Against Reduction

Provocative, hopeful essays imagine a future that is not reduced to algorithms. What is human flourishing in an age of machine intelligence, when many claim that the world's most complex problems can be reduced to narrow technical questions? Does more computing make us more intelligent, or simply more computationally powerful? We need not always resist reduction; our ability to simplify helps us interpret complicated situations. The trick is to know when and how to do so. Against Reduction offers a collection of provocative and illuminating essays that consider different ways of recognizing and addressing the reduction in our approach to artificial intelligence, and ultimately to ourselves. Inspired by a widely read manifesto by Joi Ito that called for embracing the diversity and irreducibility of the world, these essays offer persuasive and compelling variations on resisting reduction. Among other things, the writers draw on Indigenous epistemology to argue for an extended “circle of relationships” that includes the nonhuman and robotic; cast “Snow White” as a tale of AI featuring a smart mirror; point out the cisnormativity of security protocol algorithms; map the interconnecting networks of so-called noncommunicable disease; and consider the limits of moral mathematics. Taken together, they show that we should push back against some of the reduction around us and do whatever is in our power to work toward broader solutions

Excess protein O-GlcNAcylation links metabolic derangements to right ventricular dysfunction in pulmonary arterial hypertension

The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-GlcNAcylation. While numerous studies demonstrate increased right ventricle (RV) glucose uptake in pulmonary arterial hypertension (PAH), the relationship between O-GlcNAcylation and RV function in PAH is unexplored. Therefore, we examined how colchicine-mediated AMP-kinase activation altered HBP intermediates, O-GlcNAcylation, mitochondrial function, and RV function in pulmonary artery-banded (PAB) and monocrotaline (MCT) rats. AMPK activation induced GFAT phosphorylation and reduced HBP intermediates and O-GlcNAcylation in MCT but not PAB rats. Reduced O-GlcNAcylation partially restored the RV metabolic signature and improved RV function in MCT rats. Proteomics revealed elevated expression of O-GlcNAcylated mitochondrial proteins in MCT RVs, which fractionation studies corroborated. Seahorse micropolarimetry analysis of H9c2 cardiomyocytes demonstrated colchicine improved mitochondrial function and reduced O-GlcNAcylation. Presence of diabetes in PAH, a condition of excess O-GlcNAcylation, reduced RV contractility when compared to nondiabetics. Furthermore, there was an inverse relationship between RV contractility and HgbA1C. Finally, RV biopsy specimens from PAH patients displayed increased O-GlcNAcylation. Thus, excess O-GlcNAcylation may contribute to metabolic derangements and RV dysfunction in PAH

Macrophage-NLRP3 activation promotes right ventricle failure in pulmonary arterial hypertension

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV-macrophages to PAH-RVF. Methods: Rats with decompensated RV hypertrophy (RVH) [monocrotaline (MCT) and Sugen-5416 hypoxia (SuHx)] were compared with compensated RVH rats [pulmonary artery banding (PAB)]. Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptide (ANP) and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT-rats were treated with SC-144 (a GP130 antagonist) and MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in PAH-RVF patients. Measurements and Main Results: Macrophages, fibrosis, and ANP were increased in MCT and SuHx-RVs but not LVs or PAB rats. While MCT-RV macrophages were inflammatory, lung macrophages were anti-inflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT- and SuHx-RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in PAH patients’ decompensated RVs. Cultured MCT-monocytes showed NLRP3 activation, and in co-culture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV-macrophages and NLRP3 content, prevented STAT3 activation, and improved RV function without regressing pulmonary vascular disease. Conclusion: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and PAH patients. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH-RVF results from RV inflammation rather than solely from elevated RV afterload suggest a new therapeutic paradigm

Visual Poetry Through the Lens of the Long Poem : A Conversation

A conversation between Sacha Archer, Amaranth Borsuk and Terri Witek, ReVerse Butcher, Amanda Earl, Helen Hajnoczky, James Knight, Dona Mayoora, Imogen Reid, Ben Robinson, Kate Siklosi, Barrie Tullett, Shloka Shankar, and Nicola Winborn about long format projects – both in terms of the text matter being used and the length of time the projects take to complete

An RNA-Based Vaccine Platform for Use against <i>Mycobacterium tuberculosis</i>

Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes

Pushing the Limits of Exoplanet Discovery via Direct Imaging with Deep Learning

International audienc

Pushing the Limits of Exoplanet Discovery via Direct Imaging with Deep Learning

International audienc

Pushing the Limits of Exoplanet Discovery via Direct Imaging with Deep Learning

International audienc