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PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Here we provide the 'Global Spectrum of Plant Form and Function Dataset', containing species mean values for six vascular plant traits. Together, these traits -plant height, stem specific density, leaf area, leaf mass per area, leaf nitrogen content per dry mass, and diaspore (seed or spore) mass - define the primary axes of variation in plant form and function. The dataset is based on ca. 1 million trait records received via the TRY database (representing ca. 2,500 original publications) and additional unpublished data. It provides 92,159 species mean values for the six traits, covering 46,047 species. The data are complemented by higher-level taxonomic classification and six categorical traits (woodiness, growth form, succulence, adaptation to terrestrial or aquatic habitats, nutrition type and leaf type). Data quality management is based on a probabilistic approach combined with comprehensive validation against expert knowledge and external information. Intense data acquisition and thorough quality control produced the largest and, to our knowledge, most accurate compilation of empirically observed vascular plant species mean traits to date.

Abstract Earthworms are known to stimulate soil greenhouse gas (GHG) emissions, but the majority of previous studies have used simplified model systems or lacked continuous high-frequency measurements. To address this, we conducted a 2-year study using large lysimeters (5 m2 area and 1.5 m soil depth) in an ecotron facility, continuously measuring ecosystem-level CO2, N2O, and H2O fluxes. We investigated the impact of endogeic and anecic earthworms on GHG emissions and ecosystem water use efficiency (WUE) in a simulated agricultural setting. Although we observed transient stimulations of carbon fluxes in the presence of earthworms, cumulative fluxes over the study indicated no significant increase in CO2 emissions. Endogeic earthworms reduced N2O emissions during the wheat culture (− 44.6%), but this effect was not sustained throughout the experiment. No consistent effects on ecosystem evapotranspiration or WUE were found. Our study suggests that earthworms do not significantly contribute to GHG emissions over a two-year period in experimental conditions that mimic an agricultural setting. These findings highlight the need for realistic experiments and continuous GHG measurements.

Les espèces exotiques envahissantes représentent une menace pour la biodiversité à l’échelle mondiale. Parmi les plantes problématiques en France et en Europe, les renouées asiatiques (Reynoutria spp.) posent un véritable défi, leur gestion étant coûteuse et d’efficacité aléatoire. Premièrement, les gestionnaires doivent choisir d’agir ou de ne pas intervenir. Pour décider, il leur faut mieux connaître les conséquences (y compris de la non-intervention) sur le fonctionnement de l’écosystème. Ensuite, ils doivent décider de la technique de gestion. Les techniques issues du génie végétal basées sur la réintroduction d’espèces végétales indigènes compétitives permettent de réduire la dominance de l’espèce exotique envahissante tout en réintroduisant de la diversité végétale. Si de nombreuses opérations de génie écologique ont été menées, leur efficacité pour restaurer le fonctionnement de l’écosystème n’a jamais été évaluée, encore moins sur la diversité et l’activité des organismes du sol. Cet article synthétise les résultats d’une étude portant sur les effets des renouées asiatiques et de la restauration des berges envahies par génie végétal sur la communauté végétale et le sol. Il s’appuie notamment sur une analyse fine de la chimie et de la faune du sol dans deux bassins versants (en Isère et dans le Rhône).

Measurement(s) plant trait Technology Type(s) various Factor Type(s) none Sample Characteristic - Organism Tracheophyta Sample Characteristic - Environment natural environment Sample Characteristic - Location global

Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved.

Abstract Background Induction of labour, a very common obstetric procedure, affects about one in five pregnant women in most developed countries. Induction of labour is medically indicated, is subject to risks and additional costs, and is often poorly experienced by patients. The practices concerning induction vary widely from centre to centre and therefore need to be evaluated. Our aim was to develop a tool for evaluating induction of labour which would facilitate geographical and temporal comparisons. Methods We have created a classification based on the principles of the internationally known Robson classification. It should be simple, robust, reproducible and require readily available data in each file. The groups are fully inclusive and mutually exclusive. This classification has been validated by a Delphi method. Results Our classification includes 8 clinically relevant groups according to 5 obstetrical criteria. In order to classify each patient into a group, a simple system based on a maximum of 7 successive questions (from 1 to 7 questions) is used. Our classification has been validated by 13 national experts with satisfactory overall approval. Conclusions With a view to improving the quality of care, our Grenoble classification would allow a standardization of the evaluation of practices of the induction of labour over time in the same maternity hospital. It would also allow the comparison of practices within different maternity hospitals in a network, a country or even different countries.

