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Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.

Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.

Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.

Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.

Barbara Grüning examines the representation of embodiment in fictional and autobiographical graphic narratives about anorexia to show how the so-called anorexic body is not just a surface bearing specific meanings but also a vector of knowledge. Most discourses on anorexia circulating in the transnational public sphere share a similar iconography, based on timeless images of skinny bodies. Graphic narrative representation of mental and physical disease has a long history that has changed over time, particularly with the emergence of the autobiographical genre in the 1970s. Grüning analyzes fictional and autobiographical graphic narratives published since 2000 in English, German, French and Italian from eight countries (England, United States, Canada, Germany, Austria, Switzerland, France and Italy). Fictional graphic narratives generally describe anorexia as limited in time, related to defined social causes, and concluded for the main characters as a specific phase of life. Conversely, autobiographical graphic narratives use innovative methods to create a sense of spatial and temporal disorientation toward the social world that mimics the experiences of the narrators. These life stories open an interpretative space to readers that presents the complexity of living with anorexia, stressing the impossibility of neatly confined narratives.

Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.

This paper presents a novel approach to modeling human driving behavior, designed for use in evaluating autonomous vehicle control systems in a simulation environments. Our methodology leverages a hierarchical forward-looking, risk-aware estimation framework with learned parameters to generate human-like driving trajectories, accommodating multiple driver levels determined by model parameters. This approach is grounded in multimodal trajectory prediction, using a deep neural network with LSTM-based social pooling to predict the trajectories of surrounding vehicles. These trajectories are used to compute forward-looking risk assessments along the ego vehicle's path, guiding its navigation. Our method aims to replicate human driving behaviors by learning parameters that emulate human decision-making during driving. We ensure that our model exhibits robust generalization capabilities by conducting simulations, employing real-world driving data to validate the accuracy of our approach in modeling human behavior. The results reveal that our model effectively captures human behavior, showcasing its versatility in modeling human drivers in diverse highway scenarios., Comment: 7 pages, 5 figures, accepted to the 2024 IEEE International Conference on Robotics and Automation (ICRA 2024)

3D cell culture models are important tools in translational research but have been out of reach for high-throughput screening due to complexity, requirement of large cell numbers and inadequate standardization. Microfluidics and culture model miniaturization technologies could overcome these challenges. Here, we present a high throughput workflow to produce and characterize the formation of miniaturized spheroids using deep learning. We train a convolutional neural network (CNN) for cell ensemble morphology classification for droplet microfluidic minispheroid production, benchmark it against more conventional image analysis, and characterize minispheroid assembly determining optimal surfactant concentrations and incubation times for minispheroid production for three cell lines with different spheroid formation properties. Notably, this format is compatible with large-scale spheroid production and screening. The presented workflow and CNN offer a template for large scale minispheroid production and analysis and can be extended and re-trained to characterize morphological responses in spheroids to additives, culture conditions and large drug libraries., QC 20240213

Severe drought conditions in 2018 prompted concerted efforts by Irish authorities to establish a formal planning process for drought risks as part of the wider national water management strategy. More than two decades had passed since Ireland had experienced a socioeconomically significant drought, but recently reconstructed long-term data have shown that drought is a much more frequent hazard here than previously thought. With climate change impacts likely to affect the temporal and spatial distribution of precipitation in coming decades, there is an ongoing need for further planning and preparation to reduce the vulnerability of the Irish water system to droughts. In this article we report results of a systematic comparison of Irish drought management plans and policies with those in southwestern Ontario, Canada, a region that shares many similar drought risk factors and management challenges but has longer established institutional practices for managing droughts. Key recommendations for Irish water managers emerging from this project include fostering a culture of water conservation among the Irish public; using catchments as the spatial unit for drought monitoring and management decisions; creation of standing drought management teams that involve and broaden key stakeholders and user groups; and further refining data collection to support planning for future challenges associated with climate change. Pursuing future opportunities for peer-to-peer learning between Irish water managers and their counterparts in other jurisdictions is a wider opportunity for developing best practices for drought management in the Irish context.

