Search for: All records

ABSTRACT Evolutionary genomic approaches provide powerful tools to understand variation in and evolution of physiological processes. Untargeted genomic or transcriptomic screens can identify functionally annotated candidate genes linked to specific physiological processes, in turn suggesting evolutionary roles for these processes. Such studies often aim to inform modeling of the potential of natural populations to adapt to climate change, but these models are most accurate when evolutionary responses are repeatable, and thus predictable. Here, we synthesize the evolutionary genetic and comparative transcriptomic literature on terrestrial and marine invertebrates to assess whether evolutionary responses to temperature are repeatable within populations, across populations and across species. There is compelling evidence for repeatability, sometimes even across species. However, responses to laboratory selection and geographic variation across thermal gradients appear to be highly idiosyncratic. We also survey whether genetic/transcriptomic studies repeatedly identify candidate genes in three functional groups previously associated with the response to thermal stress: heat shock protein (Hsp) genes, proteolysis genes and immunity genes. Multiple studies across terrestrial and marine species identify candidates included in these gene sets. Yet, each of the gene sets are identified in only a minority of studies. Together, these patterns suggest that there is limited predictability of evolutionary responses to natural selection, including across studies within species. We discuss specific patterns for the candidate gene sets, implications for predictive modeling, and other potential applications of evolutionary genetics in elucidating physiology and gene function. Finally, we discuss limitations of inferences from available evolutionary genetic studies and directions for future research. 

In the Iron Age, the Neo-Assyrian empire (c. 900–600 BC) conquered territory across southwest Asia and established regional capitals along its borders to secure its gains. Governors at these centers oversaw resource extraction and craft production for shipment to the imperial heartland in modern-day northern Iraq. Metals and textiles were the crafts most carefully managed by the administration. We know less about centralized control over ceramic production but hypothesize that fineware production and distribution would have been of interest to imperial administrators. A fineware type known as Palace Ware has been found throughout the empire and is considered an indicator of elite Assyrian dining traditions. Excavations at one regional capital, Ziyaret Tepe (ancient Tušhan) produced pottery of various skill levels used by residents. In this study neutron activation analysis (NAA) was used to characterize and compare the fabrics used to make Palace Ware vessels with more common wares to see if the former vessels were imported from the imperial heartland. Palace Ware is macroscopically distinct, but this does not always indicate an import. Chemical composition of the samples fell into four main groups, and both Palace and common ware were found to have similar compositions. Comparison of these data with those from contemporary sites showed that the two main Ziyaret groups matched the chemical composition of pottery from the Assyrian capitals of Nimrud and Nineveh. Our conclusions show that there is considerable homogeneity in the clays of the upper Tigris river valley in Turkey and the lower Tigris in northern Iraq. Given this similarity, it is possible that Palace Ware at Tušhan was produced locally, imported, or both. If it was manufactured locally, as has been shown at the urban center of Tell Sheikh Hamad, potters in the imperial peripheries may have produced fineware pottery independent of direct imperial control. 

Abstract Targeted protein degradation (TPD) is a powerful strategy for targeting and eliminating disease-causing proteins. While heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) are more modular, the rational design of monovalent or molecular glue degraders remains challenging. In this study, we generated a small library of BET-domain inhibitor JQ1 analogs bearing elaborated electrophilic handles to identify permissive covalent degradative handles and E3 ligase pairs. We identified an elaborated fumaramide handle that, when appended onto JQ1, led to the proteasome-dependent degradation of BRD4. Further characterization revealed that the E3 ubiquitin ligase CUL4^DCAF16—a common E3 ligase target of electrophilic degraders—was responsible for BRD4 loss by covalently targeting C173 on DCAF16. While this original fumaramide handle, when appended onto other protein-targeting ligands, did not accommodate the degradation of other neo-substrates, a truncated version of this handle attached to JQ1 was still capable of degrading BRD4, now through targeting both C173 and C178. This truncated fumaramide handle, when appended on various protein targeting ligands, and was also more permissive in degrading other neo-substrates, including CDK4/6, SMARCA2/4, and the androgen receptor (AR). We further demonstrated that this optimized truncated fumaramide handle, when transplanted onto an AR DNA binding domain-targeting ligand, could degrade both AR and the undruggable truncation variant of AR, AR-V7, in androgen-independent prostate cancer cells in a DCAF16-dependent manner. Overall, we have identified a unique DCAF16-targeting covalent degradative handle that can be transplanted across several protein-targeting ligands to induce the degradation of their respective targets for the modular design of monovalent or bifunctional degraders. 

The Darkveti multi-layered site in the Imereti region of Georgia offers valuable insights into prehistoric human activity. Despite extensive research conducted in the 1960s and 1970s by Lamara Nebieridze, certain aspects of the site's chronology and inhabitants' mobility remained unclear. This study aims to address these gaps through collaborative, interdisciplinary research involving Georgian and foreign scientists. The primary objective is to precisely date the cultural layers belonging to the Mesolithic and Neolithic epochs using absolute dating methods. By combining archaeological evidence with palaeontological, geoarchaeological, and palaeobotanical data, this study aims to reconstruct the palaeoenvironment and subsistence strategies of the Darkveti inhabitants. Additionally, the analysis of stone tools and lithic raw materials will shed light on technological developments and possible connections with neighbouring regions. The findings will contribute to a better understanding of the cultural dynamics, mobility patterns, and adaptations of prehistoric communities in the Imereti region and the wider Caucasus.