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This is a dynamic visual journey through the landscape of illustration that maps the evolution of the discipline from the industrial revolution to the post-digital age and showcases over 180 of its most iconic practitioners, including Laura Knight, Antonio Lopez, Käthe Kollwitz and Hayao Miyazaki. By contextualizing the subject within a framework of key political events, cultural innovations and technological advances, Andrew Hall redefines how we might think about illustration and the place that it has in our ever-evolving global network. The second half of this introductory volume follows on from the ten chapters charting the chronology of illustration to provide a more in-depth look at its specific commercial genres across eleven feature sections, each including mini-histories, practical career advice and biographies of inspirational practitioners who operated within the field.

Purpose of ReviewArticular chondrocytes are exclusively responsible for the turnover of the extracellular matrix (ECM) of hyaline cartilage. However, chondrocytes are phenotypically unstable and, if they de-differentiate into hypertrophic or fibroblastic forms, will produce a defective and weak matrix. Chondrocyte volume and morphology exert a strong influence over phenotype and a full appreciation of the factors controlling chondrocyte phenotype stability is central to understanding (a) the mechanisms underlying the cartilage failure in osteoarthritis (OA), (b) the rationale for hyaline cartilage repair, and (c) the strategies for improving the engineering of resilient cartilage. The focus of this review is on the factors involved in, and the importance of regulating, chondrocyte morphology and volume as key controllers of chondrocyte phenotype.Recent FindingsThe visualisation of fluorescently-labelled in situ chondrocytes within non-degenerate and mildly degenerate cartilage, by confocal scanning laser microscopy (CLSM) and imaging software, has identified the marked heterogeneity of chondrocyte volume and morphology. The presence of chondrocytes with cytoplasmic processes, increased volume, and clustering suggests important early changes to their phenotype. Results from experiments more closely aligned to the normal physico-chemical environment of in situ chondrocytes are emphasising the importance of understanding the factors controlling chondrocyte morphology and volume that ultimately affect phenotype.SummaryAn appreciation of the importance of chondrocyte volume and morphology for controlling the chondrocyte phenotype is advancing at a rapid pace and holds particular promise for developing strategies for protecting the chondrocytes against deleterious changes and thereby maintaining healthy and resilient cartilage.

This article studies the interplay of U.S. primary and general elections. I examine how the nomination of an extremist changes general-election outcomes and legislative behavior in the U.S. House, 1980–2010, using a regression discontinuity design in primary elections. When an extremist—as measured by primary-election campaign receipt patterns—wins a “coin-flip” election over a more moderate candidate, the party’s general-election vote share decreases on average by approximately 9–13 percentage points, and the probability that the party wins the seat decreases by 35–54 percentage points. This electoral penalty is so large that nominating the more extreme primary candidate causes the district’s subsequent roll-call representation to reverse, on average, becoming more liberal when an extreme Republican is nominated and more conservative when an extreme Democrat is nominated. Overall, the findings show how general-election voters act as a moderating filter in response to primary nominations.

The kidney proximal tubule reabsorbs and degrades filtered plasma proteins to reclaim valuable nutrients and maintain body homeostasis. Defects in this process result in proteinuria, one of the most frequently used biomarkers of kidney disease. Filtered proteins enter proximal tubules via receptor-mediated endocytosis and are processed within a highly developed apical endo-lysosomal system (ELS). Proteinuria is a strong risk factor for chronic kidney disease progression and genetic disorders of the ELS cause hereditary kidney diseases, so deepening understanding of how the proximal tubule handles proteins is crucial for translational nephrology. Moreover, the ELS is both an entry point for nephrotoxins that induce tubular damage and a target for novel therapies to prevent it. Cutting-edge research techniques, such as functional intravital imaging and computational modelling, are shedding light on spatial and integrative aspects of renal tubular protein processing in vivo, how these are altered under pathological conditions and the consequences for other tubular functions. These insights have potentially important implications for understanding the origins of systemic complications arising in proteinuric states, and might lead to the development of new ways of monitoring and treating kidney diseases. The kidney tubules have a crucial role in homeostasis as they modify and regulate the kidney filtrate. This Review examines current data on how filtered proteins are processed along the kidney tubule, including evidence from defects in the endo-lysosomal system, and their therapeutic implications. Key points Uptake and degradation of filtered plasma proteins by kidney proximal tubules (PTs) is an important process in kidney physiology and body homeostasis. Defects in protein reabsorption lead to proteinuria, one of the most widely used disease biomarkers in nephrology. PT cells are highly adapted to protein uptake and processing. These cells express large, multi-ligand receptors that bind a wide range of proteins and facilitate their internalization, and have a sophisticated apical endo-lysosomal system (ELS) that rapidly sorts and metabolizes proteins. Protein uptake occurs mainly in the early PT, whereas small peptides are reclaimed in later regions, which shapes the axial topography of the PT. Some studies suggest that early PT cells release endocytic material, which can then be reabsorbed downstream, suggesting that tubular protein metabolism is an integrated process. In response to increased glomerular protein filtration, PTs ramp up endocytic activity and uptake extends to the later regions to limit urinary protein loss. However, this axial remodelling might result in loss of other tubular functions, and dramatic increases in protein filtration can overwhelm and damage PTs, which is likely to be an important pathogenic mechanism in proteinuric kidney diseases. Genetic defects in the PT ELS cause proteinuria and progressive loss of kidney function. Elucidation of underlying disease pathways is helping to identify potential molecular targets for therapeutic intervention. The ELS provides protein nephrotoxins with an entry point into PT cells; temporary blockade of endocytosis might lower toxin uptake and reduce tubular damage. Moreover, conjugating compounds to proteins or peptides provides a mechanism for targeting PTs in vivo in drug development.

