Lithic artifact assemblage transport and micro-wear modification in a fluvial setting: a radio frequency identification tag experiment

River processes are widely assumed to have impacted the integrity of lithic assemblages when artifacts are found in fluvial sediments, but the specifics of these influences remain largely unknown. We conducted a real-world experiment to determine how the initial stages of fluvial entrainment affected lithic artifact assemblages. We inserted replica artifacts with Radio Frequency Identification (RFID) tags into a gravel-bedded river in Wales (UK) for seven months and related their transport distances to their morphology and the recorded streamflow. Additionally, nine artifacts were recovered at the end of the experiment and analyzed for micro-wear traces. In sum, our results show that in a gravel bedded river with a mean discharge of 5.1 m3s-1, artifact length and width were the main variables influencing artifact transport distances. The experiment also resulted in characteristic micro-wear traces developing on the artifacts over distances of 485 m or less. These results emphasize the multifaceted nature of alluvial site formation processes in a repeatable experiment and highlight new ways to identify the transport of replica Paleolithic material

The Palaeolithic record of Warsash, Hampshire, UK: implications for late Lower and early Middle Palaeolithic occupation history of Southern Britain

This paper presents new work on the Lower and Middle Palaeolithic assemblages recovered from Pleistocene gravels of the River Test at Warsash, Hampshire. Historic map and artefact analyses enable the geological context to be established for substantial portions of the Warsash Palaeolithic record, which, when combined with new data relating to regional terrace stratigraphy and chronology, enables Warsash to be incorporated within regional and national Palaeolithic frameworks. Three key assemblages are identified: (1) a handaxe-dominated assemblage associated with gravels of the Lower Warsash Terrace that is likely to relate to hominin occupation during MIS 9; (2) a Levallois assemblage probably related to sediments overlying the Lower Warsash Terrace and likely to represent occupation in late MIS 8 and/or MIS 7; (3) a handaxe-dominated assemblage recovered from gravels of the Hamble Terrace, which is likely to have been reworked from older terrace fragments. The presence at Warsash of ficrons, cleavers and plano-convex handaxes is confirmed and their potential chronological significance considered. The Levallois record of the Solent Basin is discussed, highlighting its impoverished nature relative to the rich Levallois record of the Thames Valley. It is argued that preservation bias and/or collection history have not played a major role in creating these differences. Instead, it is likely to represent the limited dispersal of Neanderthal populations further into Britain from an entry point in the southern North Sea Basin

The Assessment of Fecal Volatile Organic Compounds in Healthy Infants: Electronic Nose Device Predicts Patient Demographics and Microbial Enterotype

Background: The assessment of fecal volatile organic compounds (VOCs) has emerged as a noninvasive biomarker in many different pathologies. Before assessing whether VOCs can be used to diagnose intestinal diseases, including necrotizing enterocolitis (NEC), it is necessary to measure the impact of variable infant demographic factors on VOC signals. Materials and methods: Stool samples were collected from term infants at four hospitals in a large metropolitan area. Samples were heated, and fecal VOCs assessed by the Cyranose 320 Electronic Nose. Twenty-eight sensors were combined into an overall smellprint and were also assessed individually. 16s rRNA gene sequencing was used to categorize infant microbiomes. Smellprints were correlated to feeding type (formula versus breastmilk), sex, hospital of birth, and microbial enterotype. Overall smellprints were assessed by PERMANOVA with Euclidean distances, and individual sensors from each smellprint were assessed by Mann-Whitney U-tests. P < 0.05 was significant. Results: Overall smellprints were significantly different according to diet. Individual sensors were significantly different according to sex and hospital of birth, but overall smellprints were not significantly different. Using a decision tree model, two individual sensors could reliably predict microbial enterotype. Conclusions: Assessment of fecal VOCs with an electronic nose is impacted by several demographic characteristics of infants and can be used to predict microbiome composition. Further studies are needed to design appropriate algorithms that are able to predict NEC based on fecal VOC profiles

Stereospecific Lasofoxifene Derivatives Reveal the Interplay between Estrogen Receptor Alpha Stability and Antagonistic Activity in <i>ESR1</i> Mutant Breast Cancer Cells

