Explore the vast range of titles available.

\"What was history's biggest empire? Or the tallest building of the ancient world? What was the plumbing like in medieval Byzantium? The average wage in the Mughal Empire? Where did scientific writing first emerge? What was the bloodiest ever ritual human sacrifice? We are used to thinking about history in terms of stories. Yet we understand our own world through data: cast arrays of statistics that reveal the workings of our societies. In Figuring Out the Past, radical historians Peter Turchin and Dan Hoyer dive into the numbers that reveal the true shape of the past, drawing on their own Seshat project, a staggeringly ambitious attempt to log every data point that can be gathered for every society that has ever existed. This book does more than tell the story of humanity: it shows you the big picture, by the numbers.\"--Amazon.com

This paper is a personal account on the discovery and characterization of the 5-HT 2C receptor (first known as the 5-HT 1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT 2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT 1C R, the 5-HT 2C R was discovered while studying the pharmacological features and the distribution of [ 3 H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [ 3 H]mesulergine-labelling to the rat choroid plexus. [ 3 H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT 2 binding, the new binding site was called 5-HT 1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT 1C R (later named 5-HT 2C ) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT 2C R is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT 2C R variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT 2C R splice variants. Intense research led to therapeutically active 5-HT 2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HT 2C R antagonists/inverse agonists. Agomelatine, a 5-HT 2C R antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT 2C R is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT 2C R antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT 2C R may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT 2C R agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT 2C R ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT 2C R is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain.

Non-technical summaryThis study combines revolutionary theory with emerging polycrisis discourses to show how various international and national factors and events can become intertwined, creating polycrisis events that can lead to revolutionary moments. Revolutionary moments can further contribute to stresses that cause polycrisis or systemic dysfunction elsewhere, due to our entanglement of global systems. Through the help of two case studies, the Young Turk Revolution and the Arab Spring, this study highlights how revolutions emerge and how they can unfold in the future.Technical summaryRevolutions – the overthrow or unseating of governmental forces through mass mobilization – have played a crucial role in major societal transformations throughout history (Lawson, 2019, Anatomies of revolution; Goldstone, 2014, Revolutions: A very short introduction). One component of revolutionary theory, past and present, are the ways different factors and forces interact to create revolutionary moments, specifically how international/transnational and internal societal events interconnect to generate revolutionary situations, trajectories, and outcomes. Revolutionary theorist George Lawson (2019) notes that global networks are intermeshed in that they can produce multiple, complex stressors and triggers that cause revolution in what he terms an ‘inter-social approach’. Building on these insights, we argue here through the case studies of the Young Turk Revolution and Arab Spring that the conceptualization of polycrisis as a causal entanglement of crises in multiple global systems provides a critical lens to understand revolutions.Social media summaryIn an age of polycrisis, risk of revolution increases. Explore how revolutions form and learn their future paths.

Archaeological evidence suggests that the population dynamics of Mid-Holocene (Late Mesolithic to Initial Bronze Age, ca. 7000–3000 BCE) Europe are characterized by recurrent booms and busts of regional settlement and occupation density. These boom-bust patterns are documented in the temporal distribution of 14C dates and in archaeological settlement data from regional studies. We test two competing hypotheses attempting to explain these dynamics: climate forcing and social dynamics leading to inter-group conflict. Using the framework of spatially-explicit agent-based models, we translated these hypotheses into a suite of explicit computational models, derived quantitative predictions for population fluctuations, and compared these predictions to data. We demonstrate that climate variation during the European Mid-Holocene is unable to explain the quantitative features (average periodicities and amplitudes) of observed boom-bust dynamics. In contrast, scenarios with social dynamics encompassing density-dependent conflict produce population patterns with time scales and amplitudes similar to those observed in the data. These results suggest that social processes, including violent conflict, played a crucial role in the shaping of population dynamics of European Mid-Holocene societies.

What have been the causes and consequences of technological evolution in world history? In particular, what propels innovation and diffusion of military technologies, details of which are comparatively well preserved and which are often seen as drivers of broad socio-cultural processes? Here we analyze the evolution of key military technologies in a sample of pre-industrial societies world-wide covering almost 10,000 years of history using Seshat : Global History Databank . We empirically test previously speculative theories that proposed world population size, connectivity between geographical areas of innovation and adoption, and critical enabling technological advances, such as iron metallurgy and horse riding, as central drivers of military technological evolution. We find that all of these factors are strong predictors of change in military technology, whereas state-level factors such as polity population, territorial size, or governance sophistication play no major role. We discuss how our approach can be extended to explore technological change more generally, and how our results carry important ramifications for understanding major drivers of evolution of social complexity.

