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Abstract Background Mortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications. Methods We used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence. Results We demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo. Conclusions Our findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.

Abstract Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin’s multiaxial role in breast cancer progression and recurrence.

Summary: Background: This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer’s disease. Methods: Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed. Findings: Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point (95% CI: −0.7, 2.7), but increased significantly by 2.0 points (95% CI: 0.1, 4.0) in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by −3.0% (95% CI: −13.0, 7.1). Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores (r = −0.65, p = 0.02), such that reductions in TNF- α were correlated with increases in MoCA scores. Interpretation: This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer’s disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously. Funding: National Institute on Ageing grants R21AG073886 and R33AG061456 funded this research.

Citrulline malate (CM) has been touted as a nutritional ergogenic aid for sports performance, with purported mechanisms of increased muscle blood flow, ammonia clearance, and adenosine triphosphate resynthesis. Combined, these physiological benefits may be best applied to whole-body endurance exercises, such as swimming, though this postulate has not yet been explored. In a double-blind, randomised, and crossover design, 11 national-level swimmers (age: 17 ± 3 years, height: 1.71 ± 0.05 m, body mass: 60.6 ± 8.3 kg) from a high-performance swimming club ingested either 15 g CM or a placebo (PLA) 60 min before six × 300 m freestyle bouts (at 4.5 min intervals). Blood lactate, blood pressure, and ratings of perceived exertion were measured at baseline, 60 min post-ingestion, and immediately post-exercise. Neither mean 300 m swimming time (CM: 212.0 ± 9.6 vs. PLA: 212.8 ± 7.7 s, p = 0.683, g = 0.09) nor any individual swimming bouts (p = 0.679, Pŋ2 = 0.02) were improved with CM ingestion. Moreover, no differences in any physiological or subjective measures were identified between conditions (all p > 0.05). Whether the proposed CM mechanisms were active was unclear as more direct physiological measures (i.e., plasma NO, ammonia) may have been required. Resultantly, these observations do not support an ergogenic effect of acute CM ingestion in highly trained swimmers.

Abstract Global Plate Models are widely used in the Earth Sciences to reconstruct the past geographic position of geological and palaeontological samples. However, the application of Global Plate Models to retrieve ‘palaeocoordinates’ is not trivial. Different Global Plate Models exist which vary in their complexity, spatiotemporal coverage, reference frame, and intended use. Consequently, careful consideration of which models are appropriate for any given research question is required. Here, we document and provide access to reconstruction datasets for five Global Plate Models in the palaeomagnetic reference frame. These datasets provide ‘true’ palaeolatitudes for three discrete global grids reconstructed at one-million-year intervals throughout the Phanerozoic (540–0 Ma), offering three key benefits for the Earth Science community: (1) allow users to look up palaeocoordinates for their samples (e.g. fossil occurrences) through simple indexing without having to learn additional software packages; (2) provide palaeocoordinates which have been generated consistently with thorough documentation; (3) provide static files which preserve model output and which can be used to evaluate palaeogeographic differences between Global Plate Models.

Selection into a County Age Group (CAG; under 10–18) programme is the first step for young aspiring cricketers on their journey to achieving professional status. Recognising that the British South Asian (BSA) community represents 30% of those who play recreational cricket compared to less than 5% of those who are selected to play at the professional level in England and Wales, it is important to better understand the characteristics of selected and non-selected players based on ethnicity to identify potential sociocultural differences during selection. Thus, the purpose of this study was to investigate the multidimensional factors that differentiated between selected and non-selected adolescent male cricketers as well as between White British (WB) and BSA selected players into a CAG programme. A total of 82 male participants aged between 14 and 17 years were included (mean = 15.3 ± 1.1 years: selected n = 33 and non-selected n = 49: WB n = 34, BSA n = 44, Other n = 4). In total, 104 characteristics were measured over nine tests, which were subsequently placed into five overarching factors: (a) physiological and anthropometrical, (b) perceptual–cognitive expertise, (c) psychological, (d) participation history, and (e) socio-cultural influences. A Bayesian binomial regression was performed in rSTAN using a weak normal prior to highlight differentiators in selection as well as differences between WB and BSA selected players. The results highlighted that athleticism, wellbeing and cohesion, the number of older brothers, and being born in birth quarters two and three were positively correlated with player selection into a CAG. Conversely, increases in psychological scores, a greater number of younger brothers and older sisters, as well as antisocial behaviour resulted in a reduced chance of player selection. Finally, several developmental factors (i.e., athleticism, wellbeing and cohesion, psychological distress, and levels of anti-social behaviour) differed based on ethnicity. These exploratory findings serve as a useful opening to highlight there are important differences to consider based on selection and ethnicity in CAG cricket.

