The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6

Biallelic mutations in the photoreceptor-expressed aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) are associated with autosomal recessive Leber congenital amaurosis (LCA), the most severe form of inherited retinopathy in early childhood. AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 to facilitate the stable assembly of the retinal cyclic GMP (cGMP) phosphodiesterase (PDE6) holoenzyme. In this study, we characterized the functional deficits of AIPL1 variations, some of which induce aberrant pre-mRNA AIPL1 splicing leading to the production of al- ternative AIPL1 isoforms. We investigated the ability of the AIPL1 variants to mediate an interaction with HSP90 and modulate the rod cGMP PDE6 stability and activity. Our data revealed that both the FK506 binding protein (FKBP)-like domain and the tetra- tricopeptide repeat (TPR) domain of AIPL1 are required for interaction with HSP90. We further demonstrate that AIPL1 signifi- cantly modulates the catalytic activity of heterologously expressed rod PDE6. Although the N-terminal FKBP-like domain of AIPL1 binds the farnesylated PDE6a subunit through direct interaction with the farnesyl moiety, mutations compromising the integrity of the C-terminal TPR domain of AIPL1 also failed to modulate PDE6 activity efficiently. These AIPL1 variants moreover failed to promote the HSP90-dependent stabilization of the PDE6a subunit in the cytosol. In summary, we have successfully vali- dated the disease-causing status of the AIPL1 variations in vitro. Our findings provide insight into the mechanism underlying the co-chaperone role of AIPL1 and will be critical for ensuring an early and effective diagnosis of AIPL1 LCA patients

Development of a candidate reference material for adventitious virus detection in vaccine and biologicals manufacturing by deep sequencing.

Unbiased deep sequencing offers the potential for improved adventitious virus screening in vaccines and biotherapeutics. Successful implementation of such assays will require appropriate control materials to confirm assay performance and sensitivity. A common reference material containing 25 target viruses was produced and 16 laboratories were invited to process it using their preferred adventitious virus detection assay. Fifteen laboratories returned results, obtained using a wide range of wet-lab and informatics methods. Six of 25 target viruses were detected by all laboratories, with the remaining viruses detected by 4-14 laboratories. Six non-target viruses were detected by three or more laboratories. The study demonstrated that a wide range of methods are currently used for adventitious virus detection screening in biological products by deep sequencing and that they can yield significantly different results. This underscores the need for common reference materials to ensure satisfactory assay performance and enable comparisons between laboratories

Evaluation de l'état hydrique et de la masse volumique d'un sol argileux par méthodes géophysiques combinées

In geotechnical engineering, there is a need for a technique to measure in-place density and water content of soil quickly, precisely, and preferably, in a non-destructive manner. Combined traditional electric and electromagnetic methods could answer to this need : they are used in this study to determine the relationships of electrical conductivity and dielectrical permittivity versus hydric properties of loamy sand on a density and moisture controlled site. This plurimetric experimental site is composed of three basins of the same material. Each basin is at one soil water content and composed of several parts compacted at different dry densities. Previous laboratory studies showed that electrical conductivity and dielectrical permittivity increase with the increase of dry density and with the increase of gravimetric water content. The aim of this study is to compare laboratory and in-situ measurement data in order to obtain a model useable on site

A study of a multi-level intervention to improve non-adherence in difficult to control asthma.

SummaryBackgroundDifficult to control asthma accounts for significant morbidity and healthcare cost, and non-adherence to medication is a common cause. It remains unclear if targeting non-adherence in this population improves healthcare outcomes.MethodsAll subjects were referred to a Specialist Difficult Asthma Service (60% from Respiratory physicians); poor adherence was identified using prescription refill records for inhaled combination therapy. A sequential 2 phase study examined the effect of identifying and targeting non-adherence to inhaled long-acting β-agonist/inhaled steroid combination therapy; phase 1 – an observational study utilising objective measures of non-adherence to facilitate a medical concordance discussion followed by phase 2, a 12 month prospective single blind randomised controlled trial where subjects with persistent poor adherence were randomised to a nurse-led menu driven intervention.ResultsA total of 239 patients were assessed; 31 of 83 subjects (37%) who were initially non-adherent, significantly improved adherence after concordance interview, with reduced prescribed daily dose of ICS (data p<0.001), rescue prednisolone courses (data, p<0.001) and hospital admissions (data, p=0.006). With the menu driven intervention, adherence also improved (intervention 37.6% to 61.9%, control group 31.7% to 28.8%) with reduced maintenance oral steroid dose in subjects on maintenance steroids.ConclusionPoor adherence in difficult-to control asthma is common, but when identified and targeted can be improved and this is associated with large improvements in important healthcare outcomes. Previous nihilism towards non-adherence in this population is not supported by this study

Progress on nuclear reaction rates affecting the stellar production of 26Al

The radioisotope 26Al is a key observable for nucleosynthesis in the Galaxy and the environment of the early Solar System. To properly interpret the large variety of astronomical and meteoritic data, it is crucial to understand both the nuclear reactions involved in the production of 26Al in the relevant stellar sites and the physics of such sites. These range from the winds of low- and intermediate-mass asymptotic giant branch (AGB) stars; to massive and very massive stars, both their Wolf-Rayet (WR) winds and their final core-collapse supernovae (CCSN); and the ejecta from novae, the explosions that occur on the surface of a white dwarf accreting material from a stellar companion. Several reactions affect the production of 26Al in these astrophysical objects, including (but not limited to) 25Mg(p,γ)26Al, 26Al(p,γ)27Si, and 26Al(n,p/α). Extensive experimental effort has been spent during recent years to improve our understanding of such key reactions. Here we present a summary of the astrophysical motivation for the study of 26Al, a review of its production in the different stellar sites, and a timely evaluation of the currently available nuclear data. We also provide recommendations for the nuclear input into stellar models and suggest relevant, future experimental work.peerReviewe