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Changes in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA, and we have used a combined experimental, bioinformatic, and systems biology approach to explore the multiple miRNA–mRNA interactions that regulate chondrogenesis. A longitudinal chondrogenesis bioinformatic analysis identified paralogues miR-199a-5p and miR-199b-5p as pro-chondrogenic regulators. Experimental work in human cells demonstrated alteration of miR-199a-5p or miR-199b-5p expression led to significant inverse modulation of key chondrogenic genes and extracellular matrix production. miR-199a/b-5p targets FZD6, ITGA3 and CAV1 were identified by inhibition experiments and verified as direct targets by luciferase assay. The experimental work was used to generate and parameterise a multi-miRNA 14-day chondrogenesis kinetic model to be used as a repository for the experimental work and as a resource for further investigation of this system. This is the first multi-miRNA model of a chondrogenesis-based system, and highlights the complex relationships between regulatory miRNAs, and their target mRNAs. more...

Abstract CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2–74.2%) and 46.5% (95%CI 37.6–57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1–44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3–75.8) and 55.3% (95%CI 43.6–70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival. more...

Climate change-related challenges faced by forest managers are ecological, economic, and social in nature. While several past assessments have looked at the climate-related perceptions and needs of foresters working in rural contexts, urban foresters are not often included in these assessments. Examining foresters’ risk perceptions, adaptation interests and intentions, and need for information/support in rural and urban contexts side-by-side reveals unique opportunities for learning across the rural-to-urban gradient. Through two surveys targeting both rural and urban foresters, we have identified key learning opportunities that support climate-adaptive forest management.Our analysis shows that many foresters are seeking to maintain current forest conditions or restore forest conditions following a disruption or change, though some see value in transitioning forests to be more resistant and resilient to future climates. We also show a difference in confidence between urban and rural foresters when it comes to addressing climate change through specific adaptation strategies. Based on our findings, we propose facilitated learning opportunities across the rural-to-urban gradient. This would allow urban foresters to learn from rural foresters on topics such as establishment and maintenance of long-term, large, ecologically complex forested areas within cities. Rural foresters could gain insights from their urban counterparts on planting strategies and other approaches that are common in urban settings but novel in rural settings, including stock sourcing and species selection.To better enable foresters to implement climate adaptation strategies, we suggest: (1) facilitating learning across the rural-to-urban gradient, (2) public engagement trainings and opportunities targeting foresters, (3) workforce development programing, and (4) programs that limit the financial risk that foresters, landowners, and municipalities face when applying forest adaptation strategies to rural or urban lands. more...

AT 2019azh is a H+He tidal disruption event (TDE) with one of the most extensive ultraviolet and optical data sets available to date. We present our photometric and spectroscopic observations of this event starting several weeks before and out to approximately 2 yr after the g -band's peak brightness and combine them with public photometric data. This extensive data set robustly reveals a change in the light-curve slope and a possible bump in the rising light curve of a TDE for the first time, which may indicate more than one dominant emission mechanism contributing to the pre-peak light curve. Indeed, we find that the MOSFiT -derived parameters of AT 2019azh, which assume reprocessed accretion as the sole source of emission, are not entirely self-consistent. We further confirm the relation seen in previous TDEs whereby the redder emission peaks later than the bluer emission. The post-peak bolometric light curve of AT 2019azh is better described by an exponential decline than by the canonical t ^−5/3 (and in fact any) power-law decline. We find a possible mid-infrared excess around the peak optical luminosity, but cannot determine its origin. In addition, we provide the earliest measurements of the H α emission-line evolution and find no significant time delay between the peak of the V -band light curve and that of the H α luminosity. These results can be used to constrain future models of TDE line formation and emission mechanisms in general. More pre-peak 1–2 days cadence observations of TDEs are required to determine whether the characteristics observed here are common among TDEs. More importantly, detailed emission models are needed to fully exploit such observations for understanding the emission physics of TDEs. more...

Abstract The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. However, it is unknown whether glucose metabolism regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant accumulation of glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites including nucleotides upon injury. Inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level, suggesting that the glucose enhances the cardiomyocyte regeneration through the supply of nucleotides. Our data suggest that the increase in glucose metabolism promotes cardiac regeneration in neonatal mouse heart. more...

Experimental procedures have been developed to provide at the laboratory scale an efficient and relatively inexpensive continuous flow processing system to undertake metathesis chemistry. Glass discs, coated with porous silica particles impregnated with Grubbs (I) generation or Hoveyda–Grubbs (II) generation catalysts through non-covalent interactions, have been successfully used as annular zones for in situ metathesis reactions. The supported catalysts were active for ring closing metathesis and self-metathesis reactions with a variety of substrates with nearly quantitative conversion depending on the substrate structure. Advantages of these procedures include the ability to conduct reactions efficiently at small (low mmole) scale under ambient laboratory conditions, thereby avoiding the need for high energy/thermal procedures. Multiple experiments can be undertaken during the same day if catalyst screening is required. Moreover, separation of starting materials from products can be achieved using the same unit operations, avoiding the need for additional purification steps, thereby reducing the total solvent consumption. more...

The impact of humans on megafaunal extinction is Australia is unclear. Here, the authors show burn patterns on eggshells of the extinct megafaunal bird, Genyornis newtoni, created by humans across Australia, suggesting that human predation contributed to the extinction of this bird around 47 thousand years ago. more...

