The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all ...those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer’s disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer’s disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain.
Abstract The final common pathway of all routes of complement activation involves the non-enzymatic assembly of a complex comprising newly formed C5b with the plasma proteins C6, C7, C8 and C9. When ...assembly occurs on a target cell membrane the forming complex inserts into and through the bilayer to create a pore, the membrane attack complex (MAC). On some targets, pore formation causes rapid lytic destruction; however, most nucleated cell targets resist lysis through a combination of ion pumps, membrane regulators and active recovery processes. Cells survive but not without consequence. The MAC pore causes ion fluxes and directly or indirectly impacts several important signalling pathways that in turn activate a diverse series of events in the cell, many of which are highly pro-inflammatory. Although this non-lytic, pro-inflammatory role of MAC has been recognised for thirty years, no consensus signalling pathway has emerged. Recent work, summarised here, has implicated specific signalling routes and, in some cells, inflammasome involvement, opening the door to novel approaches to therapy in complement-driven pathologies.
The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled ...activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.
This study compared diagonal weighted least squares robust estimation techniques available in 2 popular statistical programs: diagonal weighted least squares (DWLS; LISREL version 8.80) and weighted ...least squares-mean (WLSM) and weighted least squares-mean and variance adjusted (WLSMV; Mplus version 6.11). A 20-item confirmatory factor analysis was estimated using item-level ordered categorical data. Three different nonnormality conditions were applied to 2- to 7-category data with sample sizes of 200, 400, and 800. Convergence problems were seen with nonnormal data when DWLS was used with few categories. Both DWLS and WLSMV produced accurate parameter estimates; however, bias in standard errors of parameter estimates was extreme for select conditions when nonnormal data were present. The robust estimators generally reported acceptable model-data fit, unless few categories were used with nonnormal data at smaller sample sizes; WLSMV yielded better fit than WLSM for most indices.
This Monte Carlo study examines the performance of fit indices commonly used by applied researchers interested in finite mixture modeling for the purposes of classification. Conditions for the ...simulation study were selected to reflect conditions found in applied educational and psychological research. The factors included in the investigation were metric level of indicators, sample size, and class prevalence. All models contained a combination of categorical and continuous indicators. All categorical indicators were dichotomous, and continuous indicators were normally distributed. The fit indices examined were Akaike's information criterion, Bayesian information criterion (BIC), sample size-adjusted Bayesian information criterion (SSBIC), integrated classification likelihood criterion with Bayesian-type approximation, and Lo-Mendell-Rubin likelihood ratio test. Overall, SSBIC tended to identify the correct solution with higher frequency than other indices. BIC tended to identify the correct solution with higher frequency than the other indices in models with more continuous than categorical indicators, or when rare classes were absent.
The membrane attack complex of complement (MAC), apart from its classical role of lysing cells, can also trigger a range of non-lethal effects on cells, acting as a drive to inflammation. In the ...present study, we chose to investigate these non-lethal effects on inflammasome activation. We found that, following sublytic MAC attack, there is increased cytosolic Ca(2+) concentration, at least partly through Ca(2+) release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This increase in intracellular Ca(2+) concentration leads to Ca(2+) accumulation in the mitochondrial matrix via the 'mitochondrial calcium uniporter' (MCU), and loss of mitochondrial transmembrane potential, triggering NLRP3 inflammasome activation and IL-1β release. NLRP3 co-localises with the mitochondria, probably sensing the increase in calcium and the resultant mitochondrial dysfunction, leading to caspase activation and apoptosis. This is the first study that links non-lethal effects of sublytic MAC attack with inflammasome activation and provides a mechanism by which sublytic MAC can drive inflammation and apoptosis.
In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. MAC directly lyses pathogens by a 'multi-hit' mechanism; ...however, sublytic MAC pores on host cells activate signalling pathways. Previous studies have described the structures of individual MAC components and subcomplexes; however, the molecular details of its assembly and mechanism of action remain unresolved. Here we report the electron cryo-microscopy structure of human MAC at subnanometre resolution. Structural analyses define the stoichiometry of the complete pore and identify a network of interaction interfaces that determine its assembly mechanism. MAC adopts a 'split-washer' configuration, in contrast to the predicted closed ring observed for perforin and cholesterol-dependent cytolysins. Assembly precursors partially penetrate the lipid bilayer, resulting in an irregular β-barrel pore. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration.
Whilst data recognise both myeloid cell accumulation during choroidal neovascularisation (CNV) as well as complement activation, none of the data has presented a clear explanation for the angiogenic ...drive that promotes pathological angiogenesis. One possibility that is a pre-eminent drive is a specific and early conditioning and activation of the myeloid cell infiltrate. Using a laser-induced CNV murine model, we have identified that disruption of retinal pigment epithelium (RPE) and Bruch's membrane resulted in an early recruitment of macrophages derived from monocytes and microglia, prior to angiogenesis and contemporaneous with lesional complement activation. Early recruited CD11b(+) cells expressed a definitive gene signature of selective inflammatory mediators particularly a pronounced Arg-1 expression. Accumulating macrophages from retina and peripheral blood were activated at the site of injury, displaying enhanced VEGF expression, and notably prior to exaggerated VEGF expression from RPE, or earliest stages of angiogenesis. All of these initial events, including distinct VEGF (+) Arg-1(+) myeloid cells, subsided when CNV was established and at the time RPE-VEGF expression was maximal. Depletion of inflammatory CCR2-positive monocytes confirmed origin of infiltrating monocyte Arg-1 expression, as following depletion Arg-1 signal was lost and CNV suppressed. Furthermore, our in vitro data supported a myeloid cell uptake of damaged RPE or its derivatives as a mechanism generating VEGF (+) Arg-1(+) phenotype in vivo. Our results reveal a potential early driver initiating angiogenesis via myeloid-derived VEGF drive following uptake of damaged RPE and deliver an explanation of why CNV develops during any of the stages of macular degeneration and can be explored further for therapeutic gain.
The medical market is a continuing success story for the application of shape memory alloy products. Increasing life expectancy and advances in surgical procedures mean that the medical market will ...remain an area of great opportunity for commercial applications.
This paper will consider just why the shape memory effect holds so many opportunities for medical devices and will review a selection of current applications. Interventional radiology in particular has benefited from the unique properties of superelastic nitinol and this will be reviewed in detail.
As well as considering the benefits of shape memory alloys in medical devices this paper will also consider the factors that impinge on the associated risk analysis of using nitinol in medical applications.
The membrane attack complex (MAC) is the pore-forming toxin of the complement system, a relatively early evolutionary acquisition that confers upon complement the capacity to directly kill pathogens. ...The MAC is more than just a bactericidal missile, having the capacity when formed on self-cells to initiate a host of cell activation events that can have profound consequences for tissue homeostasis in the face of infection or injury. Although the capacity of complement to directly kill pathogens has been recognised for over a century, and the pore-forming killing mechanism for at least 50 years, there remains considerable uncertainty regarding precisely how MAC mediates its killing and cell activation activities. A recent burst of new information on MAC structure provides context and opportunity to re-assess the ways in which MAC kills bacteria and modulates cell functions. In this brief review we will describe key aspects of MAC evolution, function and structure and seek to use the new structural information to better explain how the MAC works.
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