Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material.The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders

Total hip replacement infected with Mycobacterium tuberculosis complicated by Addison disease and psoas muscle abscess: a case report

Abstract Introduction Prosthetic joint infection due to Mycobacterium tuberculosis is occasionally encountered in clinical practice. To the best of our knowledge, this is the first report of a prosthetic joint infection due to Mycobacterium tuberculosis complicated by psoas abscesses and secondary Addison disease. Case presentation A 67-year-old immunocompetent Caucasian woman underwent total left hip arthroplasty because of osteoarthritis. After 18 months, she underwent arthroplasty revision for a possible prosthetic infection. Periprosthetic tissue specimens for bacteria were negative, and empirical antibiotic therapy was unsuccessful. She was then admitted to our department because of complications arising 22 months after arthroplasty. A physical examination revealed a sinus tract overlying her left hip and skin and mucosal pigmentation. Her levels of C-reactive protein, basal cortisol, adrenocorticotropic hormone, and sodium were out of normal range. Results of the tuberculin skin test and QuantiFERON-TB Gold test were positive. Computed tomography revealed a periprosthetic abscess and the inclusion of the left psoas muscle. Results of microbiological tests were negative, but polymerase chain reaction of a specimen taken from the hip fistula was positive for Mycobacterium tuberculosis. Our patient's condition was diagnosed as prosthetic joint infection and muscle psoas abscess due to Mycobacterium tuberculosis and secondary Addison disease. She underwent standard treatment with rifampicin, ethambutol, isoniazid, and pyrazinamide associated with hydrocortisone and fludrocortisone. At 15 months from the beginning of therapy, she was in good clinical condition and free of symptoms. Conclusions Prosthetic joint infection with Mycobacterium tuberculosis is uncommon. A differential diagnosis of tuberculosis should be considered when dealing with prosthetic joint infection, especially when repeated smears and histology examination from infected joints are negative. Clinical outcomes of prosthetic joint infection by Mycobacterium tuberculosis are unpredictable, especially given the limited literature in this field and the uncertainty of whether medical treatment alone can eradicate the infection without prosthesis removal. Furthermore, this case report raises interesting issues such as the necessity of a follow-up evaluation after treatment based on clinical conditions, the utility of a more standardized length of treatment for periprosthetic tuberculous infection, and the importance of a high diffusion capacity of anti-mycobacterial agents in order to eradicate the infection.</p

The Artificial Society Analytics Platform

Author's accepted manuscriptSocial simulation routinely involves the construction of artificial societies and agents within such societies. Currently there is insufficient discussion of best practices regarding the construction process. This chapter introduces the artificial society analytics platform (ASAP) as a way to spark discussion of best practices. ASAP is designed to be an extensible architecture capable of functioning as the core of many different types of inquiries into social dynamics. Here we describe ASAP, focusing on design decisions in several key areas, thereby exposing our assumptions and reasoning to critical scrutiny, hoping for discussion that can advance debate over best practices in artificial society construction. The five design decisions are related to agent characteristics, neighborhood interactions, evaluating agent credibility, agent marriage, and heritability of personality.acceptedVersio

Altered Storage and Function of von Willebrand Factor in Human Cardiac Microvascular Endothelial Cells Isolated from Recipient Transplant Hearts

The assembly of von Willebrand factor (VWF) into ordered helical tubules within endothelial Weibel–Palade bodies (WPBs) is required for the efficient deployment of the protein at sites of vascular injury. VWF trafficking and storage are sensitive to cellular and environmental stresses that are associated with heart disease and heart failure. Altered storage of VWF manifests as a change in WPB morphology from a rod shape to a rounded shape and is associated with impaired VWF deployment during secretion. In this study, we examined the morphology, ultrastructure, molecular composition and kinetics of exocytosis of WPBs in cardiac microvascular endothelial cells isolated from explanted hearts of patients with a common form of heart failure, dilated cardiomyopathy (DCM; HCMECD), or from nominally healthy donors (controls; HCMECC). Using fluorescence microscopy, WPBs in HCMECC (n = 3 donors) showed the typical rod-shaped morphology containing VWF, P-selectin and tPA. In contrast, WPBs in primary cultures of HCMECD (n = 6 donors) were predominantly rounded in shape and lacked tissue plasminogen activator (t-PA). Ultrastructural analysis of HCMECD revealed a disordered arrangement of VWF tubules in nascent WPBs emerging from the trans-Golgi network. HCMECD WPBs still recruited Rab27A, Rab3B, Myosin-Rab Interacting Protein (MyRIP) and Synaptotagmin-like protein 4a (Slp4-a) and underwent regulated exocytosis with kinetics similar to that seen in HCMECc. However, secreted extracellular VWF strings from HCMECD were significantly shorter than for endothelial cells with rod-shaped WPBs, although VWF platelet binding was similar. Our observations suggest that VWF trafficking, storage and haemostatic potential are perturbed in HCMEC from DCM hearts