Severe drought conditions in 2018 prompted concerted efforts by Irish authorities to establish a formal planning process for drought risks as part of the wider national water management strategy. More than two decades had passed since Ireland had experienced a socioeconomically significant drought, but recently reconstructed long-term data have shown that drought is a much more frequent hazard here than previously thought. With climate change impacts likely to affect the temporal and spatial distribution of precipitation in coming decades, there is an ongoing need for further planning and preparation to reduce the vulnerability of the Irish water system to droughts. In this article we report results of a systematic comparison of Irish drought management plans and policies with those in southwestern Ontario, Canada, a region that shares many similar drought risk factors and management challenges but has longer established institutional practices for managing droughts. Key recommendations for Irish water managers emerging from this project include fostering a culture of water conservation among the Irish public; using catchments as the spatial unit for drought monitoring and management decisions; creation of standing drought management teams that involve and broaden key stakeholders and user groups; and further refining data collection to support planning for future challenges associated with climate change. Pursuing future opportunities for peer-to-peer learning between Irish water managers and their counterparts in other jurisdictions is a wider opportunity for developing best practices for drought management in the Irish context.

This briefing explores the motives, narratives, and membership realities of the three states that acceded to the European Communities (EC) in its first enlargement, in 1973: the United Kingdom, Ireland, and Denmark. It argues that, despite the different conditions and context at the time, it is possible to draw lessons from this first enlargement experience on how applicant states can create favourable conditions for their stable long-term integration into the present-day European Union. Governments, political parties and societal groups need to define their expectations of the economic benefits of EU membership realistically. This was the case in Ireland and Denmark, which rightly expected to benefit from the common agricultural policy and – in the case of Ireland – significant fiscal transfers. It was not the case for the UK, however, leading to a negative collective experience of the economic realities of membership during the economic slump following the 1973 oil crisis. Politically, moreover, the UK was ill prepared for cooperative patterns of politics and policy- making in the EC/EU. Large sections of the British elites and citizens saw the world in a binary divide between those ruling and those being ruled. EC membership could easily be portrayed as mediating the UK's transition from a position of ruling to one of being ruled by an allegedly new imperial centre, 'Brussels'. By contrast, EC membership gave the Irish an institutionalised European voice. Sharing formal sovereignty for them enhanced their actual independence from the UK. Denmark, finally, over time developed a pragmatic approach to sharing sovereignty. This briefing also highlights the importance of defending the aim of EU membership with realistic and convincing narratives. The creation of a broad domestic consensus on the desirability of membership, and preparation for its economic and political implications, are crucial for shaping a trajectory towards stable long-term integration into

Functional precision medicine (fPM) offers an exciting, simplified approach to finding the right applications for existing molecules and enhancing therapeutic potential. Integrative and robust tools ensuring high accuracy and reliability of the results are critical. In response to this need, we previously developed Breeze, a drug screening data analysis pipeline, designed to facilitate quality control, dose-response curve fitting, and data visualization in a user-friendly manner. Here, we describe the latest version of Breeze (release 2.0), which implements an array of advanced data exploration capabilities, providing users with comprehensive post-analysis and interactive visualization options that are essential for minimizing false positive/negative outcomes and ensuring accurate interpretation of drug sensitivity and resistance data. The Breeze 2.0 web-tool also enables integrative analysis and cross-comparison of user-uploaded data with publicly available drug response datasets. The updated version incorporates new drug quantification metrics, supports analysis of both multi-dose and single-dose drug screening data and introduces a redesigned, intuitive user interface. With these enhancements, Breeze 2.0 is anticipated to substantially broaden its potential applications in diverse domains of fPM.

