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<jats:title>Abstract</jats:title><jats:p>During the Early Bronze Age, populations of the western Eurasian steppe expanded across an immense area of northern Eurasia. Combined archaeological and genetic evidence supports widespread Early Bronze Age population movements out of the Pontic–Caspian steppe that resulted in gene flow across vast distances, linking populations of Yamnaya pastoralists in Scandinavia with pastoral populations (known as the Afanasievo) far to the east in the Altai Mountains<jats:sup>1,2</jats:sup> and Mongolia<jats:sup>3</jats:sup>. Although some models hold that this expansion was the outcome of a newly mobile pastoral economy characterized by horse traction, bulk wagon transport<jats:sup>4–6</jats:sup> and regular dietary dependence on meat and milk<jats:sup>5</jats:sup>, hard evidence for these economic features has not been found. Here we draw on proteomic analysis of dental calculus from individuals from the western Eurasian steppe to demonstrate a major transition in dairying at the start of the Bronze Age. The rapid onset of ubiquitous dairying at a point in time when steppe populations are known to have begun dispersing offers critical insight into a key catalyst of steppe mobility. The identification of horse milk proteins also indicates horse domestication by the Early Bronze Age, which provides support for its role in steppe dispersals. Our results point to a potential epicentre for horse domestication in the Pontic–Caspian steppe by the third millennium <jats:sc>bc</jats:sc>, and offer strong support for the notion that the novel exploitation of secondary animal products was a key driver of the expansions of Eurasian steppe pastoralists by the Early Bronze Age.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Domestication of horses fundamentally transformed long-range mobility and warfare<jats:sup>1</jats:sup>. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling<jats:sup>2–4</jats:sup> at Botai, Central Asia around 3500 <jats:sc>bc</jats:sc><jats:sup>3</jats:sup>. Other longstanding candidate regions for horse domestication, such as Iberia<jats:sup>5</jats:sup> and Anatolia<jats:sup>6</jats:sup>, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 <jats:sc>bc</jats:sc>, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the <jats:italic>GSDMC</jats:italic> and <jats:italic>ZFPM1</jats:italic> genes. Our results reject the commonly held association<jats:sup>7</jats:sup> between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 <jats:sc>bc</jats:sc><jats:sup>8,9</jats:sup> driving the spread of Indo-European languages<jats:sup>10</jats:sup>. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium <jats:sc>bc</jats:sc> Sintashta culture<jats:sup>11,12</jats:sup>.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Humans are considered as the main host for <jats:italic>Mycobacterium leprae</jats:italic><jats:sup>1</jats:sup>, the aetiological agent of leprosy, but spillover has occurred to other mammals that are now maintenance hosts, such as nine-banded armadillos and red squirrels<jats:sup>2,3</jats:sup>. Although naturally acquired leprosy has also been described in captive nonhuman primates<jats:sup>4–7</jats:sup>, the exact origins of infection remain unclear. Here we describe leprosy-like lesions in two wild populations of western chimpanzees (<jats:italic>Pan troglodytes verus</jats:italic>) in Cantanhez National Park, Guinea-Bissau and Taï National Park, Côte d’Ivoire, West Africa. Longitudinal monitoring of both populations revealed the progression of disease symptoms compatible with advanced leprosy. Screening of faecal and necropsy samples confirmed the presence of <jats:italic>M. leprae</jats:italic> as the causative agent at each site and phylogenomic comparisons with other strains from humans and other animals show that the chimpanzee strains belong to different and rare genotypes (4N/O and 2F). These findings suggest that <jats:italic>M. leprae</jats:italic> may be circulating in more wild animals than suspected, either as a result of exposure to humans or other unknown environmental sources.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Nuclear pore complexes (NPCs) create large conduits for cargo transport between the nucleus and cytoplasm across the nuclear envelope (NE)<jats:sup>1–3</jats:sup>. These multi-megadalton structures are composed of about thirty different nucleoporins that are distributed in three main substructures (the inner, cytoplasmic and nucleoplasmic rings) around the central transport channel<jats:sup>4–6</jats:sup>. Here we use cryo-electron tomography on DLD-1 cells that were prepared using cryo-focused-ion-beam milling to generate a structural model for the human NPC in its native environment. We show that—compared with previous human NPC models obtained from purified NEs—the inner ring in our model is substantially wider; the volume of the central channel is increased by 75% and the nucleoplasmic and cytoplasmic rings are reorganized. Moreover, the NPC membrane exhibits asymmetry around the inner-ring complex. Using targeted degradation of Nup96, a scaffold nucleoporin of the cytoplasmic and nucleoplasmic rings, we observe the interdependence of each ring in modulating the central channel and maintaining membrane asymmetry. Our findings highlight the inherent flexibility of the NPC and suggest that the cellular environment has a considerable influence on NPC dimensions and architecture.</jats:p>

<jats:title>Abstract</jats:title><jats:p>LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)<jats:sup>1</jats:sup>, a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2–E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus–receptor interactions, which could inform the development of therapies to mitigate infection and disease against multiple members of this family.</jats:p>