Lineage tree analysis of immunoglobulin variable-region gene mutations in autoimmune diseases: chronic activation, normal selection

Autoimmune diseases show high diversity in the affected organs, clinical manifestations and disease dynamics. Yet they all share common features, such as the ectopic germinal centers found in many affected tissues. Lineage trees depict the diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. We previously developed an algorithm for quantifying the graphical properties of IGV gene lineage trees, allowing evaluation of the dynamical interplay between SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we apply this method to ectopic GC B cell clones from patients with Myasthenia Gravis, Rheumatoid Arthritis, and Sjögren’s Syndrome, using data scaling to minimize the effects of the large variability due to methodological differences between groups. Autoimmune trees were found to be significantly larger relative to normal controls. In contrast, comparison of the measurements for tree branching indicated that similar selection pressure operates on autoimmune and normal control clones

Data management for prospective research studies using SAS® software

<p>Abstract</p> <p>Background</p> <p>Maintaining data quality and integrity is important for research studies involving prospective data collection. Data must be entered, erroneous or missing data must be identified and corrected if possible, and an audit trail created.</p> <p>Methods</p> <p>Using as an example a large prospective study, the Missouri Lower Respiratory Infection (LRI) Project, we present an approach to data management predominantly using SAS software. The Missouri LRI Project was a prospective cohort study of nursing home residents who developed an LRI. Subjects were enrolled, data collected, and follow-ups occurred for over three years. Data were collected on twenty different forms. Forms were inspected visually and sent off-site for data entry. SAS software was used to read the entered data files, check for potential errors, apply corrections to data sets, and combine batches into analytic data sets. The data management procedures are described.</p> <p>Results</p> <p>Study data collection resulted in over 20,000 completed forms. Data management was successful, resulting in clean, internally consistent data sets for analysis. The amount of time required for data management was substantially underestimated.</p> <p>Conclusion</p> <p>Data management for prospective studies should be planned well in advance of data collection. An ongoing process with data entered and checked as they become available allows timely recovery of errors and missing data.</p

Surface acoustic wave attenuation by a two-dimensional electron gas in a strong magnetic field

The propagation of a surface acoustic wave (SAW) on GaAs/AlGaAs heterostructures is studied in the case where the two-dimensional electron gas (2DEG) is subject to a strong magnetic field and a smooth random potential with correlation length Lambda and amplitude Delta. The electron wave functions are described in a quasiclassical picture using results of percolation theory for two-dimensional systems. In accordance with the experimental situation, Lambda is assumed to be much smaller than the sound wavelength 2*pi/q. This restricts the absorption of surface phonons at a filling factor \bar{\nu} approx 1/2 to electrons occupying extended trajectories of fractal structure. Both piezoelectric and deformation potential interactions of surface acoustic phonons with electrons are considered and the corresponding interaction vertices are derived. These vertices are found to differ from those valid for three-dimensional bulk phonon systems with respect to the phonon wave vector dependence. We derive the appropriate dielectric function varepsilon(omega,q) to describe the effect of screening on the electron-phonon coupling. In the low temperature, high frequency regime T << Delta (omega_q*Lambda /v_D)^{alpha/2/nu}, where omega_q is the SAW frequency and v_D is the electron drift velocity, both the attenuation coefficient Gamma and varepsilon(omega,q) are independent of temperature. The classical percolation indices give alpha/2/nu=3/7. The width of the region where a strong absorption of the SAW occurs is found to be given by the scaling law |Delta \bar{\nu}| approx (omega_q*Lambda/v_D)^{alpha/2/nu}. The dependence of the electron-phonon coupling and the screening due to the 2DEG on the filling factor leads to a double-peak structure for Gamma(\bar{\nu}).Comment: 17 pages, 3 Postscript figures, minor changes mad

Commercial shellfish skin prick test extracts show critical variability in allergen repertoire