The merger history of a galaxy is thought to be one of the major factors determining its internal dynamics, with galaxies having undergone different types or mergers (e.g. dry, minor or major mergers) predicted to show different dynamical properties. We study the instantaneous orbital distribution of galaxies in the Eagle simulation, colouring the orbits of the stellar particles by their stellar age, in order to understand whether stars form in particular orbits (e.g. in a thin or thick disc). We first show that Eagle reproduces well the observed stellar mass fractions in different stellar orbital families as a function of stellar mass and spin parameter at z = 0. We find that the youngest stars reside in a thin disc component that can extend to the very inner regions of galaxies, and that older stars have warmer orbits, with the oldest ones showing orbits consistent with both hot and counter-rotating classifications, which is consistent with the trend found in the Milky-Way and other disc galaxies. We also show that counter-rotating orbits trace galaxy mergers - in particular dry mergers, and that in the absence of mergers, counter-rotating orbits can also be born from highly misaligned gas accretion that leads to star formation., Comment: Submitted to MNRAS, 21 pages

We perform a structural decomposition of galaxies identified in three cosmological hydrodynamical simulations by applying Gaussian Mixture Models (GMMs) to the kinematics of their stellar particles. We study the resulting disc, bulge, and intra-halo light (IHL) components of galaxies whose host dark matter haloes have virial masses in the range $M_{200}=10^{11}$-- $10^{15}\,{\rm M_\odot}$. Our decomposition technique isolates galactic discs whose mass fractions, $f_{\rm disc}$, correlate strongly with common alternative morphology indicators; for example, $f_{\rm disc}$ is approximately equal to $\kappa_{{\rm co}}$, the fraction of stellar kinetic energy in co-rotation. The primary aim of our study, however, is to characterise the IHL of galaxies in a consistent manner and over a broad mass range, and to analyse its properties from the scale of galactic stellar haloes up to the intra-cluster light. Our results imply that the IHL fraction, $f_{\rm IHL}$, has appreciable scatter and is strongly correlated with galaxy morphology: at fixed stellar mass, the IHL of disc galaxies is typically older and less massive than that of spheroids. Above $M_{200}\approx 10^{13}\,{\rm M_\odot}$, we find, on average, $f_{\rm IHL}\approx 0.45$, albeit with considerable scatter. The transition radius beyond which the IHL dominates the stellar mass of a galaxy is roughly $30\,{\rm kpc}$ for $M_{200}\lesssim 10^{12.8}\,{\rm M_\odot}$, but increases strongly towards higher masses. However, we find that no alternative IHL definitions -- whether based on the ex-situ stellar mass, or the stellar mass outside a spherical aperture -- reproduce our dynamically-defined IHL masses., Comment: 16 pages, 11 figures. MNRAS published

We use two cosmological simulations to study the impact of spurious heating of stellar motions within simulated galaxies by dark matter (DM) particles. The simulations share the same numerical and subgrid parameters, but one used a factor of 7 more DM particles. Many galaxy properties are unaffected by spurious heating, including their masses, star formation histories, and the spatial distribution of their gaseous baryons. The distribution and kinematics of stellar and DM particles, however, are affected. Below a resolution-dependent virial mass, $M_{200}^{\rm spur}$, galaxies have higher characteristic velocities, larger sizes, and more angular momentum in the simulation with lower DM mass resolution; haloes have higher central densities and lower velocity dispersions. Above $M_{200}^{\rm spur}$, galaxies and haloes have similar properties in both runs. The differences arise due to spurious heating, which transfers energy from DM to stellar particles, causing galaxies to heat up and haloes to cool down. The value of $M_{200}^{\rm spur}$ can be derived from an empirical disc heating model, and coincides with the mass below which the predicted {\em spurious} velocity dispersion exceeds the {\em measured} velocity dispersion of simulated galaxies. We predict that galaxies in the $100^3\, {\rm Mpc}^3$ \eagle\, run and IllustrisTNG-100 are robust to spurious collisional effects at their half-mass radii provided $M_{200}^{\rm spur}\approx 10^{11.7}{\rm M_\odot}$; for the $25^3\, {\rm Mpc}^3$ \eagle\, run and IllustrisTNG-50, we predict $M_{200}^{\rm spur}\approx 10^{11}{\rm M_\odot}$. Suppressing spurious heating at smaller/larger radii, or for older/younger stellar populations, requires haloes to be resolved with more/fewer DM particles., Comment: 17 pages, 15 figures. MNRAS published. A basic python script for calculating spurious disc heating rates is available at https://github.com/AaronDLudlow/hot-disc.git