Excessive production of Transforming Growth Factor β (TGFβ) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFβ-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFβ is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFβ signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFβ from 79.2 g/L in the control to 60.0 ng/ml following losartan (p

Abstract Background A new commercially available sodium bicarbonate (SB) supplement claims to limit gastrointestinal (GI) discomfort and increase extracellular buffering capacity. To date, no available data exists to substantiate such claims. Therefore, the aim of this study was to measure blood acid–base balance and GI discomfort responses following the ingestion of SB using the novel “Bicarb System” (M-SB). Twelve well-trained male cyclists completed this randomised crossover designed study. Maximal oxygen consumption was determined in visit one, whilst during visits two and three participants ingested 0.3 g∙kg−1 BM SB using M-SB (Maurten, Sweden) or vegetarian capsules (C-SB) in a randomised order. Finger prick capillary blood samples were measured every 30 min for pH, bicarbonate (HCO3 −), and electrolytes (potassium, chloride, calcium, and sodium), for 300 min. Visual analogue scales (VAS) were used to assess GI symptoms using the same time intervals. Results Peak HCO3 − was 0.95 mmol∙L−1 greater following M-SB (p = 0.023, g = 0.61), with time to peak HCO3 − achieved 38.2 min earlier (117 ± 37 vs. 156 ± 36 min; p = 0.026, r = 0.67) and remained elevated for longer (p = 0.043, g = 0.51). No differences were observed for any electrolytes between the conditions. Aggregated GI discomfort was reduced by 79 AU following M-SB (p

Abstract Background Evolutionary models of breast cancer progression differ on the extent to which metastatic potential is pre-encoded within primary tumors. Although metastatic recurrences often harbor putative driver mutations that are not detected in their antecedent primary tumor using standard sequencing technologies, whether these mutations were acquired before or after dissemination remains unclear. Methods To ascertain whether putative metastatic driver mutations initially deemed specific to the metastasis by whole exome sequencing were, in actuality, present within rare ancestral subclones of the primary tumors from which they arose, we employed error-controlled ultra-deep sequencing (UDS-UMI) coupled with FFPE artifact mitigation by uracil-DNA glycosylase (UDG) to assess the presence of 132 “metastasis-specific” mutations within antecedent primary tumors from 21 patients. Maximum mutation detection sensitivity was ~1% of primary tumor cells. A conceptual framework was developed to estimate relative likelihoods of alternative models of mutation acquisition. Results The ancestral primary tumor subclone responsible for seeding the metastasis was identified in 29% of patients, implicating several putative drivers in metastatic seeding including LRP5 A65V and PEAK1 K140Q. Despite this, 93% of metastasis-specific mutations in putative metastatic driver genes remained undetected within primary tumors, as did 96% of metastasis-specific mutations in known breast cancer drivers, including ERRB2 V777L, ESR1 D538G, and AKT1 D323H. Strikingly, even in those cases in which the rare ancestral subclone was identified, 87% of metastasis-specific putative driver mutations remained undetected. Modeling indicated that the sequential acquisition of multiple metastasis-specific driver or passenger mutations within the same rare subclonal lineage of the primary tumor was highly improbable. Conclusions Our results strongly suggest that metastatic driver mutations are sequentially acquired and selected within the same clonal lineage both before, but more commonly after, dissemination from the primary tumor, and that these mutations are biologically consequential. Despite inherent limitations in sampling archival primary tumors, our findings indicate that tumor cells in most patients continue to undergo clinically relevant genomic evolution after their dissemination from the primary tumor. This provides further evidence that metastatic recurrence is a multi-step, mutation-driven process that extends beyond primary tumor dissemination and underscores the importance of longitudinal tumor assessment to help guide clinical decisions.

Abstract Global plate models (GPMs) aim to reconstruct the tectonic evolution of the Earth by modelling the motion of the plates and continents through time. These models enable palaeobiologists to study the past distribution of extinct organisms. However, different GPMs exist that vary in their partitioning of the Earth's surface and the modelling of continental motions. Consequently, the preferred use of one GPM will influence palaeogeographic reconstruction of fossil occurrences and any inferred palaeobiological and palaeoclimatic conclusion. Here, using five open‐access GPMs, we reconstruct the palaeogeographic distribution of cell centroids from a global hexagonal grid and quantify palaeogeographic uncertainty across the entire Phanerozoic (540–0 Ma). We measure uncertainty between reconstructed coordinates using two metrics: (1) palaeolatitudinal standard deviation and (2) mean pairwise geodesic distance. Subsequently, we evaluate the impact of GPM choice on palaeoclimatic reconstructions when using fossil occurrence data. To do so, we use two climatically sensitive entities (coral reefs and crocodylomorphs) to infer the palaeolatitudinal extent of subtropical climatic conditions for the last 240 million years. Our results indicate that differences between GPMs increase with the age of reconstruction. Specifically, cell centroids rotated to older intervals show larger differences in palaeolatitude and geographic spread than those rotated to younger intervals. However, high palaeogeographic uncertainty is also observed in younger intervals within tectonically complex regions (i.e. in the vicinity of terrane and plate boundaries). We also show that when using fossil data to infer the distribution of subtropical climatic conditions across the last 240 Ma, estimates vary by 6–7° latitude on average, and up to 24° latitude in extreme cases. Our findings confirm that GPM choice is an important consideration when studying past biogeographic patterns and palaeoclimatic trends. We recommend using GPMs that report true palaeolatitudes (i.e. use a palaeomagnetic reference frame) and incorporating palaeogeographic uncertainty into palaeobiological analyses.

