Operationalizing Complex Causes: A Pragmatic View of Mediation

We examine the problem of causal response estimation for complex objects (e.g., text, images, genomics). In this setting, classical \emph{atomic} interventions are often not available (e.g., changes to characters, pixels, DNA base-pairs). Instead, we only have access to indirect or \emph{crude} interventions (e.g., enrolling in a writing program, modifying a scene, applying a gene therapy). In this work, we formalize this problem and provide an initial solution. Given a collection of candidate mediators, we propose (a) a two-step method for predicting the causal responses of crude interventions; and (b) a testing procedure to identify mediators of crude interventions. We demonstrate, on a range of simulated and real-world-inspired examples, that our approach allows us to efficiently estimate the effect of crude interventions with limited data from new treatment regimes

Targeting therapy to the neuromuscular junction: Proof of concept

Introduction: The site of pathology in myasthenia gravis (MG) is the neuromuscular junction (NMJ). Our goal was to determine the ability to direct complement inhibition to the NMJ. Methods: A single-chain antibody directed against the alpha subunit of the acetylcholine receptor was synthesized (scFv-35) and coupled to decay-accelerating factor (DAF, scFv-35-DAF). scFv-35-DAF was tested in a passive model of experimentally acquired MG. Results: Administration of scFv-35-DAF to mice deficient in intrinsic complement inhibitors produced no weakness despite confirmation of its localization to the NMJ and no evidence of tissue destruction related to complement activation. Rats with experimentally acquired MG treated with scFV-35-DAF showed less weakness and a reduction of complement deposition. Conclusions: We demonstrate a method to effectively target a therapeutic agent to the NMJ. Muscle Nerve 49: 749–756, 201

Bogomol'nyi Decomposition for Vesicles of Arbitrary Genus

We apply the Bogomol'nyi technique, which is usually invoked in the study of solitons or models with topological invariants, to the case of elastic energy of vesicles. We show that spontaneous bending contribution caused by any deformation from metastable bending shapes falls in two distinct topological sets: shapes of spherical topology and shapes of non-spherical topology experience respectively a deviatoric bending contribution a la Fischer and a mean curvature bending contribution a la Helfrich. In other words, topology may be considered to describe bending phenomena. Besides, we calculate the bending energy per genus and the bending closure energy regardless of the shape of the vesicle. As an illustration we briefly consider geometrical frustration phenomena experienced by magnetically coated vesicles.Comment: 8 pages, 1 figure; LaTeX2e + IOPar

Premi\`ere valeur propre du laplacien, volume conforme et chirurgies

We define a new differential invariant a compact manifold by $V_{\mathcal M}(M)=\inf_g V_c(M,[g])$, where $V_c(M,[g])$ is the conformal volume of $M$ for the conformal class $[g]$, and prove that it is uniformly bounded above. The main motivation is that this bound provides a upper bound of the Friedlander-Nadirashvili invariant defined by \inf_g\sup_{\tilde g\in[g]}\lambda_1(M,\tilde g)\Vol(M,\tilde g)^{\frac 2n}. The proof relies on the study of the behaviour of $V_{\mathcal M}(M)$ when one performs surgeries on $M$.Comment: 11 pages, 5 figures, in Frenc

A Geometric Theory of Diblock Copolymer Phases

We analyze the energetics of sphere-like micellar phases in diblock copolymers in terms of well-studied, geometric quantities for their lattices. We argue that the A15 lattice with Pm3n symmetry should be favored as the blocks become more symmetric and corroborate this through a self-consistent field theory. Because phases with columnar or bicontinuous topologies intervene, the A15 phase, though metastable, is not an equilibrium phase of symmetric diblocks. We investigate the phase diagram of branched diblocks and find thatthe A15 phase is stable.Comment: 4 pages, RevTeX, 3 eps figures include

Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model - recommendations for methods and experimental designs.

Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies

Differential mRNA expression in ectopic germinal centers of myasthenia gravis thymus

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder resulting in weakness of voluntary muscles. It is caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction (NMJ). A characteristic pathology of patients with early onset MG is thymic hyperplasia with ectopic germinal centers (GC). However, mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. In order to determine the central mechanisms involved in the pathology, thymus samples from MG patients were assessed by histology and grouped based on appearance of GC compared to samples without them. We assessed the differential mRNA expression profiles between the two groups by GeneChip® Human Transcriptome Array 2.0. Partek Genomic Suite 6.6 and Transcript Analysis Console 2.0 programs were used for further analysis. Forty eight annotated mRNA transcripts were identified that were differentially expressed between the two groups with greater than 1.5 fold difference in expression (ANOVA p\u3c0.05). We verified their expression by RT-PCR. We identified Regulator of G protein Signaling 13 or RGS13 that is known to be expressed in GC B-cells and regulate responsiveness to chemokine signaling. Upregulation of RGS13 was found to be associated with specimens having GC. We verified its expression in GC by immunohistochemistry. Gene ontology (GO) enrichment analysis and Ingenuity Pathway Analysis (IPA) core analysis of differentially expressed genes indicate involvement of immune response regulation and cell proliferation pathways, indicating their importance in GC formation and regulation

Fairness in Algorithmic Decision Making: An Excursion Through the Lens of Causality

As virtually all aspects of our lives are increasingly impacted by algorithmic decision making systems, it is incumbent upon us as a society to ensure such systems do not become instruments of unfair discrimination on the basis of gender, race, ethnicity, religion, etc. We consider the problem of determining whether the decisions made by such systems are discriminatory, through the lens of causal models. We introduce two definitions of group fairness grounded in causality: fair on average causal effect (FACE), and fair on average causal effect on the treated (FACT). We use the Rubin-Neyman potential outcomes framework for the analysis of cause-effect relationships to robustly estimate FACE and FACT. We demonstrate the effectiveness of our proposed approach on synthetic data. Our analyses of two real-world data sets, the Adult income data set from the UCI repository (with gender as the protected attribute), and the NYC Stop and Frisk data set (with race as the protected attribute), show that the evidence of discrimination obtained by FACE and FACT, or lack thereof, is often in agreement with the findings from other studies. We further show that FACT, being somewhat more nuanced compared to FACE, can yield findings of discrimination that differ from those obtained using FACE.Comment: 7 pages, 2 figures, 2 tables.To appear in Proceedings of the International Conference on World Wide Web (WWW), 201

Simulations of Two-Dimensional Melting on the Surface of a Sphere

We have simulated a system of classical particles confined on the surface of a sphere interacting with a repulsive $r^{-12}$ potential. The same system simulated on a plane with periodic boundary conditions has van der Waals loops in pressure-density plots which are usually interpreted as evidence for a first order melting transition, but on the sphere such loops are absent. We also investigated the structure factor and from the width of the first peak as a function of density we can show that the growth of the correlation length is consistent with KTHNY theory. This suggests that simulations of two dimensional melting phenomena are best performed on the surface of a sphere.Comment: 4 eps figure

The Role of Osteopontin and Its Gene on Glucocorticoid Response in Myasthenia Gravis

Biomarkers that assess treatment response for patients with the autoimmune disorder, myasthenia gravis (MG), have not been evaluated to a significant extent. We hypothesized the pro-inflammatory cytokine, osteopontin (OPN), may be associated with variability of response to glucocorticoids (GCs) in patients with MG. A cohort of 250 MG patients treated with standardized protocol of GCs was recruited, and plasma OPN and polymorphisms of its gene, secreted phosphoprotein 1 (SPP1), were evaluated. Mean OPN levels were higher in patients compared to healthy controls. Carriers of rs11728697*T allele (allele definition: one of two or more alternative forms of a gene) were more frequent in the poorly GC responsive group compared to the GC responsive group indicating an association of rs11728697*T allele with GC non-responsiveness. One risk haplotype (AGTACT) was identified associated with GC non-responsiveness compared with GC responsive MG group. Genetic variations of SPP1 were found associated with the response to GC among MG patients