD) and should be distinguished from peripheral muscular weakness as observed in 'ICU-acquired weakness (ICU-AW)'. Interestingly, VIDD and ICU-AW may often be observed in critically ill patients with, e.g. severe sepsis or septic shock, and recent data demonstrate that the pathophysiology of these conditions may overlap. VIDD may mainly be characterized on a histopathological level as disuse muscular atrophy, and data demonstrate increased proteolysis and decreased protein synthesis as important underlying pathomechanisms. However, atrophy alone does not explain the observed loss of muscular force. When, e.g. isolated muscle strips are examined and force is normalized for cross-sectional fibre area, the loss is disproportionally larger than would be expected by atrophy alone. Nevertheless, although the exact molecular pathways for the induction of proteolytic systems remain incompletely understood, data now suggest that VIDD may also be triggered by mechanisms including decreased diaphragmatic blood flow or increased oxidative stress. Here we provide a concise review on the available literature on respiratory muscle weakness and VIDD in the critically ill. Potential underlying pathomechanisms will be discussed before the background of current diagnostic options. Furthermore, we will elucidate and speculate on potential novel future therapeutic avenues.