Abstract Effective data visualisation is vital for data exploration, analysis and communication in research. In ecology and evolutionary biology, data are often associated with various taxonomic entities. Graphics of organisms associated with these taxa are valuable for framing results within a broader biological context. However, acquiring and using such resources can be challenging due to availability and licensing constraints. The PhyloPic database solves many of these issues by making organism silhouettes freely available. Tools that integrate this database with existing research workflows are needed to remove hurdles associated with data visualisation in the biological sciences. Here, we introduce rphylopic, an R package for fetching, transforming and visualising silhouettes of organisms from the PhyloPic database. In addition to making over 8000 organism silhouettes available within the R programming language, rphylopic empowers users to modify the appearance of these silhouettes for ultimate customisability when coding production–quality visualisations in both base R and ggplot2 workflows. In this work, we provide details about how the package can be installed, its implementation and potential use cases. For the latter, we showcase three examples across the ecology and evolutionary biology spectrum. Our hope is that rphylopic will make it easier for biologists to develop more accessible and engaging data visualisations by making external resources readily accessible, customisable and usable within R. In turn, by integrating into existing workflows, rphylopic helps to ensure that science is reproducible and accessible.

Abstract The open‐source programming language ‘R' has become a standard tool in the palaeobiologist's toolkit. Its popularity within the palaeobiological community continues to grow, with published articles increasingly citing the usage of R and R packages. However, there are currently a lack of agreed standards for data preparation and available frameworks to support the implementation of such standards. Consequently, data preparation workflows are often unclear and not reproducible, even when code is provided. Moreover, due to a lack of code accessibility and documentation, palaeobiologists are often forced to ‘reinvent the wheel’ to find solutions to issues already solved by other members of the community. Here, we introduce palaeoverse, a community‐driven R package to aid data preparation and exploration for quantitative palaeobiological research. The package is freely available and has three core principles: (1) streamline data preparation and analyses; (2) enhance code readability; and (3) improve reproducibility of results. To develop these aims, we assessed the analytical needs of the broader palaeobiological community using an online survey, in addition to incorporating our own experiences. In this work, we first report the findings of the survey, which shaped the development of the package. Subsequently, we describe and demonstrate the functionality available in palaeoverse and provide usage examples. Finally, we discuss the resources we have made available for the community and our future plans for the broader Palaeoverse project. palaeoverse is a community‐driven R package for palaeobiology, developed with the intention of bringing palaeobiologists together to establish agreed standards for high‐quality quantitative research. The package provides a user‐friendly platform for preparing data for analysis with well‐documented open‐source code to enhance transparency. The functionality available in palaeoverse improves code reproducibility and accessibility, which is beneficial for both the review process and future research.

The purpose of this research was two-fold: (a) to observe whether highly trained adolescent swimmers abide to vitamin D supplement recommendations; and (b) to monitor changes in circulating 25-hydroxyvitamin D (25(OH)D) that occur between the autumn and winter months. Twenty swimmers (age: 17 ± 2 years) from a UK high-performance swimming club volunteered to complete two blood spot cards to determine their 25(OH)D concentration: the first in an autumn training phase (October) and the second during winter training (January). All swimmers were advised to consume vitamin D3 supplements across the assessment period; however, only 50% of swimmers adhered to this recommendation. Resultantly, a winter decline in 25(OH)D was observed in non-supplementing swimmers (79.6 ± 25.2 to 52.6 ± 15.1 nmol·L−1, p = 0.005), with swimmers either displaying an ‘insufficient’ (60%) or ‘deficient’ (40%) vitamin D status. In comparison, a greater maintenance of 25(OH)D occurred in supplementing swimmers (92.0 ± 25.5 to 97.2 ± 38.3 nmol·L−1, p = 0.544), although variable outcomes occurred at the individual level (four increased, three maintained, three declined). These findings highlight the possible risks of vitamin D insufficiency during the winter for swimmers in the UK, possibly requiring standardised supplement practices. Moreover, alternative educational strategies may be required for swimmers to transfer knowledge to practice in order to improve supplement adherence in future.

