Efficient, multi-hundred-gram scale access to E3 ubiquitin ligase ligands for degrader development.

Small molecule heterobifunctional degraders (commonly also known as PROTACs) offer tremendous potential to deliver new therapeutics in areas of unmet medical need. To deliver on this promise, a new discipline directed at degrader design and optimization has emerged within medicinal chemistry to address a central challenge, namely how to optimize relatively large, heterobifunctional molecules for activity, whilst maintaining drug-like properties. This process involves simultaneous optimization of the three principle degrader components: E3 ubiquitin ligase ligand, linker, and protein of interest (POI) ligand. A substantial degree of commonality exists with the E3 ligase ligands typically used at the early stages of degrader development, resulting in demand for these compounds as chemical building blocks in degrader research programs. We describe herein a collation of large scale, high-yielding syntheses to access the most utilized E3 ligase ligands to support early-stage degrader development.

Environmental influences on human innovation and behavioural diversity in southern Africa 92-80 thousand years ago.

Africa's Middle Stone Age preserves sporadic evidence for novel behaviours among early modern humans, prompting a range of questions about the influence of social and environmental factors on patterns of human behavioural evolution. Here we document a suite of novel adaptations dating approximately 92-80 thousand years before the present at the archaeological site Varsche Rivier 003 (VR003), located in southern Africa's arid Succulent Karoo biome. Distinctive innovations include the production of ostrich eggshell artefacts, long-distance transportation of marine molluscs and systematic use of heat shatter in stone tool production, none of which occur in coeval assemblages at sites in more humid, well-studied regions immediately to the south. The appearance of these novelties at VR003 corresponds with a period of reduced regional wind strength and enhanced summer rainfall, and all of them disappear with increasing winter rainfall dominance after 80 thousand years before the present, following which a pattern of technological similarity emerges at sites throughout the broader region. The results indicate complex and environmentally contingent processes of innovation and cultural transmission in southern Africa during the Middle Stone Age.

Multiple hominin dispersals into Southwest Asia over the past 400,000 years.

Pleistocene hominin dispersals out of, and back into, Africa necessarily involved traversing the diverse and often challenging environments of Southwest Asia1-4. Archaeological and palaeontological records from the Levantine woodland zone document major biological and cultural shifts, such as alternating occupations by Homo sapiens and Neanderthals. However, Late Quaternary cultural, biological and environmental records from the vast arid zone that constitutes most of Southwest Asia remain scarce, limiting regional-scale insights into changes in hominin demography and behaviour1,2,5. Here we report a series of dated palaeolake sequences, associated with stone tool assemblages and vertebrate fossils, from the Khall Amayshan 4 and Jubbah basins in the Nefud Desert. These findings, including the oldest dated hominin occupations in Arabia, reveal at least five hominin expansions into the Arabian interior, coinciding with brief 'green' windows of reduced aridity approximately 400, 300, 200, 130-75 and 55 thousand years ago. Each occupation phase is characterized by a distinct form of material culture, indicating colonization by diverse hominin groups, and a lack of long-term Southwest Asian population continuity. Within a general pattern of African and Eurasian hominin groups being separated by Pleistocene Saharo-Arabian aridity, our findings reveal the tempo and character of climatically modulated windows for dispersal and admixture.

Earliest known human burial in Africa.

The origin and evolution of hominin mortuary practices are topics of intense interest and debate1-3. Human burials dated to the Middle Stone Age (MSA) are exceedingly rare in Africa and unknown in East Africa1-6. Here we describe the partial skeleton of a roughly 2.5- to 3.0-year-old child dating to 78.3 ± 4.1 thousand years ago, which was recovered in the MSA layers of Panga ya Saidi (PYS), a cave site in the tropical upland coast of Kenya7,8. Recent excavations have revealed a pit feature containing a child in a flexed position. Geochemical, granulometric and micromorphological analyses of the burial pit content and encasing archaeological layers indicate that the pit was deliberately excavated. Taphonomical evidence, such as the strict articulation or good anatomical association of the skeletal elements and histological evidence of putrefaction, support the in-place decomposition of the fresh body. The presence of little or no displacement of the unstable joints during decomposition points to an interment in a filled space (grave earth), making the PYS finding the oldest known human burial in Africa. The morphological assessment of the partial skeleton is consistent with its assignment to Homo sapiens, although the preservation of some primitive features in the dentition supports increasing evidence for non-gradual assembly of modern traits during the emergence of our species. The PYS burial sheds light on how MSA populations interacted with the dead.

