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

Angiogenesis: A Cellular Response to Traumatic Injury

The development of new vasculature plays a significant role in a number of chronic disease states, including neoplasm growth, peripheral arterial disease, and coronary artery disease, among many others. Traumatic injury and hemorrhage, however, is an immediate, often dramatic pathophysiologic insult which can also necessitate neovascularization to promote healing. Traditional understanding of angiogenesis involved resident endothelial cells branching outward from localized niches in the periphery. Additionally, there are a small number of circulating endothelial progenitor cells which participate directly in the process of neovessel formation. The bone marrow stores a relatively small number of so-called pro-angiogenic hematopoietic progenitor cells (PACs) – that is, progenitor cells of a hematopoietic potential that differentiate into key structural cells and stimulate or otherwise support local cell growth/differentiation at the site of angiogenesis. Following injury, a number of cytokines and intercellular processes are activated or modulated to promote development of new vasculature. These processes initiate and maintain a robust response to vascular insult, allowing new vessels to canalize and anastomose and provide timely oxygen delivering to healing tissue. Ultimately as we better understand the key players in the process of angiogenesis we can look to develop novel techniques to promote healing following injury

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

Active site substitutions delineate distinct classes of eubacterial flap endonuclease

FENs (flap endonucleases) play essential roles in DNA replication, pivotally in the resolution of Okazaki fragments. In eubacteria, DNA PolI (polymerase I) contains a flap processing domain, the N-terminal 5′→3′ exonuclease. We present evidence of paralogous FEN-encoding genes present in many eubacteria. Two distinct classes of these independent FEN-encoding genes exist with four groups of eubacteria, being identified based on the number and type of FEN gene encoded. The respective proteins possess distinct motifs hallmarking their differentiation. Crucially, based on primary sequence and predicted secondary structural motifs, we reveal key differences at their active sites. These results are supported by biochemical characterization of two family members - ExoIX (exonuclease IX) from Escherichia coli and SaFEN (Staphylococcus aureus FEN). These proteins displayed marked differences in their ability to process a range of branched and linear DNA structures. On bifurcated substrates, SaFEN exhibited similar substrate specificity to previously characterized FENs. In quantitative exonuclease assays, SaFEN maintained a comparable activity with that reported for PolI. However, ExoIX showed no observable enzymatic activity. A threaded model is presented for SaFEN, demonstrating the probable interaction of this newly identified class of FEN with divalent metal ions and a branched DNA substrate. The results from the present study provide an intriguing model for the cellular role of these FEN sub-classes and illustrate the evolutionary importance of processing aberrant DNA, which has led to their maintenance alongside DNA PolI in many eubacteria

Structural basis of nuclear import of flap endonuclease 1 (FEN1)

Flap endonuclease 1 (FEN1) is a member of the nuclease family and is structurally conserved from bacteriophages to humans. This protein is involved in multiple DNA-processing pathways, including Okazaki fragment maturation, stalled replication-fork rescue, telomere maintenance, long-patch base-excision repair and apoptotic DNA fragmentation. FEN1 has three functional motifs that are responsible for its nuclease, PCNA-interaction and nuclear localization activities, respectively. It has been shown that the C-terminal nuclear localization sequence (NLS) facilitates nuclear localization of the enzyme during the S phase of the cell cycle and in response to DNA damage. To determine the structural basis of the recognition of FEN1 by the nuclear import receptor importin alpha, the crystal structure of the complex of importin alpha with a peptide corresponding to the FEN1 NLS was solved. Structural studies confirmed the binding of the FEN1 NLS as a classical bipartite NLS; however, in contrast to the previously proposed (KRKX8KKK367)-K-354 sequence, it is the (354)KRX(10)KKAK(369) sequence that binds to importin alpha. This result explains the incomplete inhibition of localization that was observed on mutating residues (KKK367)-K-365. Acidic and polar residues in the X-10 linker region close to the basic clusters play an important role in binding to importin alpha. These results suggest that the basic residues in the N-terminal basic cluster of bipartite NLSs may play roles that are more critical than those of the many basic residues in the C-terminal basic cluster