An Upper Bound for Random Measurement Error in Causal Discovery

Causal discovery algorithms infer causal relations from data based on several assumptions, including notably the absence of measurement error. However, this assumption is most likely violated in practical applications, which may result in erroneous, irreproducible results. In this work we show how to obtain an upper bound for the variance of random measurement error from the covariance matrix of measured variables and how to use this upper bound as a correction for constraint-based causal discovery. We demonstrate a practical application of our approach on both simulated data and real-world protein signaling data.Comment: Published in Proceedings of the 34th Annual Conference on Uncertainty in Artificial Intelligence (UAI-18

An Analysis of Regulative Speech Acts in English Contracts - Qualitative and Quantitative Methods

This paper deals with the language used to express legal speech acts in simple contracts within the field of English Contract Law. The central objects of study are regulative functions, i.e. directive and commissive speech acts with a particular view to establishing realisation patterns of these rhetorical functions. The hypothesis that the speech acts subjecte to analysis are homogeneously distributed linguistic realisations typical for simple contracts is tested by means of partly manual analysis, partly machine-based quantification of the data of investigation. The findings show that statistically significant items are distributed homogenously in the corpus examined, and that the choice of individual strategies can be interpreted in terms of the face redress required by the socio-pragmatic situation

Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies.

Activation of the complement system by tumor cells was long believed to only benefit the host. Overexpression of complement inhibitors by many tumor cell types and results obtained in several experimental animal models were all in agreement with this hypothesis. However, recent reports imply that the situation is more complex than initially believed and that under certain circumstances tumor cells may use complement to their own advantage, e.g. by recruitment of suppressor T cells or promoting local angiogenesis. Such a dual role of complement may also be apparent when considering the effect of therapeutic monoclonal antibodies (mAb) used to successfully treat B cell malignancies, such as CD20 mAbs. Some argue that besides direct tumor cell killing by mAbs, two main immune effector mechanisms, complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC), may be competing with each other. Experiments aiming at answering the question whether complement is our friend or foe in mAb therapy ended up with seemingly contradictory conclusions. Herein, we revisit the existing knowledge on this pivotal issue based on rituximab and other anti-CD20 mAb as a model of therapeutic agents

C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice.

OBJECTIVES: To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis. METHODS: We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody induced arthritis (CAIA), an acute antibody induced disease and the collagen induced arthritis (CIA), which carries the full complexity of arthritis. RESULTS: Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement. CONCLUSIONS: Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA

Killing of CLL and NHL cells by rituximab and ofatumumab under limited availability of complement.

Rituximab and ofatumumab are anti-CD20 antibodies applicable to treatment for non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). Effectiveness of both immunotherapeutics may depend on exhaustible complement system. To model the efficacy of complement usage by ofatumumab and rituximab under limited complement availability, we compared complement-dependent cytotoxicity exerted by these antibodies at low (5 and 10 %) and physiological (50 %) serum concentration in twelve CD20-positive cell lines and six freshly isolated CLL cells. Simultaneously, we assessed the expression of CD20 and membrane-bound complement inhibitors. Ratios of CD20 to CD59 and/or CD55 distinguished highly sensitive cells lysed equally efficient by both antibodies from the moderately sensitive cells, which were killed more efficiently by ofatumumab

PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex

PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins

Post combustion carbon capture with supported amine sorbents: From adsorbent characterization to process simulation and optimization

Supported amine sorbents are extensively studied in literature due to their moisture tolerating abilities. Most of the work with this group of adsorbents pertain to experimental studies on adsorption capacity, kinetics, and stability tests on powdered sorbents. Only a handful of published studies have carried out thermodynamic assessment and process modelling to evaluate the performance of supported amine sorbents in the context of pressure and temperature swing adsorption processes. In this work, we have evaluated a commercially available mesoporous silica (PERLKAT) adsorbent grafted with N-[3-(trimethoxysilyl)propyl] ethylenediamine for post-combustion carbon capture by vacuum swing adsorption process (VSA). Experiments were first carried out to obtain information on single component and ternary equilibrium data. The adsorbent has a total capacity of 0.95 mmol/g at 0.15 bar CO2 and 0.8 mmol/g at 0.05 bar CO2 respectively at 70 °C. Ternary experiments at low relative humidity shows that the CO2 capacity is not affected in the presence of moisture. These results were used as input to simulate and optimize a 6-step dual reflux vacuum swing adsorption (VSA) cycle. Detailed process optimization shows that it is possible to capture 90% of the CO2 at 95% purity using our adsorbent. The minimum specific energy is 1 MJ/kg CO2 captured on an electric basis when the VSA process is operated at 90 °C.publishedVersio

Artificial intelligence-based image analysis can predict outcome in high-grade serous carcinoma via histology alone

High-grade extrauterine serous carcinoma (HGSC) is an aggressive tumor with high rates of recurrence, frequent chemotherapy resistance, and overall 5-year survival of less than 50%. Beyond determining and confirming the diagnosis itself, pathologist review of histologic slides provides no prognostic or predictive information, which is in sharp contrast to almost all other carcinoma types. Deep-learning based image analysis has recently been able to predict outcome and/or identify morphology-based representations of underlying molecular alterations in other tumor types, such as colorectal carcinoma, lung carcinoma, breast carcinoma, and melanoma. Using a carefully stratified HGSC patient cohort consisting of women (n = 30) with similar presentations who experienced very different treatment responses (platinum free intervals of either = 18 months), we used whole slide images (WSI, n = 205) to train a convolutional neural network. The neural network was trained, in three steps, to identify morphologic regions (digital biomarkers) that are highly associating with one or the other treatment response group. We tested the classifier using a separate 22 slide test set, and 18/22 slides were correctly classified. We show that a neural network based approach can discriminate extremes in patient response to primary platinum-based chemotherapy with high sensitivity (73%) and specificity (91%). These proof-of-concept results are novel, because for the first time, prospective prognostic information is identified specifically within HGSC tumor morphology.Peer reviewe

Streptococcus pneumoniae endopeptidase O (PepO): a multifunctional plasminogen and fibronectin binding protein, facilitating evasion of innate immunity and invasion of host cells.

Streptococcus pneumoniae infections remain a major cause of morbidity and mortality worldwide. Therefore a detailed understanding and characterization of the mechanism of host cell colonization and dissemination is critical in order to gain control over this versatile pathogen. Here we identified a novel 72 kDa pneumococcal protein endopeptidase O (PepO), as a plasminogen and fibronectin binding protein. Using a collection of clinical isolates, representing different serotypes, we found PepO to be ubiquitously present both at the gene and at the protein level. In addition, PepO protein was secreted in a growth-phase dependent manner to the culture supernatants of the pneumococcal isolates. Recombinant PepO bound human plasminogen and fibronectin in a dose-dependent manner and plasminogen did not compete with fibronectin for binding PepO. PepO bound plasminogen via lysine residues and the interaction was influenced by ionic strength. Moreover, upon activation of PepO bound plasminogen by urokinase-type plasminogen activator, generated plasmin cleaved complement protein C3b thus assisting in complement control. Furthermore, direct binding assays demonstrated the interaction of PepO with epithelial and endothelial cells that in turn blocked pneumococcal adherence. Moreover, a pepO-mutant strain showed impaired adherence to and invasion of host cells compared to their isogenic wild-type strains. Taken together, the results demonstrated that PepO is ubiquitously expressed plasminogen and fibronectin binding protein, which plays role in pneumococcal invasion of host cells and aids in immune evasion