The expansion of Acheulean hominins into the Nefud Desert of Arabia.

The Arabian Peninsula is a critical geographic landmass situated between Africa and the rest of Eurasia. Climatic shifts across the Pleistocene periodically produced wetter conditions in Arabia, dramatically altering the spatial distribution of hominins both within and between continents. This is particularly true of Acheulean hominins, who appear to have been more tethered to water sources than Middle Palaeolithic hominins. However, until recently, chrono-cultural knowledge of the Acheulean of Arabia has been limited to one dated site, which indicated a hominin presence in Marine Isotope Stages (MIS) 7-6. Here, we report the first dated Acheulean site from the Nefud Desert of northern Saudi Arabia, together with palaeoecological evidence for an associated deep, probably fresh-water, lake. The site of An Nasim features varied and often finely flaked façonnage handaxes. Luminescence ages together with geomorphological and palaeoecological evidence indicates that the associated artefacts date to MIS 9. At present, An Nasim represents the oldest yet documented Acheulean sites in Arabia, and adds to a growing picture of regionally diverse stone tool assemblages used by Middle Pleistocene hominins, and likely indicative of repeated population re-entry into the peninsula in wet 'Green Arabia' phases.

The oldest Homo erectus buried lithic horizon from the Eastern Saharan Africa. EDAR 7 - an Acheulean assemblage with Kombewa method from the Eastern Desert, Sudan.

Although essential for reconstructing hominin behaviour during the Early Palaeolithic, only a handful of Acheulean sites have been dated in the Eastern Sahara region. This is due to the scarcity of sites for this time period and the lack of datable material. However, recent excavations in the Atbara region (Sudan) have provided unique opportunities to analyse and date Acheulean stone tools. We report here on EDAR 7, part of a cluster of Acheulean and Middle Stone Age (MSA) sites that were recently discovered in the Eastern Desert Atbara River (EDAR) region, located in the Eastern Desert (Sudan) far from the Nile valley. At EDAR 7, a 3.5 metre sedimentary sequence was excavated, allowing an Acheulean assemblage to be investigated using a combination of sedimentology, stone tool studies and optically stimulated luminescence dating (OSL). The site has delivered a complete Acheulean knapping chaine opératoire, providing new information about the Saharan Acheulean. The EDAR 7 site is interpreted as a remnant of a campsite based on the co-occurrence of two reduction modes: one geared towards the production of Large Cutting Tools (LCTs), and the other based on the flaking of small debitage and production of flake tools. Particularly notable in the EDAR 7 assemblage is the abundance of cleavers, most of which display evidence of flake production. Implementation of giant Kombewa flakes was also observed. A geometric morphometric analysis of hand-axes was conducted to verify a possible Late Acheulean assemblage standardisation in the Nubian Sahara. In addition, the analysis of micro-traces and wear on the artefacts has provided information on the use history of the Acheulean stone tools. Sediment analyses and OSL dating show that the EDAR 7 sequence contains the oldest Acheulean encampment remains in the Eastern Sahara, dated to the MIS 11 or earlier. This confirms that Homo erectus occupied the EDAR region during Middle Pleistocene humid periods, and demonstrates that habitable corridors existed between the Ethiopian Highlands, the Nile and the Red Sea coast, allowing population dispersals across the continent and out of it.

Human footprints provide snapshot of last interglacial ecology in the Arabian interior.

