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"Fitzpatrick, Susan"
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The best American mystery stories 2016
The Best American Mystery Stories 2016 is a feast of both literary crime and hard-boiled detection, featuring a seemingly innocent murderer, a drug dealer in love, a drunken prank gone terribly wrong, and plenty of other surprising twists and turns.
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Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis
IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
Journal Article
NFκB and HIF display synergistic behaviour during hypoxic inflammation
The oxygen-sensitive transcription factor hypoxia inducible factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor nuclear factor kappa B (NFκB) during hypoxic inflammation. We describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel
Gaussia princeps
luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus, Gluc constructs under the control of either HIF or NFκB were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli, respectively. We also investigated the interactions between HIF and NFκB activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NFκB. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NFκB to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NFκB transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a co-ordinated role for both HIF and NFκB in the expression of COX-2 in hypoxic inflammation.
Journal Article
Hand Transplants, Daily Functioning, and the Human Capacity for Limb Regeneration
Unlike some of our invertebrate and vertebrate cousins with the capacity to regenerate limbs after traumatic loss, humans do not have the ability to regrow arms or legs lost to injury or disease. For the millions of people worldwide who have lost a limb after birth, the primary route to regaining function and minimizing future complications is via rehabilitation, prosthetic devices, assistive aids, health system robustness, and social safety net structures. The majority of limbs lost are lower limbs (legs), with diabetes and vascular disorders being significant causal contributors. Upper limbs (arms) are lost primarily because of trauma; digits and hands are the most common levels of loss. Even if much of the arm remains intact, upper limb amputation significantly impacts function, largely due to the loss of the hand. Human hands are marvels of evolution and permit a dexterity that enables a wide variety of function not readily replaced by devices. It is not surprising, therefore, for some individuals, dissatisfaction with available prosthetic options coupled with remarkable advances in hand surgery techniques is resulting in patients undertaking the rigors of a hand transplantation. While not “regeneration” in the sense of the enviable ability with which Axolotls can replace a lost limb, hand transplants do require significant regeneration of tissues and nerves. Regaining sophisticated hand functions also depends on “reconnecting” the donated hand with the areas of the human brain responsible for the sensory and motor processing required for complex actions. Human hand transplants are not without controversy and raise interesting challenges regarding the human regenerative capacity and the status of transplants for enabling function. More investigation is needed to address medical and ethical questions prior to expansion of hand transplants to a wider patient population.
Journal Article
Who is taking part? Political subjectivity and Glasgow's Commonwealth Games
This paper examines the problems of locating political subjectivity in the midst of the Glasgow Commonwealth Games of 2014 and takes as its starting point Rancière's contention that politics cannot be defined on the basis of any pre‐existing subject. The Commonwealth Games, as both policy vehicle and a form of knowing the world, constructs subjects through the invocation of “legacy”. This involves assuming a consensual populism within which social problems are identified and rectified through the eventfulness of the event. However, leading on from Rancière's contention above, this paper suggests a critical perspective where the event itself is de‐centred in order to move beyond the citational response to mega‐events: that policy constructs subjugated subjects. The paper proceeds by examining how the logics of local residents of East Glasgow elude subjugation in their encounters with the official discourses of the mega‐event. It outlines the ways that political subjectivity is brought forth in two discursive spaces: first, within Games Legacy Evaluation Reports. Second, a public meeting organised by Glasgow City Council as part of their Get Ready Glasgow series. These spaces are considered alongside recent academic criticism that focuses on the corrective elements of social policy relating to sporting mega events.
Journal Article
Asking the Right Questions in Alzheimer's Research
Forty years into a full-on effort to defeat Alzheimer's disease as a major cause of cognitive decline and death-- indeed, it is the sixth leading cause of death in the US, afflicting nearly six million people and wreaking enormous emotional and financial tolls on patients and families--this is where things stand: we have no treatments, and though efforts to improve early-stage diagnosis have had some success, their main impact is to inject enormous new uncertainties and anxieties into a patient's view of the future and sense of self. Once a field commits to a particular hypothesis, the research resources--funding, experimental models, and training--all get in line. Alternative hypotheses struggle to survive. An important consequence of hitching the field of ALZ research to the amyloid hypothesis is the dependence of researchers on established experimental animal models that have little or nothing to say about human neurodegeneration.
Journal Article