Abstract Background Aviation has used a real-time observation method to advance anonymised feedback to the front-line and improve safe practice. Using an experiential learning method, this pilot study aimed to develop an observation-based real-time learning tool for final-year medical students with potential wider use in clinical practice. Methods Using participatory action research, we collected data on medical students’ observations of real-time clinical practice. The observation data was analysed thematically and shared with a steering group of experts to agree a framework for recording observations. A sample of students (observers) and front-line clinical staff (observed) completed one-to-one interviews on their experiences. The interviews were analysed using thematic analysis. Results Thirty-seven medical students identified 917 issues in wards, theatres and clinics in an acute hospital trust. These issues were grouped into the themes of human influences, work environment and systems. Aviation approaches were adapted to develop an app capable of recording real-time positive and negative clinical incidents. Five students and eleven clinical staff were interviewed and shared their views on the value of a process that helped them learn and has the potential to advance the quality of practice. Concerns were shared about how the observational process is managed. Conclusion The study developed an app (Healthcare Team Observations for Patient Safety—HTOPS), for recording good and poor clinical individual and team behaviour in acute-care practice. The process advanced medical student learning about patient safety. The tool can identify the totality of patient safety practice and illuminate strength and weakness. HTOPS offers the opportunity for collective ownership of safety concerns without blame and has been positively received by all stakeholders. The next steps will further refine the app for use in all clinical areas for capturing light noise.

Our ability to understand and predict the response of ecosystems to a changing environment depends on quantifying vegetation functional diversity. However, representing this diversity at the global scale is challenging. Typically, in Earth system models, characterization of plant diversity has been limited to grouping related species into plant functional types (PFTs), with all trait variation in a PFT collapsed into a single mean value that is applied globally. Using the largest global plant trait database and state of the art Bayesian modeling, we created fine-grained global maps of plant trait distributions that can be applied to Earth system models. Focusing on a set of plant traits closely coupled to photosynthesis and foliar respiration-specific leaf area (SLA) and dry mass-based concentrations of leaf nitrogen ([Formula: see text]) and phosphorus ([Formula: see text]), we characterize how traits vary within and among over 50,000 [Formula: see text]-km cells across the entire vegetated land surface. We do this in several ways-without defining the PFT of each grid cell and using 4 or 14 PFTs; each model's predictions are evaluated against out-of-sample data. This endeavor advances prior trait mapping by generating global maps that preserve variability across scales by using modern Bayesian spatial statistical modeling in combination with a database over three times larger than that in previous analyses. Our maps reveal that the most diverse grid cells possess trait variability close to the range of global PFT means.

ABSTRACT Human papillomavirus (HPV) circulating tumor DNA (HPV ctDNA) was proposed as a biomarker for the detection and disease monitoring of HPV-related cancers. One hundred eighty plasma samples obtained from women diagnosed with HPV16-positive cervical cancer (CC) (n = 100), HPV16-positive premalignant lesions (cervical intraepithelial neoplasia grade 3 [CIN3]) (n = 20), and HPV DNA-negative controls (n = 60) were randomly selected from the archives for evaluating the performance of a bead-based HPV genotyping assay (E7 type-specific multiplex genotyping assay [E7-MPG]) in detecting HPV16 ctDNA. The performance of the E7-MPG was compared with those of DNA detection by droplet digital PCR (ddPCR) and detection of HPV16 E6 antibodies evaluated in an independent study. Internal controls to assess DNA quality were included in the molecular assays, i.e., beta-globin and ESR1, respectively. The sensitivity and specificity of E7-MPG and/or E6 antibodies to detect HPV16-positive CCs were evaluated. HPV16 ctDNA was detected using the E7-MPG in 42.3% of all plasma samples and in 74.7% of plasma samples from HPV16-positive CC cases. The validation of E7-MPG data by ddPCR showed that the sensitivity of the E7-MPG test for HPV16-positive CC detection was higher than that of ddPCR (74.7% versus 63.1%; P

BACKGROUND:BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS:We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS:The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS:These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

This paper reports on school-university collaboration during an action research project, which aimed to build a writing pedagogy for students with Learning Disabilities in the trilingual, biliterate educational context of Hong Kong. The project was established through interpersonal relationships built from the ground up between stakeholders from a university department and a secondary school. The informal social networks were the locus of innovation and creativity within the project. This paper examines four broad dimensions of collaboration: the relationships created, the resources shared, the action taken and the pedagogy created. We discuss these dimensions of collaboration from the perspectives of the stakeholders. We found that each stakeholder aligned their motivations and expectations with other stakeholders to achieve the common goals of the research and consequently we call such alignments of interests "research networks". Finally, we suggest that "research networks" constitute an important, yet overlooked component of action research.