Functional precision medicine (fPM) offers an exciting, simplified approach to finding the right applications for existing molecules and enhancing therapeutic potential. Integrative and robust tools ensuring high accuracy and reliability of the results are critical. In response to this need, we previously developed Breeze, a drug screening data analysis pipeline, designed to facilitate quality control, dose-response curve fitting, and data visualization in a user-friendly manner. Here, we describe the latest version of Breeze (release 2.0), which implements an array of advanced data exploration capabilities, providing users with comprehensive post-analysis and interactive visualization options that are essential for minimizing false positive/negative outcomes and ensuring accurate interpretation of drug sensitivity and resistance data. The Breeze 2.0 web-tool also enables integrative analysis and cross-comparison of user-uploaded data with publicly available drug response datasets. The updated version incorporates new drug quantification metrics, supports analysis of both multi-dose and single-dose drug screening data and introduces a redesigned, intuitive user interface. With these enhancements, Breeze 2.0 is anticipated to substantially broaden its potential applications in diverse domains of fPM.

This briefing explores the motives, narratives, and membership realities of the three states that acceded to the European Communities (EC) in its first enlargement, in 1973: the United Kingdom, Ireland, and Denmark. It argues that, despite the different conditions and context at the time, it is possible to draw lessons from this first enlargement experience on how applicant states can create favourable conditions for their stable long-term integration into the present-day European Union. Governments, political parties and societal groups need to define their expectations of the economic benefits of EU membership realistically. This was the case in Ireland and Denmark, which rightly expected to benefit from the common agricultural policy and – in the case of Ireland – significant fiscal transfers. It was not the case for the UK, however, leading to a negative collective experience of the economic realities of membership during the economic slump following the 1973 oil crisis. Politically, moreover, the UK was ill prepared for cooperative patterns of politics and policy- making in the EC/EU. Large sections of the British elites and citizens saw the world in a binary divide between those ruling and those being ruled. EC membership could easily be portrayed as mediating the UK's transition from a position of ruling to one of being ruled by an allegedly new imperial centre, 'Brussels'. By contrast, EC membership gave the Irish an institutionalised European voice. Sharing formal sovereignty for them enhanced their actual independence from the UK. Denmark, finally, over time developed a pragmatic approach to sharing sovereignty. This briefing also highlights the importance of defending the aim of EU membership with realistic and convincing narratives. The creation of a broad domestic consensus on the desirability of membership, and preparation for its economic and political implications, are crucial for shaping a trajectory towards stable long-term integration into

This thesis examines selected musical compositions of Pete Seeger through the lens of his musical education and his life experiences and how those influenced his creative output.Drawing on his vast knowledge of the folk music tradition, Seeger crafted songs that gave voice to his own personal sociopolitical philosophy, which often found expression in political activism. The body of the thesis comprises three case studies, each of which provides an analysis of three paradigmatic songs that explore Seeger’s creative compositional processes and musical influences, his deeply held anti-war stance, and his efforts on behalf of the environment.

This thesis examines selected musical compositions of Pete Seeger through the lens of his musical education and his life experiences and how those influenced his creative output.Drawing on his vast knowledge of the folk music tradition, Seeger crafted songs that gave voice to his own personal sociopolitical philosophy, which often found expression in political activism. The body of the thesis comprises three case studies, each of which provides an analysis of three paradigmatic songs that explore Seeger’s creative compositional processes and musical influences, his deeply held anti-war stance, and his efforts on behalf of the environment.