Diverse causes and explanations have been proposed to help explain the absence, scarcity, and discontinuity of Mid-Holocene archaeological records in Central Argentina. Evidence for Mid-Holocene (∼6300–4100 14C yr BP/7.4–4.8 ka) hunter-gatherers occupations have been recognized in the eastern Pampa-Patagonia transition of Argentina. Here, we review and summarize the state-of-the-art archaeological knowledge that we have generated from Mid-Holocene archaeological sites from our study area. In doing so, we describe and discuss the geoarchaeological issues and the geomorphic evidence, radiocarbon and optically stimulated luminescence dating, lithics and raw materials provenience, zooarchaeology and taphonomy, subsistence and diet, bioarchaeology, and portable art. Our main objective is to address whether the already proposed Mid-Holocene sedimentary and chronologic discontinuities produced by geologic and taphonomic biases also respond to cultural discontinuities, e.g., abandonments, decreasing human density, and changes in mobility. Material culture and the structure of the archaeological record suggest that social and behavioral characteristics of hunter-gatherer societies are similar during the Mid-Holocene and the initial Late Holocene (∼6300–1000 14C yr BP/7.4–1.0 ka). Archaeological evidence from these periods indicates effective and stable human occupation with social interaction networks operating with neighboring regions such as the Pampa and Patagonia. Even though sedimentary and chronologic discontinuities exist, cultural continuity is likely. This review contributes to the understanding of Mid-Holocene discontinuities in Central Argentina.

Guidelines for the management of in-hospital cardiac arrest resuscitation are often drawn from evidence generated in out-of-hospital cardiac arrest populations and applied to the in-hospital setting. Approach to airway management during resuscitation is one example of this phenomenon, with the recommendation to place either a supraglottic airway or endotracheal tube when performing advanced airway management during in-hospital cardiac arrest based mainly in clinical trials conducted in the out-of-hospital setting. The Hospital Airway Resuscitation Trial (HART) is a pragmatic cluster-randomized superiority trial comparing a strategy of first choice supraglottic airway to a strategy of first choice endotracheal intubation during resuscitation from in-hospital cardiac arrest. The design includes a number of innovative elements such as a highly pragmatic design drawing from electronic health records and a novel primary outcome measure for cardiac arrest trials—alive-and-ventilator free days. Many of the topics explored in the design of HART have wide relevance to other trials in in-hospital cardiac arrest populations.

Recent experimental tests of Bell inequalities confirm that entangled quantum systems cannot be described by local classical theories but still do not answer the question whether or not quantum systems could, in principle, be modeled by linear hidden variable theories. In this paper, we study the quantum trajectories of a single qubit that experiences a sequence of repeated generalized measurements. It is shown that this system, which constitutes a hidden quantum Markov model, is more likely to produce complex time correlations than any classical hidden Markov model with two output symbols. From this, we conclude that quantum physics cannot be replaced by linear hidden variable theories. Indeed, it has already been recognized that not only entanglement but also non-classical time correlations of quantum systems with quantum feedback are a valuable resource for quantum technology applications.

Abstract Background In recent years, the length of elite sporting competitions has raised concerns regarding player well-being, highlighting a need to review current match calendars. Therefore, this study aimed to explore the perceptions of elite National Rugby League (NRL) players and staff on the annual training and competition calendar from a player workload and well-being perspective. Methods This study adopted a mixed-methods approach, using a sequential explanatory design. Phase one implemented a cross-sectional survey, and phase two utilised semi-structured interviews. Four hundred and thirty-nine elite rugby league players and 46 staff completed the survey. Eighteen elite professional NRL players and six football staff were interviewed, and verbal data were analysed into pre-defined topic summaries using qualitative coding reliability methods. Topics included in-season, off-season, pre-season and well-being. Results Data analysis suggests that elite NRL players and staff believe players appear particularly comfortable with the current number of games; however, they are at their maximum capacity. Importantly, this study identified several minority groups that may require support to enhance player well-being. Players believe reducing the pre-season would negate fatigue experienced later in the subsequent season. Players and staff believe this timeframe still provides sufficient time to prepare for the upcoming season. Further, players were open to extending the off-season to 8–10 weeks and believed that extra time would allow for greater recovery from the previous season. Mid-season congested scheduling affects players following the intensified period and requires attention to alleviate fatigue. Conclusion The results of this study convey important implications for the NRL, emphasising a need to review their annual training and competitive calendar, or to implement specific strategies to enhance the well-being of minority groups. The findings from this study should be considered when discussing the ideal length and structure of the match calendar to support players’ physical and mental welfare.