The nature of human dispersals out of Africa has remained elusive because of the poor resolution of paleoecological data in direct association with remains of the earliest non-African people. Here, we report hominin and non-hominin mammalian tracks from an ancient lake deposit in the Arabian Peninsula, dated within the last interglacial. The findings, it is argued, likely represent the oldest securely dated evidence for Homo sapiens in Arabia. The paleoecological evidence indicates a well-watered semi-arid grassland setting during human movements into the Nefud Desert of Saudi Arabia. We conclude that visitation to the lake was transient, likely serving as a place to drink and to forage, and that late Pleistocene human and mammalian migrations and landscape use patterns in Arabia were inexorably linked.

Publisher Correction: 78,000-year-old record of Middle and Later Stone Age innovation in an East African tropical forest.

The originally published version of this Article contained an error in Fig. 3, whereby an additional unrelated graph was overlaid on top of the magnetic susceptibility plot. Furthermore, the Article title contained an error in the capitalisation of 'Stone Age'. Both of these errors have now been corrected in both the PDF and HTML versions of the Article.

78,000-year-old record of Middle and Later stone age innovation in an East African tropical forest.

The Middle to Later Stone Age transition in Africa has been debated as a significant shift in human technological, cultural, and cognitive evolution. However, the majority of research on this transition is currently focused on southern Africa due to a lack of long-term, stratified sites across much of the African continent. Here, we report a 78,000-year-long archeological record from Panga ya Saidi, a cave in the humid coastal forest of Kenya. Following a shift in toolkits ~67,000 years ago, novel symbolic and technological behaviors assemble in a non-unilinear manner. Against a backdrop of a persistent tropical forest-grassland ecotone, localized innovations better characterize the Late Pleistocene of this part of East Africa than alternative emphases on dramatic revolutions or migrations.

Homo sapiens in Arabia by 85,000 years ago.

Understanding the timing and character of the expansion of Homo sapiens out of Africa is critical for inferring the colonization and admixture processes that underpin global population history. It has been argued that dispersal out of Africa had an early phase, particularly ~130-90 thousand years ago (ka), that reached only the East Mediterranean Levant, and a later phase, ~60-50 ka, that extended across the diverse environments of Eurasia to Sahul. However, recent findings from East Asia and Sahul challenge this model. Here we show that H. sapiens was in the Arabian Peninsula before 85 ka. We describe the Al Wusta-1 (AW-1) intermediate phalanx from the site of Al Wusta in the Nefud desert, Saudi Arabia. AW-1 is the oldest directly dated fossil of our species outside Africa and the Levant. The palaeoenvironmental context of Al Wusta demonstrates that H. sapiens using Middle Palaeolithic stone tools dispersed into Arabia during a phase of increased precipitation driven by orbital forcing, in association with a primarily African fauna. A Bayesian model incorporating independent chronometric age estimates indicates a chronology for Al Wusta of ~95-86 ka, which we correlate with a humid episode in the later part of Marine Isotope Stage 5 known from various regional records. Al Wusta shows that early dispersals were more spatially and temporally extensive than previously thought. Early H. sapiens dispersals out of Africa were not limited to winter rainfall-fed Levantine Mediterranean woodlands immediately adjacent to Africa, but extended deep into the semi-arid grasslands of Arabia, facilitated by periods of enhanced monsoonal rainfall.

West African monsoon dynamics inferred from abrupt fluctuations of Lake Mega-Chad.

From the deglacial period to the mid-Holocene, North Africa was characterized by much wetter conditions than today. The broad timing of this period, termed the African Humid Period, is well known. However, the rapidity of the onset and termination of the African Humid Period are contested, with strong evidence for both abrupt and gradual change. We use optically stimulated luminescence dating of dunes, shorelines, and fluviolacustrine deposits to reconstruct the fluctuations of Lake Mega-Chad, which was the largest pluvial lake in Africa. Humid conditions first occur at ∼ 15 ka, and by 11.5 ka, Lake Mega-Chad had reached a highstand, which persisted until 5.0 ka. Lake levels fell rapidly at ∼ 5 ka, indicating abrupt aridification across the entire Lake Mega-Chad Basin. This record provides strong terrestrial evidence that the African Humid Period ended abruptly, supporting the hypothesis that the African monsoon responds to insolation forcing in a markedly nonlinear manner. In addition, Lake Mega-Chad exerts strong control on global biogeochemical cycles because the northern (Bodélé) basin is currently the world's greatest single dust source and possibly an important source of limiting nutrients for both the Amazon Basin and equatorial Atlantic. However, we demonstrate that the final desiccation of the Bodélé Basin occurred around 1 ka. Consequently, the present-day mode and scale of dust production from the Bodélé Basin cannot have occurred before 1 ka, suggesting that its role in fertilizing marine and terrestrial ecosystems is either overstated or geologically recent.