Advances in multiple sclerosis research in 2009

The following review summarizes the progress in multiple sclerosis research published in the Journal of Neurology in 2009

Psychological response of family members of patients hospitalised for influenza A/H1N1 in Oaxaca, Mexico

<p>Abstract</p> <p>Background</p> <p>The A/H1N1 pandemic originated in Mexico in April 2009, amid high uncertainty, social and economic disruption, and media reports of panic. The aim of this research project was to evaluate the psychological response of family primary caregivers of patients hospitalised in the Intensive Care Unit (ICU) with suspected influenza A/H1N1 to establish whether there was empirical evidence of high adverse psychological response, and to identify risk factors for such a response. If such evidence was found, a secondary aim was to develop a specific early intervention of psychological support for these individuals, to reduce distress and possibly lessen the likelihood of post-traumatic stress disorder (PTSD) in the longer term.</p> <p>Methods</p> <p>Psychological assessment questionnaires were administered to the family primary caregivers of patients hospitalised in the ICU in the General Hospital of Zone 1 of the Mexican Institute for Social Security (IMSS), Oaxaca, Mexico with suspected influenza A/H1N1, during the month of November 2009. The main outcome measures were ratings of reported perceived stress (PSS-10), depression (CES-D), and death anxiety (DAQ). Data were subjected to simple and multiple linear regression analysis to identify risk factors for adverse psychological response.</p> <p>Results</p> <p>Elevated levels of perceived stress and depression, compared to population normative data, and moderate levels of death anxiety were noted. Levels of depression were similar to those found in comparable studies of family members of ICU patients admitted for other conditions. Multiple regression analysis indicated that increasing age and non-spousal family relationship were significantly associated with depression and perceived stress. Female gender, increasing age, and higher levels of education were significantly associated with high death anxiety. Comparisons with data collected in previous studies in the same hospital ICU with groups affected by a range of other medical conditions indicated that the psychological response reported in this study was generally lower.</p> <p>Conclusions</p> <p>Data indicated that, contrary to widely publicised reports of 'panic' surrounding A/H1N1, that some of those most directly affected did not report excessive psychological responses; however, we concluded that there was sufficient evidence to support provision of limited psychological support to family caregivers.</p

Combination of scoring schemes for protein docking

<p>Abstract</p> <p>Background</p> <p>Docking algorithms are developed to predict in which orientation two proteins are likely to bind under natural conditions. The currently used methods usually consist of a sampling step followed by a scoring step. We developed a weighted geometric correlation based on optimised atom specific weighting factors and combined them with our previously published amino acid specific scoring and with a comprehensive SVM-based scoring function.</p> <p>Results</p> <p>The scoring with the atom specific weighting factors yields better results than the amino acid specific scoring. In combination with SVM-based scoring functions the percentage of complexes for which a near native structure can be predicted within the top 100 ranks increased from 14% with the geometric scoring to 54% with the combination of all scoring functions. Especially for the enzyme-inhibitor complexes the results of the ranking are excellent. For half of these complexes a near-native structure can be predicted within the first 10 proposed structures and for more than 86% of all enzyme-inhibitor complexes within the first 50 predicted structures.</p> <p>Conclusion</p> <p>We were able to develop a combination of different scoring schemes which considers a series of previously described and some new scoring criteria yielding a remarkable improvement of prediction quality.</p