Abstract Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

Abstract Background Breast cancer mortality is principally due to recurrent disease that becomes resistant to therapy. We recently identified copy number (CN) gain of the putative membrane progesterone receptor PAQR8 as one of four focal CN alterations that preferentially occurred in recurrent metastatic tumors compared to primary tumors in breast cancer patients. Whether PAQR8 plays a functional role in cancer is unknown. Notably, PAQR8 CN gain in recurrent tumors was mutually exclusive with activating ESR1 mutations in patients treated with anti-estrogen therapies and occurred in > 50% of both patients treated with anti-estrogen therapies and those treated with chemotherapy or anti-Her2 agents. Methods We used orthotopic mouse models to determine whether PAQR8 overexpression or deletion alters breast cancer dormancy or recurrence following therapy. In vitro studies, including assays for colony formation, cell viability, and relative cell fitness, were employed to identify effects of PAQR8 in the context of therapy. Cell survival and proliferation were quantified by immunofluorescence staining for markers of apoptosis and proliferation. Sphingolipids were quantified by liquid chromatography-high resolution mass spectrometry. Results We show that PAQR8 is necessary and sufficient for efficient mammary tumor recurrence in mice, spontaneously upregulated and CN gained in recurrent tumors that arise following therapy in multiple mouse models, and associated with poor survival following recurrence as well as poor overall survival in breast cancer patients. PAQR8 promoted resistance to therapy by enhancing tumor cell survival following estrogen receptor pathway inhibition by fulvestrant or estrogen deprivation, Her2 pathway blockade by lapatinib or Her2 downregulation, and treatment with chemotherapeutic agents. Pro-survival effects of PAQR8 were mediated by a Gi protein-dependent reduction in cAMP levels, did not require progesterone, and involved a PAQR8-dependent decrease in ceramide levels and increase in sphingosine-1-phosphate levels, suggesting that PAQR8 may possess ceramidase activity. Conclusions Our data provide in vivo evidence that PAQR8 plays a functional role in cancer, implicate PAQR8, cAMP, and ceramide metabolism in breast cancer recurrence, and identify a novel mechanism that may commonly contribute to the acquisition of treatment resistance in breast cancer patients.

Whether there were more extensive glaciations during the Marine Isotope Stage (MIS) 3 relative to MIS 2 across the Tian Shan in Central Asia is intensely debated because of the uncertainty in chronological data and fully understanding the driving mechanisms. To help resolve the ongoing debate, we assess the climate sensitivity of the glaciers and reconstruct the extent of glaciation during MIS 2 and 3 across the Tian Shan, using a glacier-resolving (250 × 250 m) ice sheet model asynchronously coupled with a global climate model. Our results demonstrate that the equilibrium-line altitude (ELA) over the Tian Shan decreases by ∼180 m for every 1 °C cooling under a modern precipitation regime, but precipitation reduction greatly lowers the sensitivity of the glaciers to temperature decrease (e.g., the effect of 2 °C cooling is broadly offset by a 50% decrease in precipitation). Under the modeled colder/drier-than-present climate, the model predicts an ELA depression (∆ELA) of ∼75 m (162 m) over the Tian Shan during MIS 3 interstadials (stadials). The extent of MIS 3 glaciation is much smaller than that during MIS 2 (i.e., ∆ELA = ∼726 m). The more extensive glaciation during MIS 2 is largely attributed to the enhanced summer cooling. Furthermore, through a site-to-site model-data comparison, we find that the closest match between the modeled glacier margin and the locations of the glacial deposits previously argued to be MIS 3 is generally achieved under MIS 2 climatic conditions. These results suggest more extensive glacier advances over the Tian Shan during MIS 2 than MIS 3 on a regional scale, although MIS 3 glaciation may still occur in individual glacier catchments. This pattern suggests general synchronicity with the timing of maximum Northern Hemisphere ice sheets during the last glacial, which should be further tested in a multimodel framework in the future.

The process of cellular senescence is hypothesized to play a critical role in the development of age-related mobility and cognitive impairments, both of which precede the development of Alzheimer's disease. Therefore, senolytic compounds that eliminate senescent cells represent an alternative strategy that may help improve mobility and cognition in older adults; however, clinical trials are lacking. The goal of this paper is to describe the rationale and study design of a 12-week single arm, open label, pre-post pilot study that administers intermittent doses of two senolytic compounds, Dasatinib and quercetin (DQ), in 12 older adults ≥65 years with slow gait speed (

Treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC) patients remain limited, meaning that death within weeks of diagnosis unfortunately remains a common occurrence. Whilst metastases from other malignancy sites, such as colorectal and breast, are amenable to resection in selected patients, consensus remains largely against resection of mPDAC. Without surgical resection, chemotherapy remains the main treatment option and despite advances in regimens, a large proportion of mPDAC patients do not respond to these treatments. Understandably, investigation into whether different genetic subtypes of PDAC can explain the changes in response to chemotherapy have been carried out but as yet has not demonstrated any marked differences between those that do and do not respond to chemotherapy treatment.This review outlines the emerging role that both the gut and tumour microbiome play in modulating the progression of PDAC, ranging from chemosensitivity to immune infiltration of the tumour This puts the gut microbiome in a promising position as a potential future therapeutic route for mPDAC patients. Possible methods to modulate the gut and tumour microbiome include antibiotics, probiotics and faecal microbiota transplantation (FMT). The next steps should therefore be to focus upon how we can effectively and safely introduce these beneficial bacteria into the gut and tumour microbiome of mPDAC patients through clinical trials.

