Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation : a tale of the unexpected

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms

Evaluation of elicitation methods to quantify Bayes linear models

The Bayes linear methodology allows decision makers to express their subjective beliefs and adjust these beliefs as observations are made. It is similar in spirit to probabilistic Bayesian approaches, but differs as it uses expectation as its primitive. While substantial work has been carried out in Bayes linear analysis, both in terms of theory development and application, there is little published material on the elicitation of structured expert judgement to quantify models. This paper investigates different methods that could be used by analysts when creating an elicitation process. The theoretical underpinnings of the elicitation methods developed are explored and an evaluation of their use is presented. This work was motivated by, and is a precursor to, an industrial application of Bayes linear modelling of the reliability of defence systems. An illustrative example demonstrates how the methods can be used in practice

The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition

The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation

Identification of the protein kinases Pyk3 and Phg2 as regulators of the STATc-mediated response to hyperosmolarity

Cellular adaptation to changes in environmental osmolarity is crucial for cell survival. In Dictyostelium, STATc is a key regulator of the transcriptional response to hyperosmotic stress. Its phosphorylation and consequent activation is controlled by two signaling branches, one cGMP- and the other Ca(2+)-dependent, of which many signaling components have yet to be identified. The STATc stress signalling pathway feeds back on itself by upregulating the expression of STATc and STATc-regulated genes. Based on microarray studies we chose two tyrosine-kinase like proteins, Pyk3 and Phg2, as possible modulators of STATc phosphorylation and generated single and double knock-out mutants to them. Transcriptional regulation of STATc and STATc dependent genes was disturbed in pyk3(-), phg2(-), and pyk3(-)/phg2(-) cells. The absence of Pyk3 and/or Phg2 resulted in diminished or completely abolished increased transcription of STATc dependent genes in response to sorbitol, 8-Br-cGMP and the Ca(2+) liberator BHQ. Also, phospho-STATc levels were significantly reduced in pyk3(-) and phg2(-) cells and even further decreased in pyk3(-)/phg2(-) cells. The reduced phosphorylation was mirrored by a significant delay in nuclear translocation of GFP-STATc. The protein tyrosine phosphatase 3 (PTP3), which dephosphorylates and inhibits STATc, is inhibited by stress-induced phosphorylation on S448 and S747. Use of phosphoserine specific antibodies showed that Phg2 but not Pyk3 is involved in the phosphorylation of PTP3 on S747. In pull-down assays Phg2 and PTP3 interact directly, suggesting that Phg2 phosphorylates PTP3 on S747 in vivo. Phosphorylation of S448 was unchanged in phg2(-) cells. We show that Phg2 and an, as yet unknown, S448 protein kinase are responsible for PTP3 phosphorylation and hence its inhibition, and that Pyk3 is involved in the regulation of STATc by either directly or indirectly activating it. Our results add further complexities to the regulation of STATc, which presumably ensure its optimal activation in response to different environmental cues

Directed flow of antiprotons in Au+Au collisions at AGS

Directed flow of antiprotons is studied in Au+Au collisions at a beam momentum of 11.5A GeV/c. It is shown that antiproton directed flow is anti-correlated to proton flow. The measured transverse momentum dependence of the antiproton flow is compared with predictions of the RQMD event generator.Comment: 16 pages, 6 figure

Proton and Pion Production in Au+Au Collisions at 10.8A GeV/c

We present proton and pion tranverse momentum spectra and rapidity distributions for Au+Au collisions at 10.8A GeV/c. The proton spectra exhibit collective transverse flow effects. Evidence of the influence of the Coulomb interaction from the fireball is found in the pion transverse momentum spectra. The data are compared with the predictions of the RQMD event generator.Comment: plain tex (revtex), 24 pages Submitted to Phys. Rev.

Charged Particle Pseudorapidity Distributions in Au+Al, Cu, Au, and U Collisions at 10.8 A⋅\cdotGeV/c

We present the results of an analysis of charged particle pseudorapidity distributions in the central region in collisions of a Au projectile with Al, Cu, Au, and U targets at an incident energy of 10.8~GeV/c per nucleon. The pseudorapidity distributions are presented as a function of transverse energy produced in the target or central pseudorapidity regions. The correlation between charged multiplicity and transverse energy measured in the central region, as well as the target and projectile regions is also presented. We give results for transverse energy per charged particle as a function of pseudorapidity and centrality.Comment: 31 pages + 12 figures (compressed and uuencoded by uufiles), LATEX, Submitted to PR

Two-Proton Correlations from 14.6A GeV/c Si+Pb and 11.5A GeV/c Au+Au Central Collisions

Two-proton correlation functions have been measured in Si+Pb collisions at 14.6A GeV/c and Au+Au collisions at 11.5A GeV/c by the E814/E877 collaboration. Data are compared with predictions of the transport model RQMD and the source size is inferred from this comparison. Our analysis shows that, for both reactions, the characteristic size of the system at freeze-out exceeds the size of the projectile, suggesting that the fireball created in the collision has expanded. For Au+Au reactions, the observed centrality dependence of the two-proton correlation function implies that more central collisions lead to a larger source sizes.Comment: RevTex, 12 pages, 5 figure

Hadron yields and spectra in Au+Au collisions at the AGS

Inclusive double differential multiplicities and rapidity density distributions of hadrons are presented for 10.8 A GeV/c Au+Au collisions as measured at the AGS by the E877 collaboration. The results indicate that large amounts of stopping and collective transverse flow effects are present. The data are also compared to the results from the lighter Si+Al system.Comment: 12 pages, latex, 10 figures, submitted to Nuclear Physics A (Quark Matter 1996 Proceedings