Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica

How wealth is distributed among households provides insight into the fundamental characters of societies and the opportunities they afford for social mobility. However, economic inequality has been hard to study in ancient societies for which we do not have written records, which adds to the challenge of placing current wealth disparities into a long-term perspective. Although various archaeological proxies for wealth, such as burial goods or exotic or expensive-to-manufacture goods in household assemblages, have been proposed, the first is not clearly connected with households, and the second is confounded by abandonment mode and other factors. As a result, numerous questions remain concerning the growth of wealth disparities, including their connection to the development of domesticated plants and animals and to increases in sociopolitical scale. Here we show that wealth disparities generally increased with the domestication of plants and animals and with increased sociopolitical scale, using Gini coefficients computed over the single consistent proxy of house-size distributions. However, unexpected differences in the responses of societies to these factors in North America and Mesoamerica, and in Eurasia, became evident after the end of the Neolithic period. We argue that the generally higher wealth disparities identified in post-Neolithic Eurasia were initially due to the greater availability of large mammals that could be domesticated, because they allowed more profitable agricultural extensification, and also eventually led to the development of a mounted warrior elite able to expand polities (political units that cohere via identity, ability to mobilize resources, or governance) to sizes that were not possible in North America and Mesoamerica before the arrival of Europeans. We anticipate that this analysis will stimulate other work to enlarge this sample to include societies in South America, Africa, South Asia and Oceania that were under-sampled or not included in this study

Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica

How wealth is distributed among households provides insight into the fundamental characters of societies and the opportunities they afford for social mobility. However, economic inequality has been hard to study in ancient societies for which we do not have written records, which adds to the challenge of placing current wealth disparities into a long-term perspective. Although various archaeological proxies for wealth, such as burial goods or exotic or expensive-to-manufacture goods in household assemblages, have been proposed, the first is not clearly connected with households, and the second is confounded by abandonment mode and other factors. As a result, numerous questions remain concerning the growth of wealth disparities, including their connection to the development of domesticated plants and animals and to increases in sociopolitical scale. Here we show that wealth disparities generally increased with the domestication of plants and animals and with increased sociopolitical scale, using Gini coefficients computed over the single consistent proxy of house-size distributions. However, unexpected differences in the responses of societies to these factors in North America and Mesoamerica, and in Eurasia, became evident after the end of the Neolithic period. We argue that the generally higher wealth disparities identified in post-Neolithic Eurasia were initially due to the greater availability of large mammals that could be domesticated, because they allowed more profitable agricultural extensification, and also eventually led to the development of a mounted warrior elite able to expand polities (political units that cohere via identity, ability to mobilize resources, or governance) to sizes that were not possible in North America and Mesoamerica before the arrival of Europeans. We anticipate that this analysis will stimulate other work to enlarge this sample to include societies in South America, Africa, South Asia and Oceania that were under-sampled or not included in this study

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors

Purpose: Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). Experimental design: HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. Results: VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. Conclusions: By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC

Role of CaMKIIδ phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure

The force frequency relationship (FFR), first described by Bowditch 139 years ago as the observation that myocardial contractility increases proportionally with increasing heart rate, is an important mediator of enhanced cardiac output during exercise. Individuals with heart failure have defective positive FFR that impairs their cardiac function in response to stress, and the degree of positive FFR deficiency correlates with heart failure progression. We have identified a mechanism for FFR involving heart rate dependent phosphorylation of the major cardiac sarcoplasmic reticulum calcium release channel/ryanodine receptor (RyR2), at Ser2814, by calcium/calmodulin–dependent serine/threonine kinase–δ (CaMKIIδ). Mice engineered with an RyR2-S2814A mutation have RyR2 channels that cannot be phosphorylated by CaMKIIδ, and exhibit a blunted positive FFR. Ex vivo hearts from RyR2-S2814A mice also have blunted positive FFR, and cardiomyocytes isolated from the RyR2-S2814A mice exhibit impaired rate-dependent enhancement of cytosolic calcium levels and fractional shortening. The cardiac RyR2 macromolecular complexes isolated from murine and human failing hearts have reduced CaMKIIδ levels. These data indicate that CaMKIIδ phosphorylation of RyR2 plays an important role in mediating positive FFR in the heart, and that defective regulation of RyR2 by CaMKIIδ-mediated phosphorylation is associated with the loss of positive FFR in failing hearts