The southern route "out of Africa": evidence for an early expansion of modern humans into Arabia.

The timing of the dispersal of anatomically modern humans (AMH) out of Africa is a fundamental question in human evolutionary studies. Existing data suggest a rapid coastal exodus via the Indian Ocean rim around 60,000 years ago. We present evidence from Jebel Faya, United Arab Emirates, demonstrating human presence in eastern Arabia during the last interglacial. The tool kit found at Jebel Faya has affinities to the late Middle Stone Age in northeast Africa, indicating that technological innovation was not necessary to facilitate migration into Arabia. Instead, we propose that low eustatic sea level and increased rainfall during the transition between marine isotope stages 6 and 5 allowed humans to populate Arabia. This evidence implies that AMH may have been present in South Asia before the Toba eruption.

Ancient watercourses and biogeography of the Sahara explain the peopling of the desert.

Evidence increasingly suggests that sub-Saharan Africa is at the center of human evolution and understanding routes of dispersal "out of Africa" is thus becoming increasingly important. The Sahara Desert is considered by many to be an obstacle to these dispersals and a Nile corridor route has been proposed to cross it. Here we provide evidence that the Sahara was not an effective barrier and indicate how both animals and humans populated it during past humid phases. Analysis of the zoogeography of the Sahara shows that more animals crossed via this route than used the Nile corridor. Furthermore, many of these species are aquatic. This dispersal was possible because during the Holocene humid period the region contained a series of linked lakes, rivers, and inland deltas comprising a large interlinked waterway, channeling water and animals into and across the Sahara, thus facilitating these dispersals. This system was last active in the early Holocene when many species appear to have occupied the entire Sahara. However, species that require deep water did not reach northern regions because of weak hydrological connections. Human dispersals were influenced by this distribution; Nilo-Saharan speakers hunting aquatic fauna with barbed bone points occupied the southern Sahara, while people hunting Savannah fauna with the bow and arrow spread southward. The dating of lacustrine sediments show that the "green Sahara" also existed during the last interglacial (∼125 ka) and provided green corridors that could have formed dispersal routes at a likely time for the migration of modern humans out of Africa.

Combretastatin-like chalcones as inhibitors of microtubule polymerisation. Part 2: Structure-based discovery of alpha-aryl chalcones.

Tubulin is an important molecular target in cancer chemotherapy. Antimitotic agents able to bind to the protein are currently under study, commonly used in the clinic to treat a variety of cancers and/or exploited as probes to investigate the protein's structure and function. Here we report the binding modes for a series of colchicinoids, combretastatin A4 and chalcones established from docking studies carried out on the structure of tubulin in complex with colchicine. The proposed models, in agreement with published biochemical data, show that combretastatin A4 binds to the colchicine site of beta-tubulin and that chalcones assume an orientation similar to that of podophyllotoxin. The models can be used to design a new class of podophyllotoxin mimics, the alpha-aryl chalcones, capable of binding to the colchicine-binding site of beta-tubulin with higher affinity.

Ancient biomolecules from deep ice cores reveal a forested southern Greenland.

It is difficult to obtain fossil data from the 10% of Earth's terrestrial surface that is covered by thick glaciers and ice sheets, and hence, knowledge of the paleoenvironments of these regions has remained limited. We show that DNA and amino acids from buried organisms can be recovered from the basal sections of deep ice cores, enabling reconstructions of past flora and fauna. We show that high-altitude southern Greenland, currently lying below more than 2 kilometers of ice, was inhabited by a diverse array of conifer trees and insects within the past million years. The results provide direct evidence in support of a forested southern Greenland and suggest that many deep ice cores may contain genetic records of paleoenvironments in their basal sections.