Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94

Valproate is a standard treatment for bipolar disorder and a first-line mood stabilizer. The molecular mechanisms underlying its actions in bipolar disorder are unclear. It has been suggested that the action of valproate is linked to changes in gene expression and induction of endoplasmic reticulum (ER) stress-response proteins.Here we show that valproate modulates the ER stress response through the regulation of WFS1, an important component for mitigating ER stress. Therapeutic concentrations of valproate induce expression of WFS1 mRNA and activate the WFS1 promoter. In addition, WFS1 forms a complex with GRP94, an ER stress-response protein, in which valproate dose-dependently enhances its dissociation from GRP94.These results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94

Craniodental Morphology and Systematics of a New Family of Hystricognathous Rodents (Gaudeamuridae) from the Late Eocene and Early Oligocene of Egypt

BACKGROUND: Gaudeamus is an enigmatic hystricognathous rodent that was, until recently, known solely from fragmentary material from early Oligocene sites in Egypt, Oman, and Libya. Gaudeamus' molars are similar to those of the extant cane rat Thryonomys, and multiple authorities have aligned Gaudeamus with Thryonomys to the exclusion of other living and extinct African hystricognaths; recent phylogenetic analyses have, however, also suggested affinities with South American caviomorphs or Old World porcupines (Hystricidae). METHODOLOGY/PRINCIPAL FINDINGS: Here we describe the oldest known remains of Gaudeamus, including largely complete but crushed crania and complete upper and lower dentitions. Unlike younger Gaudeamus species, the primitive species described here have relatively complex occlusal patterns, and retain a number of plesiomorphic features. Unconstrained parsimony analysis nests Gaudeamus and Hystrix within the South American caviomorph radiation, implying what we consider to be an implausible back-dispersal across the Atlantic Ocean to account for Gaudeamus' presence in the late Eocene of Africa. An analysis that was constrained to recover the biogeographically more plausible hypothesis of caviomorph monophyly does not place Gaudeamus as a stem caviomorph, but rather as a sister taxon of hystricids. CONCLUSIONS/SIGNIFICANCE: We place Gaudeamus species in a new family, Gaudeamuridae, and consider it likely that the group originated, diversified, and then went extinct over a geologically brief period of time during the latest Eocene and early Oligocene in Afro-Arabia. Gaudeamurids are the only known crown hystricognaths from Afro-Arabia that are likely to be aligned with non-phiomorph members of that clade, and as such provide additional support for an Afro-Arabian origin of advanced stem and basal crown members of Hystricognathi

An exceptionally well-preserved skeleton of Palaeothentes from the Early Miocene of Patagonia, Argentina: new insights into the anatomy of extinct paucituberculatan marsupials

International audienc

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Research priorities for aortic diseases: results of the James Lind Alliance/Vascular Society GBI priority setting exercise

Background: In order to identify research priorities for aortic disease, a partnership between the Vascular Society of Great Britain and Ireland (VSGBI) and the James Lind Alliance (JLA) was established to capture the interests of a wide group of patients, carers and health professionals. One of the aims of the partnership was to establish the top 10 research priorities in the field of aortic disease.Methods: A modified JLA Priority Setting Partnership was undertaken, during which healthcare professionals, patients and carers participated independently in two Vascular Society of Great Britain and Ireland (VSGBI)-led Delphi processes identifying research priorities in aortic disease. An aortic Special Interest Group composed of patients and healthcare professionals assessed the two lists of priorities, amalgamating similar priorities and generating a final list for ranking. An offer was sent to various patients, carers and healthcare professionals from different backgrounds with an interest in aortic disease to attend the final consensus workshop where a ranked top 10 list of aortic disease research priorities was produced using a nominal group technique.Results: A total of 1,231 research priorities relating to general vascular surgery were submitted by 481 clinicians. From these, 162 aortic-specific research priorities were identified and combined into 15 final clinical priorities. In addition, 582 research priorities related to vascular surgery in general were submitted by 373 patients or carers. From these, 24 further aortic[1]specific research priorities were identified after combining similar priorities. Amalgamation of the clinician and patient priorities resulted in 18 priorities that were taken to the final consensus workshop, where a ranked top 10 list of aortic disease research priorities was produced. These priorities include themes of diagnosis, surveillance, management, recovery and predisposition. Conclusion: A collaborative effort between healthcare professionals and patients has identified a ranked top 10 list of aortic disease research priorities. This list will inform and guide clinicians, researchers and funders for the foreseeable future and will support future research that encompasses the important interests and representation of the wider network involved and affected by aortic disease

Optimization of multiplane ?PIV for wall shear stress and wall topography characterization

Multiplane ?PIV can be utilized to determine the wall shear stress and wall topology from the measured flow over a structured surface. A theoretical model was developed to predict the measurement error for the surface topography and shear stress, based on a theoretical analysis of the precision in PIV measurements. The main parameters that affect the accuracy of the measurement are identified. The effect of different parameter settings is studied by means of Monte Carlo simulations, and the results are compared with an experimental test case. The results are used to determine the recommended parameter settings for this measurement approach.Process and EnergyAerospace Engineerin