[Extract] Crustacean and mollusc (shellfish) allergy affects up to 3% of the general population, is usually lifelong and commonly triggers anaphylaxis.1 Allergen repertoire diversity among hundreds of edible shellfish species worldwide is poorly reflected in available in vivo and in vitro diagnostic tools for shellfish allergy. Skin prick testing (SPT) is often the preferred first-line diagnostic approach. However, widely utilized commercial SPT extracts are generally not standardized, limiting the diagnostic value of results.2 Asero et al. reported a heterogeneous abundance of three shellfish allergens in five commercial crustacean SPT extracts, resulting in 32 clinical profiles among 157 shrimp-allergic patients.3 In 2019, we demonstrated considerable variability in allergen repertoire and IgE-binding for 27 commercial fish SPT extracts.4 We now report an even greater, critical variability for 11 commercial crustacean and five mollusc SPT extracts, utilizing biochemical and immunological methods and mass spectrometry (see Appendix S1 for methodology and TableS1 for allergen extract details)

Going Ballistic: Graphene Hot Electron Transistors

This paper reviews the experimental and theoretical state of the art in ballistic hot electron transistors that utilize two-dimensional base contacts made from graphene, i.e. graphene base transistors (GBTs). Early performance predictions that indicated potential for THz operation still hold true today, even with improved models that take non-idealities into account. Experimental results clearly demonstrate the basic functionality, with on/off current switching over several orders of magnitude, but further developments are required to exploit the full potential of the GBT device family. In particular, interfaces between graphene and semiconductors or dielectrics are far from perfect and thus limit experimental device integrity, reliability and performance

Quantum Hall Effect in Three Dimensional Layered Systems

Using a mapping of a layered three-dimensional system with significant inter-layer tunneling onto a spin-Hamiltonian, the phase diagram in the strong magnetic field limit is obtained in the semi-classical approximation. This phase diagram, which exhibit a metallic phase for a finite range of energies and magnetic fields, and the calculated associated critical exponent, $\nu=4/3$, agree excellently with existing numerical calculations. The implication of this work for the quantum Hall effect in three dimensions is discussed.Comment: 4 pages + 4 figure

The first reptilian allergen and major allergen for fish-allergic patients: Crocodile β-parvalbumin

Background: Clinical cross-reactivity between bony fish, cartilaginous fish, frog, and chicken muscle has previously been demonstrated in fish-allergic patients. In indicative studies, two reports of anaphylaxis following the consumption of crocodile meat and IgE-cross-binding were linked to the major fish allergen parvalbumin (PV). This study investigates IgE-binding proteins in crocodile meat with a focus on PV and their clinical relevance. Methods: Proteins were extracted from muscle tissue of crocodile, three bony fish, and two cartilaginous fish. A cohort of fish-allergic pediatric patients (n = 77) underwent allergen skin prick testing (SPT) to three fish preparations (n = 77) and crocodile (n = 12). IgE-binding proteins were identified and quantified by SDS-PAGE, mass spectrometric analyses, and immunoblotting using commercial and in-house antibodies, as well as individual and pooled patients’ serum. PV isoforms were purified or recombinantly expressed before immunological analyses, including human mast cell degranulation assay. Results: Of the tissues analyzed, PV was most abundant in heated crocodile preparation, triggering an SPT of ≥3 mm in 8 of 12 (67%) fish-allergic patients. Seventy percent (31 of 44) of fish PV-sensitized patients demonstrated IgE-binding to crocodile PV. Crocodile β-PV was the major IgE-binding protein but 20-fold less abundant than α-PV. Cellular reactivity was demonstrated for β-PV and epitopes predicted, explaining frequent IgE-cross-binding of β-PVs. Both PV isoforms are now registered as the first reptile allergens with the WHO/IUIS (β-PV as Cro p 1 and α-PV as Cro p 2). Conclusion: Fish-allergic individuals may be at risk of an allergy to crocodile and should seek specialist advice before consuming crocodilian meat

Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency

Contains fulltext : 177329.pdf (Publisher’s version ) (Open Access

Defective protein prenylation in a spectrum of patients with mevalonate kinase deficiency

The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the MVK gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous MVK genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant, MVK V377I . We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous MVK V377I patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic MVK variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD.Marcia A. Munoz, Julie Jurczyluk, Anna Simon, Pravin Hissaria, Rob J. W. Arts, David Coman, Christina Boros, Sam Mehr, and Michael J. Roger