We use a compilation of disc galaxy rotation curves to assess the role of the luminous component (‘baryons’) in the rotation curve diversity problem. As in earlier work, we find that rotation curve shape correlates with baryonic surface density: high surface density galaxies have rapidly rising rotation curves consistent with cuspy cold dark matter haloes; slowly rising rotation curves (characteristic of galaxies with inner mass deficits or ‘cores’) occur only in low surface density galaxies. The correlation, however, seems too weak to be the main driver of the diversity. In addition, dwarf galaxies exhibit a clear trend, from ‘cuspy’ systems where baryons are unimportant in the inner mass budget to ‘cored’ galaxies where baryons actually dominate. This trend constrains the various scenarios proposed to explain the diversity, such as (i) baryonic inflows and outflows during galaxy formation; (ii) dark matter self-interactions; (iii) variations in the baryonic mass structure coupled to rotation velocities through the ‘mass discrepancy–acceleration relation’ (MDAR); or (iv) non-circular motions in gaseous discs. Together with analytical modelling and cosmological hydrodynamical simulations, our analysis shows that each of these scenarios has promising features, but none seems to fully account for the observed diversity. The MDAR, in particular, is inconsistent with the observed trend between rotation curve shape and baryonic importance; either the trend is caused by systematic errors in the data or the MDAR does not apply. The origin of the dwarf galaxy rotation curve diversity and its relation to the structure of cold dark matter haloes remains an open issue.

We present a concept for a high-precision optical atomic clock (OAC) operating on an Earth-orbiting space station. This pathfinder science mission will compare the space-based OAC with one or more ultra-stable terrestrial OACs to search for space-time-dependent signatures of dark scalar fields that manifest as anomalies in the relative frequencies of station-based and ground-based clocks. This opens the possibility of probing models of new physics that are inaccessible to purely ground-based OAC experiments such as models where a dark scalar field is strongly screened near Earth's surface.

IntroductionDespite extensive evidence of its benefits and recommendation by guidelines, cardiac rehabilitation (CR) remains highly underused with only 20%–50% of eligible patients participating. We aim to implement and evaluate the Country Heart Attack Prevention (CHAP) model of care to improve CR attendance and completion for rural and remote participants.Methods and analysisCHAP will apply the model for large-scale knowledge translation to develop and implement a model of care to CR in rural Australia. Partnering with patients, clinicians and health service managers, we will codevelop new approaches and refine/expand existing ones to address known barriers to CR attendance. CHAP will codesign a web-based CR programme with patients expanding their choices to CR attendance. To increase referral rates, CHAP will promote endorsement of CR among clinicians and develop an electronic system that automatises referrals of in-hospital eligible patients to CR. A business model that includes reimbursement of CR delivered in primary care by Medicare will enable sustainable access to CR. To promote CR quality improvement, professional development interventions and an accreditation programme of CR services and programmes will be developed. To evaluate 12-month CR attendance/completion (primary outcome), clinical and cost-effectiveness (secondary outcomes) between patients exposed (n=1223) and not exposed (n=3669) to CHAP, we will apply a multidesign approach that encompasses a prospective cohort study, a pre-post study and a comprehensive economic evaluation.Ethics and disseminationThis study was approved by the Southern Adelaide Clinical Human Research Ethics Committee (HREC/20/SAC/78) and by the Department for Health and Wellbeing Human Research Ethics Committee (2021/HRE00270), which approved a waiver o

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Subtypes within B-ALL are distinguished by characteristic structural variants and mutations, which in some instances strongly correlate with responses to treatment. The World Health Organisation (WHO) recognises seven distinct classifications, or subtypes, as of 2016. However, recent studies have demonstrated that B-ALL can be segmented into 23 subtypes based on a combination of genomic features and gene expression profiles. A method to identify a patient's subtype would have clear utility. Despite this, no publically available classification methods using RNA-Seq exist for this purpose. Here we present ALLSorts: a publicly available method that uses RNA-Seq data to classify B-ALL samples to 18 known subtypes and five meta-subtypes. ALLSorts is the result of a hierarchical supervised machine learning algorithm applied to a training set of 1223 B-ALL samples aggregated from multiple cohorts. Validation revealed that ALLSorts can accurately attribute samples to subtypes and can attribute multiple subtypes to a sample. Furthermore, when applied to both paediatric and adult cohorts, ALLSorts was able to classify previously undefined samples into subtypes. ALLSorts is available and documented on GitHub (https://github.com/Oshlack/AllSorts/).

