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

Mutational patterns along different evolution paths of follicular lymphoma

Follicular lymphoma (FL) is an indolent disease, characterized by a median life expectancy of 18-20 years and by intermittent periods of relapse and remission. FL frequently transforms into the more aggressive diffuse large B cell lymphoma (t-FL). In previous studies, the analysis of immunoglobulin heavy chain variable region (IgHV) genes in sequential biopsies from the same patient revealed two different patterns of tumor clonal evolution: direct evolution, through acquisition of additional IgHV mutations over time, or divergent evolution, in which lymphoma clones from serial biopsies independently develop from a less-mutated common progenitor cell (CPC). Our goal in this study was to characterize the somatic hypermutation (SHM) patterns of IgHV genes in sequential FL samples from the same patients, and address the question of whether the mutation mechanisms (SHM targeting, DNA repair or both), or selection forces acting on the tumor clones, were different in FL samples compared to healthy control samples, or in late relapsed/transformed FL samples compared to earlier ones. Our analysis revealed differences in the distribution of mutations from each of the nucleotides when tumor and non-tumor clones were compared, while FL and transformed FL (t-FL) tumor clones displayed similar mutation distributions. Lineage tree measurements suggested that either initial clone affinity or selection thresholds were lower in FL samples compared to controls, but similar between FL and t-FL samples. Finally, we observed that both FL and t-FL tumor clones tend to accumulate larger numbers of potential N-glycosylation sites due to the introduction of new SHM. Taken together, these results suggest that transformation into t-FL, in contrast to initial FL development, is not associated with any major changes in DNA targeting or repair, or the selection threshold of the tumor clone

Cystic Fibrosis - An Ever Evolving Challenge

Cystic fibrosis (CF) is a genetic disease that results from mutations in a large single gene located on chromosome 7. More than 2000 different mutations in the gene have been identified to have caused the disease. Most of these mutations are exceedingly rare and therefore not a part of CF screening or all testing panels. This case discusses an adult female with a history of asthma, bronchiectasis, pseudomonas colonization, and respiratory failure on chronic oxygen who presented to the ED with sudden onset shortness of breath, fever, chills, body aches, nonproductive cough, and headache. The patient\u27s condition clinically improved with treatment and was discharged on day three. The patient had previously undergone a laboratory evaluation of bronchiectasis. Due to the patient\u27s history of bronchiectasis and pseudomonas colonization, there was a decision to reconsider the possibility of CF. The patient underwent a routine cystic fibrosis genetic testing panel which subsequently confirmed a CFTR mutation. The discussion highlights the importance of remaining vigilant for signs of CF, to remain open to the possibility of CF or CFTR related disorders, when patients have had evaluations for such that predate current testing standards or capabilities

Comparing Laser Diffraction and Optical Microscopy for Characterizing Superabsorbent Polymer Particle Morphology, Size, and Swelling Capacity

In this study, we determined the accuracy and practicality of using optical microscopy (OM) and laser diffraction (LD) to characterize hydrogel particle morphology, size, and swelling capacity (Q). Inverse-suspension-polymerized polyacrylamide particles were used as a model system. OM and LD showed that the average particle diameter varied with the mixing speed during synthesis for the dry (10–120 lm) and hydrated (34–240 lm) particles. The LD volume and number mean diameters showed that a few large particles were responsible for the majority of the water absorption. Excess water present in the gravimetric swelling measurements led to larger Qs (8.2 6 0.37 g/g), whereas the volumetric measurements with OM and LD resulted in reduced capacities (6.5 6 3.8 and 5.7 6 3.9 g/g, respectively). Results from the individual particle swelling measurements with OM (5.2 6 0.66 g/g) statistically confirmed that the volumetric methods resulted in a reduced and more accurate measurement of the Q than the gravimetric method

Probing Natural Killer Cell Education by Ly49 Receptor Expression Analysis and Computational Modelling in Single MHC Class I Mice

Murine natural killer (NK) cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for “missing self” recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an “educating impact” on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors

Marine environmental parameters influencing the distribution of Avicenna marina forests using logistic regression (Case Study: Hormozgan province)

This study predicates the prone areas for developing Avicenna Marina forests along the coastal areas of Hormozgan province by studying the oceanography features influencing these forests and using logistic regression models. Tidal areas, flooding level, salinity of water and waves were recognized as influencing variables. The prediction of prone areas was based on using logistic regression model and the validity of the model was studied by ROC test and Pseudo-R 2 .The results of this study indicates that; firstly the maximum wave height, the average maximum flooding level and the level of sanity of water are significantly associated with the presence of Mangrove and the high level of parameters of ROC and Pseudo-R 2 confirm the validity of the model. Secondly the maximum wave height was introduced as the main marine parameter influencing the Mangrove communities. Finally the eastern part of the Persian Gulf coast and the west coast of Oman were found as the most suitable areas for developing Mangrove forest

Metformin attenuates streptozotocin-induced diabetic nephropathy in rats through activation of AMPK signaling pathway

Background: Nephropathy is the main problem of diabetes and can be classified into several phases according to the presence of albuminuria. Adenosine monophosphate-activated protein kinase (AMPK) operates as a sensor of energy charge. Objectives: The aim of our study was to evaluate the reno-protective properties of AMPK signaling pathway against streptozotocin (STZ)-induced nephropathy in the rat. Materials and Methods: Forty male Wistar rats were randomly distributed into four groups. Group 1 was normal rats (N group); group 2 was diabetic rats (D group); group 3 received diabetic rats + metformin (DM group), and group 4 received giabetic rats + metformin + dorsomorphin (DMD group). Serum albumin, uric acid, total protein and creatinine for estimation of renal injury were measured. Finally, the histological study was evaluated. Results: Reduction of body weight, albumin and total protein in the diabetic rat was reversed by metformin administration. Our results showed that serum uric acid and creatinine were significantly increased in diabetic rats and decreased after treatment with metformin in diabetic rats. AMPK improved the histopathology and morphological changes in STZ-induced diabetic rats. Administration of dorsomorphin (AMPK inhibitor) with metformin can reverse the beneficial effects of AMPK. Conclusions: AMPK signaling pathway ameliorates diabetic nephropathy by modifications of serum albumin, uric acid, total protein, creatinine and attenuation of kidney damage

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