Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation

To identify rate-limiting steps in T cell-independent type 2 (TI-2) antibody production against polysaccharide antigens, we performed a genome-wide screen by immunizing several hundred pedigrees of C57BL/6 mice segregating ENU-induced mis-sense mutations. Two independent mutations, Tilcara and Untied, were isolated that semi-dominantly diminished antibody against polysaccharide but not protein antigens. Both mutations resulted from single amino acid substitutions within the kinase domain of Protein Kinase C Beta (PKCβ). In Tilcara, a Ser552>Pro mutation occurred in helix G, in close proximity to a docking site for the inhibitory N-terminal pseudosubstrate domain of the enzyme, resulting in almost complete loss of active, autophosphorylated PKCβI whereas the amount of alternatively spliced PKCβII protein was not markedly reduced. Circulating B cell subsets were normal and acute responses to BCR-stimulation such as CD25 induction and initiation of DNA synthesis were only measurably diminished in Tilcara homozygotes, whereas the fraction of cells that had divided multiple times was decreased to an intermediate degree in heterozygotes. These results, coupled with evidence of numerous mis-sense PRKCB mutations in the human genome, identify Prkcb as a genetically sensitive step likely to contribute substantially to population variability in anti-polysaccharide antibody levels

Protocol for a case-control diagnostic accuracy study to develop diagnostic criteria for psoriasis in children (DIPSOC study): a multicentre study recruiting in UK paediatric dermatology clinics

Introduction Diagnosing psoriasis in children can be challenging. Early and accurate diagnosis is important to ensure patients receive psoriasis specific treatment and monitoring. It is recognised that the physical, psychological, quality of life, financial and comorbid burden of psoriasis are significant. The aim of this study is to develop clinical examination and history-based diagnostic criteria for psoriasis in children to help differentiate psoriasis from other scaly inflammatory rashes. The criteria tested in this study were developed through a consensus study with a group of international psoriasis experts (International Psoriasis Council). Methods and analysis Children and young people (<18 years) with psoriasis (cases) and other scaly inflammatory skin diseases (controls) diagnosed by a dermatologist are eligible for recruitment. All participants complete a single research visit including a diagnostic criteria assessment by a trained investigator blinded to the participant’s diagnosis. The reference standard of a dermatologist’s diagnosis is extracted from the medical record. Sensitivity and specificity of the consensus derived diagnostic criteria will be calculated and the best predictive criteria developed using multivariate logistic regression. Ethics and dissemination Health Regulatory Authority and National Health Service Research Ethics Committee approvals were granted in February 2017 (REC Ref: 17/ EM/0035). Dissemination will be guided by stakeholders; patients, children and

Exact Solutions of the SU(2) Yang-Mills-Higgs Theory

Some exact static solutions of the SU(2) Yang-Mills-Higgs theory are presented. These solutions satisfy the first order Bogomol'nyi equations, and possess infinite energies. They are axially symmetric and could possibly represent monopoles and an antimonopole sitting on the z-axis.Comment: 11 pages, 3 figures, to be presented in the "30th International Conference on High Energy Physics, 27 July - 2 August 2000, Osaka, Japa

Development of efficient, integrated cellulosic biorefineries : LDRD final report.

Cellulosic ethanol, generated from lignocellulosic biomass sources such as grasses and trees, is a promising alternative to conventional starch- and sugar-based ethanol production in terms of potential production quantities, CO{sub 2} impact, and economic competitiveness. In addition, cellulosic ethanol can be generated (at least in principle) without competing with food production. However, approximately 1/3 of the lignocellulosic biomass material (including all of the lignin) cannot be converted to ethanol through biochemical means and must be extracted at some point in the biochemical process. In this project we gathered basic information on the prospects for utilizing this lignin residue material in thermochemical conversion processes to improve the overall energy efficiency or liquid fuel production capacity of cellulosic biorefineries. Two existing pretreatment approaches, soaking in aqueous ammonia (SAA) and the Arkenol (strong sulfuric acid) process, were implemented at Sandia and used to generated suitable quantities of residue material from corn stover and eucalyptus feedstocks for subsequent thermochemical research. A third, novel technique, using ionic liquids (IL) was investigated by Sandia researchers at the Joint Bioenergy Institute (JBEI), but was not successful in isolating sufficient lignin residue. Additional residue material for thermochemical research was supplied from the dilute-acid simultaneous saccharification/fermentation (SSF) pilot-scale process at the National Renewable Energy Laboratory (NREL). The high-temperature volatiles yields of the different residues were measured, as were the char combustion reactivities. The residue chars showed slightly lower reactivity than raw biomass char, except for the SSF residue, which had substantially lower reactivity. Exergy analysis was applied to the NREL standard process design model for thermochemical ethanol production and from a prototypical dedicated biochemical process, with process data supplied by a recent report from the National Research Council (NRC). The thermochemical system analysis revealed that most of the system inefficiency is associated with the gasification process and subsequent tar reforming step. For the biochemical process, the steam generation from residue combustion, providing the requisite heating for the conventional pretreatment and alcohol distillation processes, was shown to dominate the exergy loss. An overall energy balance with different potential distillation energy requirements shows that as much as 30% of the biomass energy content may be available in the future as a feedstock for thermochemical production of liquid fuels

Location Dependent Dirichlet Processes

Dirichlet processes (DP) are widely applied in Bayesian nonparametric modeling. However, in their basic form they do not directly integrate dependency information among data arising from space and time. In this paper, we propose location dependent Dirichlet processes (LDDP) which incorporate nonparametric Gaussian processes in the DP modeling framework to model such dependencies. We develop the LDDP in the context of mixture modeling, and develop a mean field variational inference algorithm for this mixture model. The effectiveness of the proposed modeling framework is shown on an image segmentation task

Evaluation of [18F]AlF-EMP-105 for molecular imaging of 2 C-Met

C-Met is a receptor tyrosine kinase that is overexpressed in a range of different cancer types, and has been identified as a potential biomarker for cancer imaging and therapy. Previously, a 68Ga-labelled peptide, [68Ga]Ga-EMP-100, has shown promise for imaging c-Met in renal cell carcinoma in humans. Herein, we report the synthesis and preliminary biological evaluation of an [18F]AlF-labelled analogue, [18F]AlF-EMP-105, for c-Met imaging by positron emission tomography. EMP-105 was radiolabelled using the aluminium-[18F]fluoride method with 46 ± 2% RCY and >95% RCP in 35–40 min. In vitro evaluation showed that [18F]AlF-EMP-105 has a high specificity for c-Met-expressing cells. Radioactive metabolite analysis at 5 and 30 min post-injection revealed that [18F]AlF-EMP-105 has good blood stability, but undergoes transformation—transchelation, defluorination or demetallation—in the liver and kidneys. PET imaging in non-tumour-bearing mice showed high radioactive accumulation in the kidneys, bladder and urine, demonstrating that the tracer is cleared predominantly as [18F]fluoride by the renal system. With its high specificity for c-Met expressing cells, [18F]AlF-EMP-105 shows promise as a potential diagnostic tool for imaging cancer