Information about the creation of Templar convents and a province in Provence, north-eastern Spain and neighbouring territories before 1150 is limited. Some types of evidence, however, suggest the establishment of convents. These include references to the construction of buildings to house Templars; the introduction of the term magister to describe some local officials; lists of brothers resident in a particular place; the appearance of the offices of claviger (“keeper of the keys”) and chaplain; and the close links formed between some laymen and Templar communities. It is clear that some convents were also setting up dependencies or granges by the middle of the 12th century. From very early on, there was a Templar official with authority on both sides of the Pyrenees, and he came to be given the title of magister, although the first reference to the province of “Provence and a certain part of Spain” does not occur until 1143. It is possible, though not certain, that provincial chapters began to be convened before 1150.

Background: Recurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring. However, the possibility of detecting these mutations in cell-free circulating DNA (cfDNA) in blood and urine, or DNA from urinary exfoliated cells (cellDNA) with a single-gene sensitive assay has never been tested in a case-control setting. Methods: We developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations. We tested 93 primary and recurrent UC cases and 94 controls recruited in France (blood, urine samples and tumours for the cases), and 50 primary UC cases and 50 controls recruited in Portugal (urinary exfoliated cell samples). We compared our assay with urine cytology. Findings: In the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87·1%; 95% CI 78·6–93·2), and five controls (Specificity 94·7%; 95%CI 88·0–98·3), with 98·6% (95% CI 92·5–99·96) concordance in matched tumours. Detection rate in plasma cfDNA among cases was 7·1%. The UroMuTERT sensitivity was (i) highest for urinary cfDNA and cellDNA combined, (ii) consistent across primary and recurrent cases, tumour stages and grades, (iii) higher for low-risk non-muscle invasive UC (86·1%) than urine cytology (23·0%) (P

Measuring relative frequencies of DNA double-strand breaks between loci does not provide the full physiological relevance of those breaks. Here Rowicka and colleagues present qDSB-Seq method which uses spike-in double-strand breaks induced by a restriction enzyme to accurately quantify DNA damage.

The nuclear membrane defines the boundaries that confine, protect and shape the genome. As such, its blebbing, ruptures and deformations are known to compromise the integrity of genetic material. Yet, drastic transitions of the nuclear membrane such as its invagination towards the nucleoplasm or its capacity to emit nuclear lipid droplets (nLD) have not been evaluated with respect to their impact on genome dynamics. To begin assessing this, in this work we used Saccharomyces cerevisiae as a model to ask whether a selection of genotoxins can trigger the formation of nLD. We report that nLD formation is not a general feature of all genotoxins, but of those engendering replication stress. Exacerbation of endogenous replication stress by genetic tools also elicited nLD formation. When exploring the lipid features of the nuclear membrane at the base of this emission, we revealed a link with the unsaturation profile of its phospholipids and, for the first time, of its sterol content. We propose that stressed replication forks may stimulate nLD birth by anchoring to the inner nuclear membrane, provided that the lipid context is adequate. Further, we point to a transcriptional feed-back process that counteracts the membrane’s proneness to emit nLD. With nLD representing platforms onto which genome-modifying reactions can occur, our findings highlight them as important players in the response to replication stress.

Background: Detecting pre-clinical bladder cancer (BC) using urinary biomarkers may provide a valuable opportunity for screening and management. Telomerase reverse transcriptase (TERT) promoter mutations detectable in urine have emerged as promising BC biomarkers. Methods: We performed a nested case-control study within the population-based prospective Golestan Cohort Study (50,045 participants, followed up to 14 years) and assessed TERT promoter mutations in baseline urine samples from 38 asymptomatic individuals who subsequently developed primary BC and 152 matched controls using a Next-Generation Sequencing-based single-plex assay (UroMuTERT) and droplet digital PCR assays. Findings: Results were obtained for 30 cases and 101 controls. TERT promoter mutations were detected in 14 pre-clinical cases (sensitivity 46·67%) and none of the controls (specificity 100·00%). At an estimated BC cumulative incidence of 0·09% in the cohort, the positive and negative predictive values were 100·00% and 99·95% respectively. The mutant allelic fractions decreased with the time interval from urine collection until BC diagnosis (p = 0·033) but the mutations were detectable up to 10 years prior to clinical diagnosis. Interpretation: Our results provide the first evidence from a population-based prospective cohort study of the potential of urinary TERT promoter mutations as promising non-invasive biomarkers for early detection of BC. Further studies should validate this finding and assess their clinical utility in other longitudinal cohorts. Funding: French Cancer League, World Cancer Research Fund International, Cancer Research UK, Tehran University of Medical Sciences, the International Agency for Research on Cancer, and the U.S. National Cancer Institute. Keywords: Early detection, TERT promoter mutations, Urinary biomarker, Bladder cancer, Prospective cohort

