The systemic inflammatory response after spinal cord injury in the rat is decreased by α4β1 integrin blockade

The systemic inflammatory response syndrome (SIRS) follows spinal cord injury (SCI) and causes damage to the lungs, kidney, and liver due to an influx of inflammatory cells from the circulation. After SCI in rats, the SIRS develops within 12 h and is sustained for at least 3 days. We have previously shown that blockade of CD11d/CD18 integrin reduces inflammation-driven secondary damage to the spinal cord. This treatment reduces the SIRS after SCI. In another study we found that blockade of α4β1 integrin limited secondary cord damage more effectively than blockade of CD11d/CD18. Therefore we considered it important to assess the effects of anti-α4β1 treatment on the SIRS in the lung, kidney, and liver after SCI. An anti-α4 antibody was given IV at 2 h after SCI at the fourth thoracic segment and the effects on the organs were evaluated at 24 h post-injury. The migration of neutrophils into the lungs and liver was markedly reduced and all three organs contained fewer macrophages. In the lungs and liver, the activation of the oxidative enzymes myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and gp91 phox, the production of free radicals, lipid peroxidation, and cell death were substantially and similarly reduced. Treatment effects were less robust in the kidney. Overall, the efficacy of the anti-α4β1 treatment did not differ greatly from that of the anti-CD11d antibody, although details of the results differed. The SIRS after SCI impedes recovery, and attenuation of the SIRS with an anti-integrin treatment is an important, clinically-relevant finding. © Mary Ann Liebert, Inc. 2012

Incomplete Wood-Ljungdahl pathway facilitates one-carbon metabolism in organohalide-respiring Dehalococcoides mccartyi.

The acetyl-CoA "Wood-Ljungdahl" pathway couples the folate-mediated one-carbon (C1) metabolism to either CO2 reduction or acetate oxidation via acetyl-CoA. This pathway is distributed in diverse anaerobes and is used for both energy conservation and assimilation of C1 compounds. Genome annotations for all sequenced strains of Dehalococcoides mccartyi, an important bacterium involved in the bioremediation of chlorinated solvents, reveal homologous genes encoding an incomplete Wood-Ljungdahl pathway. Because this pathway lacks key enzymes for both C1 metabolism and CO2 reduction, its cellular functions remain elusive. Here we used D. mccartyi strain 195 as a model organism to investigate the metabolic function of this pathway and its impacts on the growth of strain 195. Surprisingly, this pathway cleaves acetyl-CoA to donate a methyl group for production of methyl-tetrahydrofolate (CH3-THF) for methionine biosynthesis, representing an unconventional strategy for generating CH3-THF in organisms without methylene-tetrahydrofolate reductase. Carbon monoxide (CO) was found to accumulate as an obligate by-product from the acetyl-CoA cleavage because of the lack of a CO dehydrogenase in strain 195. CO accumulation inhibits the sustainable growth and dechlorination of strain 195 maintained in pure cultures, but can be prevented by CO-metabolizing anaerobes that coexist with D. mccartyi, resulting in an unusual syntrophic association. We also found that this pathway incorporates exogenous formate to support serine biosynthesis. This study of the incomplete Wood-Ljungdahl pathway in D. mccartyi indicates a unique bacterial C1 metabolism that is critical for D. mccartyi growth and interactions in dechlorinating communities and may play a role in other anaerobic communities

On Human Predictions with Explanations and Predictions of Machine Learning Models: A Case Study on Deception Detection

Humans are the final decision makers in critical tasks that involve ethical and legal concerns, ranging from recidivism prediction, to medical diagnosis, to fighting against fake news. Although machine learning models can sometimes achieve impressive performance in these tasks, these tasks are not amenable to full automation. To realize the potential of machine learning for improving human decisions, it is important to understand how assistance from machine learning models affects human performance and human agency. In this paper, we use deception detection as a testbed and investigate how we can harness explanations and predictions of machine learning models to improve human performance while retaining human agency. We propose a spectrum between full human agency and full automation, and develop varying levels of machine assistance along the spectrum that gradually increase the influence of machine predictions. We find that without showing predicted labels, explanations alone slightly improve human performance in the end task. In comparison, human performance is greatly improved by showing predicted labels (>20% relative improvement) and can be further improved by explicitly suggesting strong machine performance. Interestingly, when predicted labels are shown, explanations of machine predictions induce a similar level of accuracy as an explicit statement of strong machine performance. Our results demonstrate a tradeoff between human performance and human agency and show that explanations of machine predictions can moderate this tradeoff.Comment: 17 pages, 19 figures, in Proceedings of ACM FAT* 2019, dataset & demo available at https://deception.machineintheloop.co

CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury

Traumatic injury to the spinal cord triggers a systemic inflammatory response syndrome (SIRS), in which inflammatory cells from the circulation invade organs such as the liver, lung and kidney, leading to damage of these organs. Our previous study (Gris, et al, Exp. Neurol, 2008) demonstrated that spinal cord injury (SCI) activates circulating neutrophils that then invade the lung and kidney from 2 to 24. h after injury, increasing myeloperoxidase activity, cyclooxygenase-2 and matrix metalloproteinase-9 expression and lipid peroxidation in these organs. The present study was designed to ascertain whether a treatment that limits the influx of leukocytes into the injured spinal cord would also be effective in reducing the SIRS after SCI. This treatment is intravenous delivery of a monoclonal antibody (mAb) against the CD11d subunit of the CD11d/CD18 integrin expressed by neutrophils and monocytes. We delivered the anti-CD11d mAb at 2. h post moderate clip compression SCI at the 4th or 12th thoracic segments and assessed inflammation, oxidative activity and cellular damage within the lung, kidney and liver at 12. h post-injury. In some analyses we compared high and low thoracic injuries to evaluate the importance of injury level on the intensity of the SIRS. After T4 injury, treatment with the anti-integrin mAb reduced the presence of neutrophils and macrophages in the lung, with associated decreases in expression of NF-κB and oxidative enzymes and in the concentration of free radicals in this organ. The treatment also reduced lipid peroxidation, protein nitration and cell death in the lung. The anti-CD11d treatment also reduced the inflammatory cells within the kidney after T4 injury, as well as the free radical concentration and amount of lipid peroxidation. In the liver, the mAb treatment reduced the influx of neutrophils but most of the other measures examined were unaffected by SCI. The inflammatory responses within the lung and kidney were often greater after T4 than T12 injury. Clinical studies show that SIRS, with its associated organ failure, contributes significantly to the morbidity and mortality of SCI patients. This anti-integrin treatment may block the onset of SIRS after SCI. © 2011 Elsevier Inc

A Linear-Time Bottom-Up Discourse Parser with Constraints and Post-Editing

Text-level discourse parsing remains a challenge. The current state-of-the-art overall accuracy in relation assignment is 55.73%, achieved by Joty et al. (2013). However, their model has a high order of time complexity, and thus cannot be ap-plied in practice. In this work, we develop a much faster model whose time complex-ity is linear in the number of sentences. Our model adopts a greedy bottom-up ap-proach, with two linear-chain CRFs ap-plied in cascade as local classifiers. To en-hance the accuracy of the pipeline, we add additional constraints in the Viterbi decod-ing of the first CRF. In addition to effi-ciency, our parser also significantly out-performs the state of the art. Moreover, our novel approach of post-editing, which modifies a fully-built tree by considering information from constituents on upper levels, can further improve the accuracy.

A CD11d monoclonal antibody treatment reduces tissue injury and improves neurological outcome after fluid percussion brain injury in rats

Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of anti-CD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2 h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24-to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24 h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI. © 2012, Mary Ann Liebert, Inc

A discourse-based approach for Arabic question answering

The treatment of complex questions with explanatory answers involves searching for arguments in texts. Because of the prominent role that discourse relations play in reflecting text-producers’ intentions, capturing the underlying structure of text constitutes a good instructor in this issue. From our extensive review, a system for automatic discourse analysis that creates full rhetorical structures in large scale Arabic texts is currently unavailable. This is due to the high computational complexity involved in processing a large number of hypothesized relations associated with large texts. Therefore, more practical approaches should be investigated. This paper presents a new Arabic Text Parser oriented for question answering systems dealing with لماذا “why” and كيف “how to” questions. The Text Parser presented here considers the sentence as the basic unit of text and incorporates a set of heuristics to avoid computational explosion. With this approach, the developed question answering system reached a significant improvement over the baseline with a Recall of 68% and MRR of 0.62

Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon.

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.We thank David Sanchez for his editorial advice and Harvey Roy Herschman for his helpful discussions. This work was funded by NIH RO1 AI078389, AI056154, AI47868, and AI069120 grants, the Tumor Immunology Training Grant (5T32CA009120), the grant from the Spanish Ministry of Economy and Competitiveness (SAF2012-31483) and the Medical Scientist Training Program.S