Objective This study examined the effects of oral and topical (PR Lotion; Momentous) sodium bicarbonate (NaHCO3) during a battery of team sport-specific exercise tests. Method In a block randomized, crossover, double-blind, placebo-controlled design, 14 recreationally trained male team sport athletes performed a familiarization visit and three experimental trials receiving: (i) 0.3 g·kg−1 body mass (BM) NaHCO3 in capsules + placebo lotion (SB-ORAL), (ii) placebo capsules +0.9036 g·kg−1 BM PR Lotion (SB-LOTION), or (iii) placebo capsules + placebo lotion (PLA). Supplements were given ~120 min prior to the team sport-specific exercise tests: countermovement jumps (CMJ), 8 × 25 m repeated sprints and Yo-Yo Intermittent Recovery Level 2 (Yo-Yo IR2). Blood acid–base balance (pH, bicarbonate) and electrolytes (sodium, potassium) were measured throughout. Rating of perceived exertion (RPE) was recorded after each sprint and post-Yo-Yo IR2. Results Distance covered during the Yo-Yo IR2 was 21% greater for SB-ORAL compared with PLA (+94 m; p = 0.009, d = 0.64) whereas performance was only 7% greater for SB-LOTION compared with PLA (480 ± 122 vs. 449 ± 110 m; p = 0.084). Total completion time for the 8 × 25 m repeated sprint test was 1.9% faster for SB-ORAL compared with PLA (−0.61 s; p = 0.020, d = 0.38) and 2.0% faster for SB-LOTION compared with PLA (−0.64 s; p = 0.036, d = 0.34). CMJ performance was similar between treatments (p > 0.05). Blood acid–base balance and electrolytes were significantly improved for SB-ORAL compared with PLA, but no differences were observed for SB-LOTION. Compared to PLA, RPE was lower for SB-LOTION after the fifth (p = 0.036), sixth (p = 0.012), and eighth (p = 0.040) sprints and for SB-ORAL after the sixth (p = 0.039) sprint. Conclusions Oral NaHCO3 improved 8 × 25 m repeated sprint (~2%) and Yo-Yo IR2 performance (21%). Similar improvements in repeated sprint times were observed for topical NaHCO3 (~2%), but no significant benefits were reported for Yo-Yo IR2 distance or blood acid–base balance compared to PLA. These findings suggest that PR Lotion might not be an effective delivery system for transporting NaHCO3 molecules across the skin and into systematic circulation, therefore further research is needed to elucidate the physiological mechanisms responsible for the ergogenic effects of PR Lotion.

Abstract Background In older adults, the extent to which performing a cognitive task when standing diminishes postural control is predictive of future falls and cognitive decline. The neurophysiology of such “dual-tasking” and its effect on postural control (i.e., dual-task cost) in older adults are poorly understood. The purpose of this study was to use electroencephalography (EEG) to examine the effects of dual-tasking when standing on brain activity in older adults. We hypothesized that compared to single-task “quiet” standing, dual-task standing would decrease alpha power, which has been linked to decreased motor inhibition, as well as increase the ratio of theta to beta power, which has been linked to increased attentional control. Methods Thirty older adults without overt disease completed four separate visits. Postural sway together with EEG (32-channels) were recorded during trials of standing with and without a concurrent verbalized serial subtraction dual-task. Postural control was measured by average sway area, velocity, and path length. EEG metrics included absolute alpha-, theta-, and beta-band powers as well as theta/beta power ratio, within six demarcated regions-of-interest: the left and right anterior, central, and posterior regions of the brain. Results Most EEG metrics demonstrated moderate-to-high between-day test–retest reliability (intra-class correlation coefficients > 0.70). Compared with quiet standing, dual-tasking decreased alpha-band power particularly in the central regions bilaterally (p = 0.002) and increased theta/beta power ratio in the anterior regions bilaterally (p

Given widespread use of spike antibody in generating coronavirus disease vaccines, SARS-CoV-2 nucleocapsid antibodies are increasingly used to indicate previous infection in serologic surveys. However, longitudinal kinetics and seroreversion are poorly defined. We found substantial seroreversion of nucleocapsid total immunoglobulin, underscoring the need to account for seroreversion in seroepidemiologic studies.

Abstract Tectonics imparts a first-order control on the overall morphology of alluvial fan systems in extensional settings by influencing sediment flux and accommodation space, while other factors such as climate, catchment lithology, and fault footwall characteristics are secondary. Previous alluvial fan modeling studies have focused on the link between the three-dimensional development of alluvial fans and rock uplift, however, despite the potential influence of tectonics on the overall three-dimensional morphology of alluvial fans, the controlling mechanisms, as well as their relative importance, remain largely unquantified in a natural setting with a targeted source-to-sink approach. Here, we examine 45 alluvial fans and their catchments along the southern mountain front of the Aydın Range, delimited by segmented normal faults in the western Anatolia Extensional Province, to quantify the role of rock uplift. We quantify river incision rates and catchment-wide erosion rates together with a series of topographic analyses across the southern flank of the Aydın Range as a proxy for rock uplift. Our results indicate that the spatial distribution of thicker and steeper alluvial fans fit well with higher rock uplift rates along the strike of the mountain front. In contrast, a lower uplift rate is responsible for prograding alluvial fans with decreasing thickness and gradients. Also, our data shows that alluvial fan thickness compared to other alluvial fan metrics strongly associated with the pattern of the rock uplift. This study demonstrates a field-based, quantitative linkage between three-dimensional alluvial fan morphology and rock uplift which has significant implications for improving alluvial fan models and understanding how alluvial fans respond to tectonics in extensional regions.

