SignificanceDo human societies from around the world exhibit similarities in the way that they are structured and show commonalities in the ways that they have evolved? To address these long-standing questions, we constructed a database of historical and archaeological information from 30 regions around the world over the last 10,000 years. Our analyses revealed that characteristics, such as social scale, economy, features of governance, and information systems, show strong evolutionary relationships with each other and that complexity of a society across different world regions can be meaningfully measured using a single principal component of variation. Our findings highlight the power of the sciences and humanities working together to rigorously test hypotheses about general rules that may have shaped human history.

a b s t r a c tRadiocarbon date frequency distributions and archaeological site counts are two popular proxies used to investigate prehistoric demography, following the assumption that variations in these data reflect fluctuations in the relative size and distribution of past populations. However, the two approaches are rarely applied to the same data-set and their applicability is heavily conditioned by the archaeological record in question, particularly research histories, agendas, and funding availability. In this paper we use both types of data to examine the population history of the Upper Palaeolithic hunteregatherers (~40 000e12 000 cal BP) of Southwestern France, comparing the demographic signatures generated.Both proxies produce similar signatures across the Upper Palaeolithic sequence of the region, strengthening the interpretation of relative demographic changes as the cause of the pattern. In particular, a marked population decline is seen in both datasets during the Late Gravettian (~28 000 cal BP), as well as a population increase in the Late Solutrean (~25 000 cal BP) supporting the notion that the region acted as a population refugium during the Last Glacial Maximum. Where the two proxies diverge in the demographic signatures they produce, the radiocarbon date distribution shows peaks compared to troughs in site counts; the opposite pattern expected given taphonomic issues surrounding cultural carbon. Despite differences in chronological resolution and sampling bias, our data suggest that the two proxies can be considered broadly equivalent; a finding which warrants the investigation of prehistoric demography in regions where either extensive survey data or radiometric dating programmes are unavailable. While some preliminary observations are made, the impact of changing mobility on diachronic patterns seen in both proxies remains, however, difficult to assess.

Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non-small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR.Implications: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFRdriven NSCLC. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C. Pham-Danis, S.

Proponents of the Axial Age contend that parallel cultural developments between 800 and 200 BCE in what is today China, Greece, India, Iran, and Israel-Palestine constitute the global historical turning point toward modernity. The Axial Age concept is well-known and influential, but deficiencies in the historical evidence and sociological analysis available have thwarted efforts to evaluate the concept’s major global contentions. As a result, the Axial Age concept remains controversial. Seshat: Global History Databank provides new tools for examining this topic in social formations across Afro-Eurasia during the first two millennia BCE and first millennium CE, allowing scholars to empirically evaluate the varied and contrasting claims researchers have put forward. Results undercut the notion of a specific “age” of axiality limited to a specific geo-temporal localization. Critical traits offered as evidence of an axial transformation by proponents of the Axial Age concept appeared across Afro-Eurasia hundreds, and in some cases thousands, of years prior to the proposed Axial Age. Our analysis raises important questions for future evaluations of this period and points the way toward empirically-led, historical-sociological investigations of the ideological and institutional foundations of complex societies.

Proponents of the Axial Age contend that parallel cultural developments between 800 and 200 BCE in what is today China, Greece, India, Iran, and Israel-Palestine constitute the global historical turning point towards modernity. While the Axial Age concept is well-known and influential, deficiencies in the historical evidence and sociological analysis available have thwarted efforts to evaluate the Axial Age concept’s major global contentions. As a result, the Axial Age concept remains controversial. Seshat: Global History Databank provides new tools for examining this topic in social formations across Afro-Eurasia during the first two millennia BCE and first millennium CE, allowing scholars to empirically evaluate the many varied— and contrasting—claims put forward about this period. Our systematic investigation undercuts the notion of a specific 'age' of axiality limited to a specific geo-temporal localization. Critical traits offered as evidence of an axial transformation by proponents of the Axial Age concept are shown to have appeared across Afro-Eurasia hundreds and in some cases thousands of years prior to the proposed Axial Age. Our analysis raises important questions for future evaluations of this period and points the way towards empirically-led, historical-sociological investigations of the ideological and institutional foundations of complex societies.