Mathematical framework for human SLE Nephritis: disease dynamics and urine biomarkers

<p>Abstract</p> <p>Background</p> <p>Although the prognosis for Lupus Nephritis (LN) has dramatically improved with aggressive immunosuppressive therapies, these drugs carry significant side effects. To improve the effectiveness of these drugs, biomarkers of renal flare cycle could be used to detect the onset, severity, and responsiveness of kidney relapses, and to modify therapy accordingly. However, LN is a complex disease and individual biomarkers have so far not been sufficient to accurately describe disease activity. It has been postulated that biomarkers would be more informative if integrated into a pathogenic-based model of LN.</p> <p>Results</p> <p>This work is a first attempt to integrate human LN biomarkers data into a model of kidney inflammation. Our approach is based on a system of differential equations that capture, in a simplified way, the complexity of interactions underlying disease activity. Using this model, we have been able to fit clinical urine biomarkers data from individual patients and estimate patient-specific parameters to reproduce disease dynamics, and to better understand disease mechanisms. Furthermore, our simulations suggest that the model can be used to evaluate therapeutic strategies for individual patients, or a group of patients that share similar data patterns.</p> <p>Conclusions</p> <p>We show that effective combination of clinical data and physiologically based mathematical modeling may provide a basis for more comprehensive modeling and improved clinical care for LN patients.</p

Differential Regularization of Topologically Massive Yang-Mills Theory and Chern-Simons Theory

We apply differential renormalization method to the study of three-dimensional topologically massive Yang-Mills and Chern-Simons theories. The method is especially suitable for such theories as it avoids the need for dimensional continuation of three-dimensional antisymmetric tensor and the Feynman rules for three-dimensional theories in coordinate space are relatively simple. The calculus involved is still lengthy but not as difficult as other existing methods of calculation. We compute one-loop propagators and vertices and derive the one-loop local effective action for topologically massive Yang-Mills theory. We then consider Chern-Simons field theory as the large mass limit of topologically massive Yang-Mills theory and show that this leads to the famous shift in the parameter $k$. Some useful formulas for the calculus of differential renormalization of three-dimensional field theories are given in an Appendix.Comment: 25 pages, 4 figures. Several typewritten errors and inappropriate arguments are corrected, especially the correct adresses of authors are give

Biomarkers of lupus nephritis determined by serial urine proteomics

Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE), the treatment of which often requires the use of immunosuppressives that can have severe side effects. Here we determined the low-molecular weight proteome of serial lupus urine samples to uncover novel and predictive biomarkers of SLE renal flare. Urine from 25 flare cycles of 19 patients with WHO Class III, IV, and V SLE nephritis were obtained at baseline, pre-flare, flare and post-flare. Each sample was first fractionated to remove proteins larger than 30kDa, then applied onto weak cation exchanger protein chips for analysis by SELDI-TOF mass spectrometry. We found 176 protein ions of which 27 were differentially expressed between specific flare intervals. On-chip peptide sequencing by integrated tandem mass spectrometry positively identified the 20 and 25 amino-acid isoforms of hepcidin, as well as fragments of α1-antitrypsin and albumin among the selected differentially expressed protein ions. Hepcidin 20 increased 4 months before renal flare and returned to baseline at renal flare, whereas hepcidin 25 decreased at renal flare and returned to baseline 4 months after the flare. These studies provide a beginning proteomic analysis aimed at predicting impending renal relapse, relapse severity, and the potential for recovery after SLE nephritis flare