Near-infrared (800-2500 nm; NIR) spectroscopy coupled to hyperspectral imaging (NIR-HSI) has greatly enhanced its capability and thus widened its application and use across various industries. This non-destructive technique that is sensitive to both physical and chemical attributes of virtually any material can be used for both qualitative and quantitative analyses. This review describes the advancement of NIR to NIR-HSI in agricultural applications with a focus on seed quality features for agronomically important seeds. NIR-HSI seed phenotyping, describing sample sizes used for building high-accuracy calibration and prediction models for full or selected wavelengths of the NIR region, is explored. The molecular interpretation of absorbance bands in the NIR region is difficult; hence, this review offers important NIR absorbance band assignments that have been reported in literature. Opportunities for NIR-HSI seed phenotyping in forage grass seed are described and a step-by-step data-acquisition and analysis pipeline for the determination of seed quality in perennial ryegrass seeds is also presented.

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (al

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (al

Here, we present a methodology based on multiplexed fluorescence screening of two-or three-dimensional cell cultures in a newly designed multichambered microwell chip, allowing direct assessment of drug or im-mune cell cytotoxic efficacy. We establish a framework for cell culture, formation of tumor spheroids, fluores-cence labeling, and imaging of fixed or live cells at various magnifications directly in the chip together with data analysis and interpretation. The methodology is demonstrated by drug cytotoxicity screening using ovarian and non-small cell lung cancer cells and by cellular cytotoxicity screening targeting tumor spheroids of renal carcinoma and ovarian carcinoma with natural killer cells from healthy donors. The miniaturized format allowing long-term cell culture, efficient screening, and high-quality imaging of small sample volumes makes this methodology promising for individualized cytotoxicity tests for precision medicine., QC 20230215

Droplet microfluidics utilize a monodisperse water-in-oil emulsion, with an expanding toolbox offering a wide variety of operations on a range of droplet sizes at high throughput. However, translation of these capabilities into applications for non-expert laboratories to fully harness the inherent potential of microscale manipulations is woefully trailing behind. One major obstacle is that droplet microfluidic setups often rely on custom fabricated devices, costly liquid actuators, and are not easily set up and operated by non-specialists. This impedes wider adoption of droplet technologies in, e.g., the life sciences. Here, we demonstrate an easy-to-use minimal droplet production setup with a small footprint, built exclusively from inexpensive commercially sourced parts, powered and controlled by a laptop. We characterize the components of the system and demonstrate production of droplets ranging in volume from 3 to 21 nL in a single microfluidic device. Furthermore, we describe the dynamic tuning of droplet composition. Finally, we demonstrate the production of droplet-templated cell spheroids from primary cells, where the mobility and simplicity of the setup enables its use within a biosafety cabinet. Taken together, we believe this minimal droplet setup is ideal to drive broad adoption of droplet microfluidics technology., QC 20221129

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (al

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (al

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or surgical removal, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms. To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (>250,000 cells) of pLGGs. Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we optimized our integration and batch correction analyses by using external 293T cells as spike in controls during our single-cell and single-nuclei data generation steps to determine the most suitable method for batch-effect removal. Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors.

Mental health literacy is an important determinant of mental health help-seeking and is associated with improved mental health. There is evidence that mental health literacy may be lower amongst some migrant communities in Australia. The present study conducted the first cross-sectional survey of mental health literacy in Sri Lankan Australians between April and October 2020. Participants (N = 404) were presented with a culturally-tailored vignette describing an individual with symptoms of major depressive disorder, with correct recognition determined by the coding of an open text response to the question 'what's wrong with Mr Silva?'. Binomial linear regression modelling was conducted to identify predictors of the correct recognition of depression. Approximately 74% of participants recognised the presented symptoms as depression, though multiple other labels were also used by the respondents. The results also suggested that younger age and having a prior diagnosis of depression were significant predictors of recognising depression in the vignette. In the first study of Sri Lankan migrants' mental health literacy in an Australian context, the rates of depression recognition were comparable to those found in the general Australian population. Further research is urgently required to replicate and extend the present findings and ultimately support the development of tailored interventions aimed at improving mental health literacy across the diverse Sri Lankan Australian community.