We propose a question answering (QA) approach for standardized science exams that both identifies correct answers and produces compelling human-readable justifications for why those answers are correct. Our method first identifies the actual information needed in a question using psycholinguistic concreteness norms, then uses this information need to construct answer justifications by aggregating multiple sentences from different knowledge bases using syntactic and lexical information. We then jointly rank answers and their justifications using a reranking perceptron that treats justification quality as a latent variable. We evaluate our method on 1,000 multiple-choice questions from elementary school science exams, and empirically demonstrate that it performs better than several strong baselines, including neural network approaches. Our best configuration answers 44% of the questions correctly, where the top justifications for 57% of these correct answers contain a compelling human-readable justification that explains the inference required to arrive at the correct answer. We include a detailed characterization of the justification quality for both our method and a strong baseline, and show that information aggregation is key to addressing the information need in complex questions. more...

Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the Homology-Directed Repair (HDR) pathway, which is the hallmark of ‘BRCAness’. The mechanisms by which BRCAness arises are not fully understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype. Here, we examine the post-transcriptional effects that some members of the six-miRNA cluster known as the miR-17/92 cluster have on the abundance of BRCA2’s messenger RNA (mRNA) and protein. We discuss two interactions involving the miR-19a and miR-19b members of the cluster and the 3´UTR of BRCA2’s mRNA. We investigated these miRNA:mRNA interactions in fifteen cell lines derived from pancreatic, breast, colon, and kidney tissue. We show that over-expression of these two miRNAs results in a concomitant decrease of BRCA2’s mRNA and protein expression in a subset of the tested cell lines. Additionally, using luciferase reporter assays we identified direct interactions between miR-19a/miR-19b and a miRNA response element (MRE) in BRCA2’s 3´UTR. Our results suggest that BRCA2 is subject to a complex post-transcriptional regulatory program that has specific dependencies on the genetic and phenotypic background of cell types. more...

The FRANC project (Forecasting Rainfall exploiting new data Assimilation techniques and Novel observations of Convection) has researched improvements in numerical weather prediction of convective rainfall via the reduction of initial condition uncertainty. This article provides an overview of the project’s achievements. We highlight new radar techniques: correcting for attenuation of the radar return; correction for beams that are over 90% blocked by trees or towers close to the radar; and direct assimilation of radar reflectivity and refractivity. We discuss the treatment of uncertainty in data assimilation: new methods for estimation of observation uncertainties with novel applications to Doppler radar winds, Atmospheric Motion Vectors, and satellite radiances; a new algorithm for implementation of spatially-correlated observation error statistics in operational data assimilation; and innovative treatment of moist processes in the background error covariance model. We present results indicating a link between the spatial predictability of convection and convective regimes, with potential to allow improved forecast interpretation. The research was carried out as a partnership between University researchers and the Met Office (UK). We discuss the benefits of this approach and the impact of our research, which has helped to improve operational forecasts for convective rainfall events. more...

Las empresas suelen anunciar públicamente su longevidad. Para ellas, el pasado tiene un significado claro. Sin embargo, las teorías de la organización que consideran la pervivencia y el papel representado por los fundadores, sobre todo las de tipo ecológico y cultural, no explican los significados colectivos que van unidos al pasado. Tampoco lo hace la literatura sobre la memoria de las organizaciones, que la concibe como una serie de compartimentos estancos. La Historia empresarial se preocupa más por la reconstrucción del pasado desde el momento presente que por los significados implícitos en el pasado. Con el fin de comprender las prácticas sociales (mnemónicas) por las que el pasado es recordado y por las que cobra sentido, nosotros recurrimos al cada vez más importante campo de la memoria social. Para examinar el modo en el que las interpretaciones oficiales están presentes en el pasado de las organizaciones, nos servimos de documentos públicamente disponibles, como memorias de las compañías, informes de prensa, artículos o historias hechas por encargo. Partiendo de los puntos de vista de la memoria social, nos centramos en analizar los centenarios y la creación de lugares de memoria, así como en el tradicional debate sobre la condición histórica de memorias que vertebran la identidad. En el texto, proporcionamos breves ejemplos sobre la celebración del centenario de la Ford, la denominación del centro de formación de directivos de la General Electric como John F. Welch Learning Center, así como de la desacreditadora leyenda de la Bertelsmann, concerniente a su comportamiento durante el dominio nazi en Alemania. Concluimos que el punto de vista de la memoria social puede constituir una base idónea para investigar el significado del pasado en las organizaciones. more...

BackgroundFactor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications.Methods and findingsA comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06-2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89-1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80-1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79-1.99) or SGA (OR 1.25, 95% CI 0.92-1.70).ConclusionsWomen with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. Please see later in the article for the Editors' Summary. more...

The majority of chemotherapy drugs are dosed based on body surface area (BSA). No standard BSA values for patients being treated in the United Kingdom are available on which to base dose and cost calculations. We therefore retrospectively assessed the BSA of patients receiving chemotherapy treatment at three oncology centres in the UK between 1(st) January 2005 and 31(st) December 2005.A total of 3613 patients receiving chemotherapy for head and neck, ovarian, lung, upper GI/pancreas, breast or colorectal cancers were included. The overall mean BSA was 1.79 m(2) (95% CI 1.78-1.80) with a mean BSA for men of 1.91 m(2) (1.90-1.92) and 1.71 m(2) (1.70-1.72) for women. Results were consistent across the three centres. No significant differences were noted between treatment in the adjuvant or palliative setting in patients with breast or colorectal cancer. However, statistically significant, albeit small, differences were detected between some tumour groups.In view of the consistency of results between three geographically distinct UK cancer centres, we believe the results of this study may be generalised and used in future costings and budgeting for new chemotherapy agents in the UK. more...

J. F. Merritt (ed.), Imagining Early Modern London: Perceptions and Portrayals of the City from Stow to Strype, 1598–1720. Cambridge: Cambridge University Press, 2000. xii + 304 pp.