Confinement in Covariant Gauges

We examine the weak coupling limit of Euclidean SU(n) gauge theory in covariant gauges. Following an earlier suggestion, an equivariant BRST-construction is used to define the continuum theory on a finite torus. The equivariant gauge fixing introduces constant ghost fields as moduli of the model. We study the parameter- and moduli- space perturbatively. For $n_f \leq n$ quark flavors, the moduli flow to a non-trivial fixed point in certain critical covariant gauges and the one-loop effective potential indicates that the global SU(n) color symmetry of the gauge fixed model is spontaneously broken to $U(1)^{n-1}$. Ward identities and renormalization group arguments imply that the longitudinal gauge boson propagator at long range is dominated by $n(n-1)$ Goldstone bosons in these critical covariant gauges. In the large $n$ limit, we derive a nonlinear integral equation for the expectation value of large Wilson loops assuming that the exchange of Goldstone bosons dominates the interaction at long range in critical covariant gauges. We find numerically that the expectation value of large circular Wilson loops decreases exponentially with the enclosed area in the absence of dynamical fermions. The gauge invariance of this mechanism for confinement in critical covariant gauges is discussed.Comment: 45 pages, Latex, uses psfig.sty and epsfig.sty to include postscript-figure

Sum Rules from an Extra Dimension

Using the gravity side of the AdS/CFT correspondence, we investigate the analytic properties of thermal retarded Green's functions for scalars, conserved currents, the stress tensor, and massless fermions. We provide some results concerning their large and small frequency behavior and their pole structure. From these results, it is straightforward to prove the validity of various sum rules on the field theory side of the duality. We introduce a novel contraction mapping we use to study the large frequency behavior of the Green's functions.Comment: v2: 23 pages (plus appendix), revised presentation, discussion of branch cuts moved to appendix, and some minor changes; v1: 24 pages (plus appendix

PyCogent: a toolkit for making sense from sequence

The COmparative GENomic Toolkit, a framework for probabilistic analyses of biological sequences, devising workflows and generating publication quality graphics, has been implemented in Python

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

Listeriolysin O Is Necessary and Sufficient to Induce Autophagy during Listeria monocytogenes Infection

Recent studies have suggested that autophagy is utilized by cells as a protective mechanism against Listeria monocytogenes infection.However we find autophagy has no measurable role in vacuolar escape and intracellular growth in primary cultured bone marrow derived macrophages (BMDMs) deficient for autophagy (atg5-/-). Nevertheless, we provide evidence that the pore forming activity of the cholesterol-dependent cytolysin listeriolysin O (LLO) can induce autophagy subsequent to infection by L. monocytogenes. Infection of BMDMs with L. monocytogenes induced microtubule-associated protein light chain 3 (LC3) lipidation, consistent with autophagy activation, whereas a mutant lacking LLO did not. Infection of BMDMs that express LC3-GFP demonstrated that wild-type L. monocytogenes was encapsulated by LC3-GFP, consistent with autophagy activation, whereas a mutant lacking LLO was not. Bacillus subtilis expressing either LLO or a related cytolysin, perfringolysin O (PFO), induced LC3 colocalization and LC3 lipidation. Further, LLO-containing liposomes also recruited LC3-GFP, indicating that LLO was sufficient to induce targeted autophagy in the absence of infection. The role of autophagy had variable effects depending on the cell type assayed. In atg5-/- mouse embryonic fibroblasts, L. monocytogenes had a primary vacuole escape defect. However, the bacteria escaped and grew normally in atg5-/- BMDMs.We propose that membrane damage, such as that caused by LLO, triggers bacterial-targeted autophagy, although autophagy does not affect the fate of wild-type intracellular L. monocytogenes in primary BMDMs

The Emergence and Development of Association Football: Influential Sociocultural Factors in Victorian Birmingham

This article explores the interdependent, complex sociocultural factors that facilitated the emergence and diffusion of football in Birmingham. The focus is the development of football in the city, against the backdrop of the numerous social changes in Victorian Birmingham. The aim is to fill a gap in the existing literature which seemingly overlooked Birmingham as a significant footballing centre, and the ‘ordinary and everyday’ aspects of the game’s early progression. Among other aspects, particular heed is paid to the working classes’ involvement in football, as previous literature has often focused on the middle classes and their influence on and participation in organized sport. As the agency of the working classes along with their mass participation and central role in the game’s development is unfolded, it is argued that far from being passive cultural beings, the working classes, from the beginnings, actively negotiated the development of their own emergent football culture