Urban and environmental study of Paseo Bravo in the city of Puebla, from 1818 to 1974. The work consists of two parts, the first on the urban conformation of the city of Puebla and its 13 urban green areas including Paseo Bravo. The second on the urban and environmental history of Paseo Bravo consists of a comparative analysis of the composition and biological and ecological plant characterization, origin, uses, number, and percentages of the walk between 1836 and 1839 from three plant strata: arboreal, shrub and herbaceous being the arboreal the dominant one., El artículo es un estudio urbano y ambiental del paseo Bravo en la ciudad de Puebla, de 1818 a 1974. Consta de dos partes, la primera sobre la conformación urbana de la ciudad de Puebla y sus 13 áreas verdes urbanas, incluyendo al Paseo Bravo. La segunda, sobre la historia urbana y ambiental del Paseo Bravo, consta de un análisis comparativo de la composición y caracterización vegetal biológica y ecológica; la procedencia, usos, número y porcentajes de las plantas del paseo entre 1836 y 1839, organizados a partir de tres estratos vegetales: arbóreo, arbustivo y herbáceo, siendo el arbóreo el dominante.

Urban and environmental study of Paseo Bravo in the city of Puebla, from 1818 to 1974. The work consists of two parts, the first on the urban conformation of the city of Puebla and its 13 urban green areas including Paseo Bravo. The second on the urban and environmental history of Paseo Bravo consists of a comparative analysis of the composition and biological and ecological plant characterization, origin, uses, number, and percentages of the walk between 1836 and 1839 from three plant strata: arboreal, shrub and herbaceous being the arboreal the dominant one., El artículo es un estudio urbano y ambiental del paseo Bravo en la ciudad de Puebla, de 1818 a 1974. Consta de dos partes, la primera sobre la conformación urbana de la ciudad de Puebla y sus 13 áreas verdes urbanas, incluyendo al Paseo Bravo. La segunda, sobre la historia urbana y ambiental del Paseo Bravo, consta de un análisis comparativo de la composición y caracterización vegetal biológica y ecológica; la procedencia, usos, número y porcentajes de las plantas del paseo entre 1836 y 1839, organizados a partir de tres estratos vegetales: arbóreo, arbustivo y herbáceo, siendo el arbóreo el dominante.

We present a concept for a high-precision optical atomic clock (OAC) operating on an Earth-orbiting space station. This pathfinder science mission will compare the space-based OAC with one or more ultra-stable terrestrial OACs to search for space-time-dependent signatures of dark scalar fields that manifest as anomalies in the relative frequencies of station-based and ground-based clocks. This opens the possibility of probing models of new physics that are inaccessible to purely ground-based OAC experiments where a dark scalar field may potentially be strongly screened near Earth's surface. This unique enhancement of sensitivity to potential dark matter candidates harnesses the potential of space-based OACs., NIST, World Premier International Research Center Initiative, National Science Foundationhttps://doi.org/10.13039/100000001, Japan Society for the Promotion of Sciencehttps://doi.org/10.13039/501100001691, National Aeronautics and Space Administrationhttps://doi.org/10.13039/100000104, DOE Quantum System Accelerator, Jet Propulsion Laboratoryhttps://doi.org/10.13039/100006196, Deutsche Forschungsgemeinschafthttps://doi.org/10.13039/501100001659, Australian Research Councilhttps://doi.org/10.13039/501100000923, Federal Ministry of Economic Affairs and Climate Action (BMWK), German Federal Ministry of Education and Research, NIST Precision Measurement Grants program, NASA BPS Fundamental Physics Program, Office of Naval Research Globalhttps://doi.org/10.13039/100007297, Packard Fellowship for Science and Engineering, Army Research Officehttps://doi.org/10.13039/100000183, Peer Reviewed

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years' War (1618-1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (al