Background: Some evidence suggests environmental tobacco smoke (ETS) might cause chronic obstructive pulmonary disease (COPD). We reviewed available epidemiological data in never smokers. Methods: We identified epidemiological studies providing estimates of relative risk (RR) with 95% confidence interval (CI) for various ETS exposure indices. Confounder-adjusted RRs for COPD were extracted, or derived using standard methods. Meta-analyses were conducted for each exposure index, with tests for heterogeneity and publication bias. For the main index (spouse ever smoked or nearest equivalent), analyses investigated variation in RR by location, publication period, study type, sex, diagnosis, study size, confounder adjustment, never smoker definition, and exposure index definition. Results: Twenty-eight relevant studies were identified; nine European or Middle Eastern, nine Asian, eight American and two from multiple countries. Five were prospective, seven case-control and 16 cross-sectional. The COPD definition involved death or hospitalisation in seven studies, GOLD stage 1+ criteria in twelve, and other definitions in nine. For the main index, random-effects meta-analysis of 33 heterogeneous (p

Invasive alien plants often modify the structure of native plant communities, but their potential impact on soil communities is far less studied. In this study, we looked at the impact of invasive Asian knotweed (Reynoutria spp.) on two major soil mesofauna (Collembola) and microfauna (Nematodes) communities. We expected ingress of knotweed to differentially affect faunal groups depending on their trophic position, with the lower trophic levels being more impacted than the higher trophic groups according to the closer relationship to plants for basal trophic groups. Furthermore, we expected the knotweed impact to depend on habitat type (forest vs. meadow) with more pronounced changes in abundances of soil invertebrate in invaded meadows. Plant and soil invertebrates were sampled in six sites (three forest and three meadows) in northern France in both control and invaded plots. Our results showed that the presence of knotweed strongly reduced native plant species’ diversity and abundance. Soil fauna also responded to the invasion by Asian knotweed with different responses, as hypothesized, according to trophic position or life-forms. Furthermore, abundances of several collembolan life-forms were influenced by the interaction between the factors “Habitat” and “Knotweed”. This may explain the difficulty to easily generalize and predict the consequences of plant invasion on belowground diversity, although this is of crucial importance for alleviating negative consequences and costs of biological invasion.

Enzymes of nucleoside and nucleotide metabolism regulate important cellular processes with potential impacts on nucleotide-unrelated parameters. We have used a set of CRISPR/Cas9-modified cell models expressing both, one, or none of the 5′-nucleotidases cN-II and CD73, together with RNA sequencing and targeted metabolomics, to decipher new regulatory roles of these proteins. We observed important transcriptional modifications between models as well as upon exposure to adenosine. Metabolite content varied differently between cell models in response to adenosine exposure but was rather similar in control conditions. Our original cell models allowed us to identify a new unobvious link between proteins in the nucleotide metabolism and other cellular pathways. Further analyses of our models, including additional experiments, could help us to better understand some of the roles played by these enzymes.

It has long been established that parents play a key role in educational achievement. In this paper, we examine parental involvement in children's foreign language learning and the goal of finding ways to support families as they help their children to acquire a foreign language. The study investigated the ways in which Hong Kong families do and could support their children, aged 5-8, in English learning. The nature of existing parent involvement is described based on quantitative and qualitative data obtained via questionnaires and focus group discussions with a group of parents. In order to explore what parents could do to support their children with school-based requirements for English learning, a focus group of parents participated in a workshop that focused on the practice of reading aloud to their children in English. The results show that Hong Kong parents are involved in supporting their children's English literacy development in a variety of ways, yet they do not generally embrace culturally specific Western practices such as reading aloud; and furthermore, to adopt such practices might be problematic.