Background: The incidence of sunburn injuries continues to rise despite increased awareness of the risks of sun exposure and availability of sun protection. Whilst not a significant burden on burns care services, patients remain exposed to associated risks for future development of skin malignancies. The aims of this study were to determine the burden and severity of sunburn injury presentations to the Manchester adult and children’s burns services. Methods: A 10-year retrospective review was performed of patients with sunburn injuries, presenting to the Manchester burn services between 2010 and 2019 (inclusive). Data were collected from the International Burn Injury Database (iBID), electronic patient record (EPR) and local data collection systems. The data extracted included patient demographics, sunburn characteristics and management of the burn injury including need for admission and any documented surgical interventions. Temporal correlation was determined by linear regression analysis. Results: In total, 131 paediatric and 228 adult patients with sunburn injuries were managed by the Manchester burns services over the 10-year period. Mean % total body surface area burned was low (2.00% and 2.12% in adult and paediatric patients, respectively), with the majority of injuries either superficial or superficial partial thickness. Thirty percent (30.2%) of adult and 40.5% of paediatric patients were admitted with a mean length of stay of 3.51 and 1.11 days, respectively. The presentation of sunburn injuries progressively increased over the study period with a peak in 2017 (n = 58). Similar trends in patient demographics, burn size and depth and temporal trends were observed in national data from the same period for both adult and paediatric patients. Conclusion: This 10-year retrospective cohort study demonstrates an increasing trend of sunburn injury presentations to the Manchester specialist burns services; a pattern replicated in national data from England and Wales. The majority of sunburn injuries do not present to specialist burn services; therefore, these reported injuries reflect only a fraction of the true burden of sunburn nationwide. Despite increased awareness, an obvious need for enhanced public awareness campaigns regarding sun protection is therefore needed to address this trend. The educational and preventative role of burns care services is a key component in tackling both consequences of burn injuries themselves and associated risks such as future skin cancer development.

Articulating clear and achievable expectations is fundamental to both education and organizational management. In this article, we provide a simple intervention for clarifying expectations--and establishing that these expectations have been understood--which proved beneficial both to community college interns and to their internship mentors in biotech-related undergraduate research experiences. Internship mentors were asked to utilize a simple Expectation Clarity Tool to outline the expectations, success metrics, baseline assessments, and training strategy and support that would be foundational to their intern's project. These included expectations around conceptual, technical, performance, and professional skills and behaviors. Concurrently, but independently, community college interns were asked to complete the same type of exercise as a way of identifying gaps in their knowledge and understanding of their mentor's expectations and their internship project. The mentor's completed Expectation Clarity Tool was then shared with their intern. As a result of completing this relatively simple intervention, the majority of mentors reported that it increased their confidence as a mentor, taught them a new mentoring skill, changed how they will mentor trainees moving forward, and positively impacted their relationship with their trainee. On the intern side, the majority of interns reported that engaging in this intervention, both as an independent exercise and in obtaining their mentor's completed Expectation Clarity Tool, increased their confidence as an intern and positively impacted the success of their internship.

The nuclear data group at the RPI Gaerttner LINAC Laboratory uses a 60 MeV pulsed electron LINAC to produce short pulses of neutrons and perform cross section and other nuclear data measurements in a wide energy range from below 1 meV to about 20 MeV. This paper will cover several recent activities that are of interest to nuclear applications. Interest in thermal neutron scattering evaluations prompted the need for accurate thermal total cross section measurements for validation. To improve the neutron flux in the sub-thermal region (below 0.01 eV) a cold moderator was designed and installed. A polyethylene moderator operating at about 26 K resulted in a factor of 8 increase in neutron flux below 0.01 eV. Using this new capability, several transmission measurements were performed with samples of polyethylene, polystyrene, Plexiglas, and yttrium hydride. Neutron capture and transmission measurements in the keV energy range were made for 54Fe, which will be used in an evaluation effort that is underway. Capture measurements were collected on an array of C6D6 detectors that was expanded from 4 to 7 detectors, and a complementary transmission measurement was also performed. Finally, research aimed at experimental validation of neutron capture gamma production is in progress. Energy dependent capture gamma cascades are measured with the RPI 16-segment gamma multiplicity detector. Measurements are then compared to capture gamma cascades generated from nuclear structure evaluations processed with DICEBOX and transported with a modified version of MCNP. This system provides important information on the completeness of primary gamma-ray databases.

