Purpose of Review
Articular 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 Findings
The 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.
Summary
An 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.
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.
We combine deed-level data on homeownership with administrative data on voter turnout in local and national elections for more than 18 million individuals in Ohio and North Carolina. Using a ...difference-in-differences design, we find that buying a home leads individuals to participate substantially more in local elections, on average. We also collect data on local ballot initiatives, and we find that the homeowner turnout boost is almost twice as large in times and places where zoning issues are on the ballot. In addition, the effect of homeownership increases with the price of the home purchase, suggesting that asset investment may be an important mechanism for the participatory effects. Overall, the results suggest that individual economic circumstances importantly influence political beliefs and behavior and suggest that homeowners have special influence in American politics in part because their ownership motivates them to pay attention and participate.
Abstract Background Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes’ composition and ...the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury. Objectives This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved. Methods The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors. Results Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection. Conclusions Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs.
Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell. Other mitochondrial signals, such as ATP, are ...sensed by enzymes, including the key metabolic sensor and regulator, AMP-activated protein kinase (AMPK). AMPK responds to the cellular ATP/AMP and ATP/ADP ratios by matching mitochondrial ATP production to demand. Previous reports proposed that AMPK activity also responds to ROS, by ROS acting on redox-sensitive cysteine residues (Cys-299/Cys-304) on the AMPK α subunit. This suggests an appealing model in which mitochondria fine-tune AMPK activity by both adenine nucleotide–dependent mechanisms and by redox signals. Here we assessed whether physiological levels of ROS directly alter AMPK activity. To this end we added exogenous hydrogen peroxide (H2O2) to cells and utilized the mitochondria-targeted redox cycler MitoParaquat to generate ROS within mitochondria without disrupting oxidative phosphorylation. Mitochondrial and cytosolic thiol oxidation was assessed by measuring peroxiredoxin dimerization and by redox-sensitive fluorescent proteins. Replacing the putative redox-active cysteine residues on AMPK α1 with alanines did not alter the response of AMPK to H2O2. In parallel with measurements of AMPK activity, we measured the cell ATP/ADP ratio. This allowed us to separate the effects on AMPK activity due to ROS production from those caused by changes in this ratio. We conclude that AMPK activity in response to redox changes is not due to direct action on AMPK itself, but is a secondary consequence of redox effects on other processes, such as mitochondrial ATP production.
We explore the effects of localized economic shocks from trade on roll-call behavior and electoral outcomes in the US House, 1990–2010. We demonstrate that economic shocks from Chinese import ...competition—first studied by Autor, Dorn, and Hanson—cause legislators to vote in a more protectionist direction on trade bills but cause no change in their voting on all other bills. At the same time, these shocks have no effect on the reelection rates of incumbents, the probability an incumbent faces a primary challenge, or the partisan control of the district. Though changes in economic conditions are likely to cause electoral turnover in many cases, incumbents exposed to negative economic shocks from trade appear able to fend off these effects in equilibrium by taking strategic positions on foreign-trade bills. In line with this view, we find that the effect on roll-call voting is strongest in districts where incumbents are most threatened electorally. Taken together, these results paint a picture of responsive incumbents who tailor their roll-call positions on trade bills to the economic conditions in their districts.
The generation of mitochondrial superoxide (O2−·) by reverse electron transport (RET) at complex I causes oxidative damage in pathologies such as ischemia reperfusion injury, but also provides the ...precursor to H2O2 production in physiological mitochondrial redox signaling. Here, we quantified the factors that determine mitochondrial O2−· production by RET in isolated heart mitochondria. Measuring mitochondrial H2O2 production at a range of proton-motive force (Δp) values and for several coenzyme Q (CoQ) and NADH pool redox states obtained with the uncoupler p-trifluoromethoxyphenylhydrazone, we show that O2−· production by RET responds to changes in O2 concentration, the magnitude of Δp, and the redox states of the CoQ and NADH pools. Moreover, we determined how expressing the alternative oxidase from the tunicate Ciona intestinalis to oxidize the CoQ pool affected RET-mediated O2−· production at complex I, underscoring the importance of the CoQ pool for mitochondrial O2−· production by RET. An analysis of O2−· production at complex I as a function of the thermodynamic forces driving RET at complex I revealed that many molecules that affect mitochondrial reactive oxygen species production do so by altering the overall thermodynamic driving forces of RET, rather than by directly acting on complex I. These findings clarify the factors controlling RET-mediated mitochondrial O2−· production in both pathological and physiological conditions. We conclude that O2−· production by RET is highly responsive to small changes in Δp and the CoQ redox state, indicating that complex I RET represents a major mode of mitochondrial redox signaling.
The regression discontinuity (RD) design is a valuable tool for identifying electoral effects, but this design is only effective when relevant actors do not have precise control over election ...results. Several recent papers contend that such precise control is possible in large elections, pointing out that the incumbent party is more likely to win very close elections in the United States House of Representatives in recent periods. In this article, we examine whether similar patterns occur in other electoral settings, including the U.S. House in other time periods, statewide, state legislative, and mayoral races in the U.S. and national or local elections in nine other countries. No other case exhibits this pattern. We also cast doubt on suggested explanations for incumbent success in close House races. We conclude that the assumptions behind the RD design are likely to be met in a wide variety of electoral settings and offer a set of best practices for RD researchers going forward.
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