DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that ...direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ's role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics.
•Institutional quality may impact beliefs about fairness of inequality.•Estimates of unfair wealth inequality using Life in Transition Survey, 2010 and 2016.•With average governing institutions, ...unfair wealth inequality correlated with beliefs that processes are “unfair”.•For beliefs that processes are “fair”, above average governing institutions may substitute for reductions in unfair inequality.•Results hold when “fair” processes include effort, moral and meritocratic components.
Unfair inequality arises when incentives are not fairly tied to effort or investment across the socio-economic spectrum. The actual limitations on economic activity from this failure may depend on whether people believe the system is unfair, and how well governing institutions safeguard fair-play. In this paper, I study whether unfair wealth inequality is correlated with beliefs about fairness, and whether good governance can be a substitute in belief formations for decreases in unfair inequality. I find a that people in countries with recent increases in unfair wealth inequality are less likely to believe that inequality is due to fair processes. This relationship holds when“fair” determinants of inequality include effort, as well as moral and meritocratic components. The relationship is strongest in countries with poor quality governance. In countries with high quality governance, people appear to be more tolerant of unfair inequality, as it is only weakly reflected in their beliefs about process fairness.
Solid-state reordering of C–O bonds in the calcite lattice can alter the clumped isotope composition of paleotemperature archives such as fossil brachiopod shells without inducing significant changes ...in shell microstructure and trace element concentrations, metrics commonly used to gauge preservation quality. To correctly interpret the paleoenvironmental significance of clumped isotope-derived paleotemperatures, it is necessary to understand the temperature–time domain in which solid-state C–O bond reordering is important. We address this question using a combination of laboratory and natural geological experiments on Paleozoic brachiopod shells. The laboratory experiments involve heating fossil brachiopod calcite at different temperatures and times to directly observe rates of 13C–18O bond reordering. The resulting Arrhenius parameters are indistinguishable from values previously determined for an optical calcite with similar trace element compositions. We develop an alternative kinetic model for reordering that accounts for non-first-order reaction progress observed during the initial several hundred minutes of laboratory heating experiments, and show that the simplified first-order approximation model (Passey and Henkes, 2012) predicts reaction progress equally well for temperatures and timescales relevant to sedimentary basins. We evaluate our laboratory-based rate predictions by studying brachiopod calcite from several sedimentary basins with independently constrained burial temperature histories. Specifically, we use the laboratory-derived Arrhenius parameters to predict the evolution of brachiopod calcite clumped isotope compositions during successive one million-year time steps reflecting the burial and exhumation temperature paths of each basin. While this exercise is limited by the relatively large uncertainties in the temperature histories of these basins, we find general correspondence, within error, between predicted and observed clumped isotope values. We present simplified temperature–time diagrams for calcite showing domains where primary clumped isotope compositions will be preserved, partially reordered, and fully reordered. In conclusion, calcite samples dwelling at ∼100°C or lower for 106–108 year timescales should not be affected by solid-state C–O bond reordering.
Cell delivery reagents often exploit the endocytic pathway as a route of cell entry. Once endocytosed, these reagents must overcome endosomal entrapment to ensure the release of their macromolecular ...cargo into the cytosol of cells. In this review, we describe several examples of prototypical synthetic reagents that are capable of endosomal escape and examine their mechanisms of action, their efficiencies, and their effects on cells. Although these delivery systems are chemically distinct, some commonalities in how they interact with cellular membranes can be inferred. This, in turn, sheds some light on the process of endosomal escape, and may help guide the development and optimization of next-generation delivery tools.
We study if and how social preferences extend to risky environments. We provide experimental evidence from different versions of dictator games with risky outcomes and establish that preferences that ...are exclusively based on ex post or on ex ante comparisons cannot generate the observed behavioral patterns. The more money decision-makers transfer in the standard dictator game, the more likely they are to equalize payoff chances under risk. Risk to the recipient does, however, generally decrease the transferred amount. Ultimately, a utility function with a combination of ex post and ex ante fairness concerns may best describe behavior.
Endosomal entrapment is a severely limiting bottleneck in the delivery of biologics into cells. The compound dfTAT was recently found to circumvent this problem by mediating endosomal leakage ...efficiently and without toxicity. Herein, we report on the mechanism of endosomal escape of this cell-penetrating peptide. By modulating the trafficking of the peptide within the endocytic pathway, we identify late endosomes as the organelles rendered leaky by dfTAT. We establish that dfTAT binds bis(monoacylglycero)phosphate (BMP), a lipid found in late endosomes, and that the peptide causes the fusion and leakage of bilayers containing BMP. Together, these data identify late endosomes as desirable gateways for cell penetration and BMP as a cellular factor that can be exploited for the development of future delivery agents.
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•dfTAT cytosolic penetration requires trafficking to late endosomes•dfTAT causes the fusion and leakage of membranes that contain BMP•Anti-BMP inhibits dfTAT activity in vitro and in cellulo•Cytosolic access of macromolecules is enabled by the dfTAT/BMP lock and key pair
The endosomolytic agent dfTAT delivers macromolecules into the cytosol of cells with remarkable efficiency. Erazo-Oliveras et al. show that dfTAT interacts with the lipid BMP inside late endosomes to mediate endosomal leakage. Together, dfTAT and BMP offer a lock and key system that can be exploited for cellular delivery applications.
Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative ...biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions that overwhelm the DNA repair capacity of malignant cells. These physical and radiobiological characteristics imbue heavy ions with potent tumoricidal capacity, while having the potential for simultaneously maximally sparing normal tissues. Thus, CIRT could potentially be used to treat some of the most difficult to treat tumors, including those that are hypoxic, radio-resistant, or deep-seated. Clinical data, mostly from Japan and Germany, are promising, with favorable oncologic outcomes and acceptable toxicity. In this manuscript, we review the physical and biological rationales for CIRT, with an emphasis on DNA damage and repair, as well as providing a comprehensive overview of the translational and clinical data using CIRT.
Illegal fishing via roving banditry, or fishing illegally in other countries’ territorial waters, continues to threaten the security, sustainability, and biodiversity of global marine resources. Yet, ...little is known about the behavioral drivers of banditry, and whether interventions can shift these. We address this critical knowledge gap by quantitatively surveying 82 fishers in two known port havens (Da Nang and Sa Ky, central Vietnam) for roving banditry by Vietnamese “blue boats,” before and after interventions aimed at reducing illegal fishing. We present three key findings: (1) displacement from the South China Sea and degraded local resources were primary behavioral drivers, (2) interventions increased perceptions of risk and shame if apprehended, and (3) the source of bail money (i.e., family vs. business) was highly predictive of whether fishers saw punishment as an adequate deterrent to illegal fishing. Lastly, we discuss the implications of these findings for regional policy and management strategies.
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