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend ERα cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene derivatives that maintained the drug’s antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated lasofoxifene derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles. SIGNIFICANCE This study shows that antiestrogens that enforce a wild-type-like estrogen receptor alpha antagonist conformation demonstrate improved therapeutic activities in hormone-resistant breast cancer cells harboring activating Y537S ESR1 mutant

Exploring Late Bronze Age systems of bronzework production in Switzerland through Network Science

YesMany hundreds of Bronze Age bronze artefacts are known from excavations in Switzerland, yet the interpretation of production networks from the object find locations remain problematic. It is proposed that the decorative elements used on items, such as ring-jewellery, can be used as elements to assist in the identification of artisanal traditions and ‘schools’, and also regional or community preference and selection of specific designs. Combining the analysis of over 1700 items of ring-jewellery from Switzerland with approaches from network science has facilitated the identification of regional clustering of design elements, comparable with cultural typologies in the area. It is also possible to identify potential instances of cultural differentiation through decoration within the broader regional cultural traditions. The study highlights important facets of bronzework production in the region of Switzerland, while also demonstrating future potential directions which could build upon the European wide dataset of prehistoric bronzework.Primary research conducted under previous funding at University of Basel, Switzerland – SNF gran

Pluvial periods in Southern Arabia over the last 1.1 million-years

Past climates and environments experienced by the Saharo-Arabian desert belt are of prime importance for palaeoclimatic and palaeoanthropological research. On orbital timescales transformations of the desert into a savannah-like landscape in response to higher precipitation provided “windows of opportunity” for hominin dispersal from Africa into Eurasia. On long timescales, palaeoenvironmental reconstructions for the region are predominantly derived from marine sediments and available terrestrial records from the Arabian Peninsula are limited to 450 ka before present (BP). Here, we present a new stalagmite-based palaeoclimate record from Mukalla Cave in Yemen which extends back to ~1.1 million years BP or Marine Isotope Stage (MIS) 31, as determined by Uranium-lead dating. Stalagmite Y99 grew only during peak interglacial periods and warm substages back to ~1.1 Ma. Stalagmite calcite oxygen isotope (δ18O) values show that every past interglacial humid period was wetter than the Holocene, a period in which large lakes formed in the now arid areas of southern Arabia. Carbon isotope (δ13C) values indicate habitable savannah-like environments developed during these pluvial periods. A total of 21 pluvial periods with precipitation of more than 300 mm yr-1 occurred since ~1.1 Ma and thus numerous opportunities for hominin dispersals occurred throughout the Pleistocene. New determinations of hydrogen (δDFI) and oxygen (δ18OFI) isotopes in stalagmite fluid inclusion water demonstrates that enhanced precipitation in Southern Arabia was brought by the African and Indian Summer Monsoons. When combined with sub-annual calcite analysis of δ18O and δ13C, these data reveal a distinct wet (summer) and dry (winter) seasonality

PCNA directs type 2 RNase H activity on DNA replication and repair substrates

Ribonuclease H2 is the major nuclear enzyme degrading cellular RNA/DNA hybrids in eukaryotes and the sole nuclease known to be able to hydrolyze ribonucleotides misincorporated during genomic replication. Mutation in RNASEH2 causes Aicardi–Goutières syndrome, an auto-inflammatory disorder that may arise from nucleic acid byproducts generated during DNA replication. Here, we report the crystal structures of Archaeoglobus fulgidus RNase HII in complex with PCNA, and human PCNA bound to a C-terminal peptide of RNASEH2B. In the archaeal structure, three binding modes are observed as the enzyme rotates about a flexible hinge while anchored to PCNA by its PIP-box motif. PCNA binding promotes RNase HII activity in a hinge-dependent manner. It enhances both cleavage of ribonucleotides misincorporated in DNA duplexes, and the comprehensive hydrolysis of RNA primers formed during Okazaki fragment maturation. In addition, PCNA imposes strand specificity on enzyme function, and by localizing RNase H2 and not RNase H1 to nuclear replication foci in vivo it ensures that RNase H2 is the dominant RNase H activity during nuclear replication. Our findings provide insights into how type 2 RNase H activity is directed during genome replication and repair, and suggest a mechanism by which RNase H2 may suppress generation of immunostimulatory nucleic acids