Avian metapneumovirus (AMPV) represents a long-term threat to the poultry industry due to its etiological role in the induction of acute respiratory disease and/or egg drop syndrome in domestic turkeys, chickens, and ducks. Although this disease is commonly referred to as turkey rhinotracheitis, the host range of AMPV encompasses many avian species. We have screened 1323 oropharyngeal- and cloacal swab samples obtained from wild mallards in the Netherlands from 2017 to 2019 by RT-PCR using a degenerate primer pair to detect all members of the Paramyxoviridae and Pneumoviridae or an avian metapneumovirus subtype C (AMPV-C)-specific RT-qPCR assay. We identified a total of seven cases of AMPV-C infections in wild, healthy mallards (Anas platyrhynchos), of which two AMPV-C positive samples were further processed using next-generation sequencing. Phylogenetic analysis of the two complete genomes showed that the newly identified AMPV-C strains share closest sequence identity (97%) with Eurasian lineage AMPV-C strains identified in Muscovy ducks in China that presented with severe respiratory disease and egg production loss in 2011. Further analysis of G protein amino acid sequences showed a high degree of variability between the newly identified AMPV-C variants. PONDR scoring of the G protein has revealed the ectodomain of AMPV-C to be partitioned into a long intrinsically disordered and short ordered region, giving insights into AMPV G protein structural biology. In summary, we provide the first report of full-length AMPV-C genome sequences derived from wild birds in Europe. This emphasizes the need for further surveillance efforts to better characterize the host range, epidemiologic distribution, and pathogenicity of AMPV-C to determine the risk posed by cross-species jumps from wildfowl to domesticated avian species.

Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europe c. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.

All modern galaxy formation models employ stochastic elements in their sub-grid prescriptions to discretise continuous equations across the time domain. In this paper, we investigate how the stochastic nature of these models, notably star formation, black hole accretion, and their associated feedback, that act on small ($<$ kpc) scales, can back-react on macroscopic galaxy properties (e.g. stellar mass and size) across long ($>$ Gyr) timescales. We find that the scatter in scaling relations predicted by the EAGLE model implemented in the SWIFT code can be significantly impacted by random variability between re-simulations of the same object, even when galaxies are resolved by tens of thousands of particles. We then illustrate how re-simulations of the same object can be used to better understand the underlying model, by showing how correlations between galaxy stellar mass and black hole mass disappear at the highest black hole masses ($M_{\rm BH} > 10^8$ M$_\odot$), indicating that the feedback cycle may be interrupted by external processes. We find that although properties that are collected cumulatively over many objects are relatively robust against random variability (e.g. the median of a scaling relation), the properties of individual galaxies (such as galaxy stellar mass) can vary by up to 25\%, even far into the well-resolved regime, driven by bursty physics (black hole feedback) and mergers between galaxies. We suggest that studies of individual objects within cosmological simulations be treated with caution, and that any studies aiming to closely investigate such objects must account for random variability within their results., Comment: Accepted for publication in MNRAS

We use the EAGLE cosmological simulations to study the evolution of the vertical velocity dispersion of cold gas, $\sigma_{z}$, in central disc galaxies and its connection to stellar feedback, gravitational instabilities, cosmological gas accretion and galaxy mergers. To isolate the impact of feedback, we analyse runs that turn off stellar and (or) AGN feedback in addition to a run that includes both. The evolution of $\sigma_z$ and its dependence on stellar mass and star formation rate in EAGLE are in good agreement with observations. Galaxies hosted by haloes of similar virial mass, $\rm M_{200}$, have similar $\sigma_z$ values even in runs where feedback is absent. The prevalence of local instabilities in discs is uncorrelated with $\sigma_z$ at low redshift and becomes only weakly correlated at high redshifts and in galaxies hosted by massive haloes. $\sigma_z$ correlates most strongly with the specific gas accretion rate onto the disc as well as with the degree of misalignment between the inflowing gas and the disc's rotation axis. These correlations are significant across all redshifts and halo masses, with misaligned accretion being the primary driver of high gas turbulence at redshifts $z \lesssim 1$ and for halo masses $\rm M_{200} \lesssim 10^{11.5} M_{\odot}$. Galaxy mergers increase $\sigma_z$, but because they are rare in our sample, they play only a minor role in its evolution. Our results suggest that the turbulence of cold gas in EAGLE discs results from a complex interplay of different physical processes whose relative importance depends on halo mass and redshift., Comment: 22 pages, 12 figures. Accepted for publication in MNRAS