The orexin system comprises two G protein-coupled receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). When discussing the system’s G protein coupling capabilities, it is commonly stated that both receptors couple to Gq cascades while OX2R also couples to Gi cascades. However, a complex milieu of signalling behaviour has been reported that expands and complicates this narrative. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system’s function in vivo in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.

Human societies and ecological systems face increasingly severe risks, stemming from crossing planetary boundaries, worsening inequality, rising geo-political tensions, and new technologies. In an interconnected world, these risks can exacerbate each-other, creating systemic risks, which must be thoroughly assessed and responded to. Recent years have seen the emergence of analytical frameworks designed specifically for, or applicable to, systemic risk assessment, adding to the multitude of tools and models for analysing and simulating different systems. By assessing two recent global food and energy systemic crises, we propose a methodological framework applicable to assessing systemic risks in a polycrisis context, drawing from and building on existing approaches. Our framework’s polycrisis-specific features include: exploring system architectures including their objectives and political economy; consideration of transformational responses away from risks; and cross-cutting practices including consideration of non-human life, trans-disciplinarity, and diversity, transparency and communication of uncertainty around data, evidence and methods. This paper proposes a framework to assess systemic risks that compound and cascade within and between systems. This emphasizes political economy and transformations, as well as trans-disciplinarity and diverse participation, evidence and methods.

Non-Technical SummaryThe term ‘polycrisis’ is gaining attention among academics, policymakers, and the public. Unlike a single crisis, a polycrisis involves complex, interconnected risks across multiple regions and systems, often including ecological factors. This interconnectedness heightens the chances of widespread adverse outcomes or disasters, affecting various systems and triggering cascading effects. The article examines how traditional disaster studies concepts must be adapted for the polycrisis context and places historical events on a spectrum of such critical moments. It concludes with recommendations for communities to build resilience and respond democratically to these challenges.Technical SummaryThe term ‘polycrisis’ has entered the lexicon of a growing circle of academics, policymakers, and the public. Polycrisis is a state that encompasses a complex set of risks characterized by multiple, macroregional, and often ecologically embedded linkages between inexorably interconnected systems. The article reevaluates disaster studies concepts within this polycrisis framework, locates historical events along a spectrum of such moments, and offers recommendations for democratic resilience.Social Media SummaryDiscover how the term ‘polycrisis’ redefines our understanding of interconnected risks and informs new disaster response methods.

Abstract Sleep disruption, and especially rapid eye movement (REM) sleep disruption, is associated with fear inhibition impairment in animals and humans. The REM sleep-fear inhibition relationship raises concern for individuals with posttraumatic stress disorder (PTSD), whose sleep disturbance is commonly treated with hypnotics that disrupt and/or decrease REM sleep, such as benzodiazepines or “Z-drugs.” Here, we examined the effects of the Z-drug zolpidem, a gamma-aminobutyric acidA (GABAA) receptor positive allosteric modulator, as well as suvorexant, an orexin receptor antagonist (hypnotics which decrease and increase REM sleep, respectively) in the context of circadian disruption in murine models of fear inhibition-related processes (i.e. fear extinction and safety learning). Adult male C57Bl/6J mice completed fear and safety conditioning before undergoing shifts in the light–dark (LD) cycle or maintaining a consistent LD schedule. Fear extinction and recall of conditioned safety were thereafter tested daily. Immediately prior to the onset of the light phase between testing sessions, mice were treated with zolpidem, suvorexant, or vehicle (methylcellulose). Polysomnographic analyses showed the temporal distribution of REM sleep was misaligned during LD cycle-shifts, while REM sleep duration was preserved. Suvorexant increased REM sleep and improved fear extinction rate, relative to zolpidem, which decreased REM sleep. Survival analysis demonstrated LD shifted mice treated with suvorexant were faster to achieve complete extinction than vehicle and zolpidem-treated mice in the LD shifted condition. By contrast, retention of conditioned safety memory was not influenced by either treatment. This study thus provides preclinical evidence for the potential clinical utility of hypnotics which increase REM sleep for fear extinction after PTSD-relevant sleep disturbance.