Concerns that interest groups use their financial resources to distort the democratic process are long-standing. Surprisingly, though, firms spend little money on political campaigns, and roughly 95% of publicly traded firms in the United States have never contributed to a political campaign. Do interest groups seek political access through their modest contributions, or are these contributions only a minor and forgettable part of the political process? In this article, we present comprehensive evidence that interest groups are extremely sophisticated in the way they make campaign contributions. We collect a new data set on U.S. state legislative committee assignments and legislator procedural powers from 1988 to 2014, merged with campaign finance data, in order to analyze over 440,000 candidate–committee observations across 99 legislatures. Using a series of difference-in-differences designs based on changes in individual legislators' positions in the legislature, we not only show that interest groups seek out committee members, but we also show that they value what we call indirect access. When a legislator gains procedural powers, interest groups reallocate considerable amounts of money to her. The results reveal how interest groups in a wide range of democratic settings seek to influence the policy process not only by seeking direct access to policy makers but by seeking indirect access to legislative procedure as well.

We reassess Christopher Achen and Larry Bartels’s prominent claim that shark attacks influence presidential elections. First, we assemble data on every fatal shark attack in US history and county-level returns from every presidential election between 1872 and 2012, and we find no systematic evidence that shark attacks affect elections. Second, we show that Achen and Bartels’s county-level finding for New Jersey in 1916 becomes substantively smaller and statistically weaker under alternative specifications. Third, we find that their town-level finding in Ocean County significantly shrinks when we correct errors and does not hold for the other beach counties. Finally, implementing placebo tests in settings where there were no shark attacks, we demonstrate that Achen and Bartels’s result was likely to arise even if shark attacks do not influence elections. Overall, there is little compelling evidence that shark attacks influence presidential elections, and any such effect—if one exists—is substantively negligible.

Damage to the proximal tubule (PT) is the most frequent cause of acute kidney injury (AKI) in humans. Diagnostic and treatment options for AKI are currently limited, and a deeper understanding of pathogenic mechanisms at a cellular level is required to rectify this situation. Metabolism in the PT is complex and closely coupled to solute transport function. Recent studies have shown that major changes in PT metabolism occur during AKI and have highlighted some potential targets for intervention. However, translating these insights into effective new therapies still represents a substantial challenge. In this article, in addition to providing a brief overview of the current state of the field, we will highlight three emerging areas that we feel are worthy of greater attention. First, we will discuss the role of axial heterogeneity in cellular function along the PT in determining baseline susceptibility to different metabolic hits. Second, we will emphasize that elucidating insult specific pathogenic mechanisms will likely be critical in devising more personalized treatments for AKI. Finally, we will argue that uncovering links between tubular metabolism and whole-body homeostasis will identify new strategies to try to reduce the considerable morbidity and mortality associated with AKI. These concepts will be illustrated by examples of recent studies emanating from the authors’ laboratories and performed under the auspices of the Swiss National Competence Center for Kidney Research (NCCR Kidney.ch).

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose. Untargeted metabolomics enables simultaneous measurement of xenobiotic fate and effects in biological systems. This is demonstrated through discovering extensive biotransformation maps, measuring systemic exposures over time, and directly associating endogenous biochemical responses to internal dose.