Warm-water coral reefs are limited to tropical and subtropical latitudes today but extended poleward in the geological past. This study shows that climatic and tectonic drivers explain the past distribution of coral reefs and associated biodiversity.

Abstract Background Parathyroid hormone-related protein (PTHrP) is required for embryonic breast development and has important functions during lactation, when it is produced by alveolar epithelial cells and secreted into the maternal circulation to mobilize skeletal calcium used for milk production. PTHrP is also produced by breast cancers, and GWAS studies suggest that it influences breast cancer risk. However, the exact functions of PTHrP in breast cancer biology remain unsettled. Methods We developed a tetracycline-regulated, MMTV (mouse mammary tumor virus)-driven model of PTHrP overexpression in mammary epithelial cells (Tet-PTHrP mice) and bred these mice with the MMTV-PyMT (polyoma middle tumor-antigen) breast cancer model to analyze the impact of PTHrP overexpression on normal mammary gland biology and in breast cancer progression. Results Overexpression of PTHrP in luminal epithelial cells caused alveolar hyperplasia and secretory differentiation of the mammary epithelium with milk production. This was accompanied by activation of Stat5 and increased expression of E74-like factor-5 (Elf5) as well as a delay in post-lactation involution. In MMTV-PyMT mice, overexpression of PTHrP (Tet-PTHrP;PyMT mice) shortened tumor latency and accelerated tumor growth, ultimately reducing overall survival. Tumors overproducing PTHrP also displayed increased expression of nuclear pSTAT5 and Elf5, increased expression of markers of secretory differentiation and milk constituents, and histologically resembled secretory carcinomas of the breast. Overexpression of PTHrP within cells isolated from tumors, but not PTHrP exogenously added to cell culture media, led to activation of STAT5 and milk protein gene expression. In addition, neither ablating the Type 1 PTH/PTHrP receptor (PTH1R) in epithelial cells nor treating Tet-PTHrP;PyMT mice with an anti-PTH1R antibody prevented secretory differentiation or altered tumor latency. These data suggest that PTHrP acts in a cell-autonomous, intracrine manner. Finally, expression of PTHrP in human breast cancers is associated with expression of genes involved in milk production and STAT5 signaling. Conclusions Our study suggests that PTHrP promotes pathways leading to secretory differentiation and proliferation in both normal mammary epithelial cells and in breast tumor cells.

The US Chukchi Sea consists of the waters off the northwest of Alaska and is a naturally dynamic ice-driven ecosystem. The impacts from climate change are affecting the Arctic marine ecosystem as well as the coastal communities that rely on healthy marine ecosystems. In anticipation of increased ecosystem monitoring in the area, there is an opportunity to evaluate improved sampling designs for future ecological monitoring of the Chukchi Sea, an area that is sampled less comprehensively compared to other regions in Alaska. This analysis focused on standardized NOAA-NMFS-AFSC bottom trawl surveys (otter and beam trawls) and three types of survey designs: simple random, stratified random, and systematic. First, spatiotemporal distributions for 18 representative demersal fish and invertebrate taxa were fitted using standardized catch and effort data. We then simulated spatiotemporal taxon densities to replicate the three survey design types to evaluate design-based estimates of abundance and precision across a range of sampling effort. Modest increases in precision were gained from stratifying the design when compared to a simple random design with either similar or lower uncertainty and bias of the precision estimates. There were often strong tradeoffs between the precision and bias of the systematic estimates of abundance (and associated variance) across species and gear type. The stratified random design provided the most consistent, reliable, and precise estimates of abundance indices and is likely to be the most robust to changes in the survey design. This analysis provides a template for changing bottom trawl survey designs in the Chukchi Sea and potentially other survey regions in Alaska going forward and will be important when integrating new survey objectives that are more ecosystem-focused.

Abstract Reduction of the carbon footprint of historic buildings is urgent, given their exceptionally large energy demand. In this study, the performance and cost of a roof mounted photovoltaic system has been simulated for Bath Abbey, a grade I listed building, to test the financial viability of installing such a system. The electrical output of the panels was generated by the software package PVsyst with inputs such as the known dimensions of the Abbey, historical weather data, the orientation of the Abbey's roof, module azimuthal and tilt angles and shading by the spire and roof features. An important result is that even though the roof is not shadowed by other buildings, shading causes a 19% loss of peak power. This model was used to determine a recommended configuration comprising 164 solar panels, separated into two subsystems located on two parts of the roof, each with an inverter. Its predicted electrical output, 45 ± 2 MWh generated in the first year of operation, formed the basis of a cost–benefit analysis. This system will become profitable after 13.3 ± 0.6 years and provide a profit of £139,000 ± £12,000 over its 25‐year lifetime. Financial stress tests were performed for key assumptions to ensure that this result was true in all likely scenarios. This result shows that it is likely to make financial sense to install a photovoltaic system on a historic grade I listed building.