Putting theory into practice - a case study in one U.K. Medical school of the nature and extent of unprofessional behaviour over a 6-year period

Producing a medical profession which is fit for the demands and expectations of society involves ensuring that practitioners learn what it means to behave in a 'professional' way. Codes of professional conduct have been developed for medical students in the UK, but the literature on how medical schools actually apply these is small. More detail is needed to evaluate approaches to assessing professionalism, or to analyse the extent to which students 'fail' this aspect

A parametric level-set method for partially discrete tomography

This paper introduces a parametric level-set method for tomographic reconstruction of partially discrete images. Such images consist of a continuously varying background and an anomaly with a constant (known) grey-value. We represent the geometry of the anomaly using a level-set function, which we represent using radial basis functions. We pose the reconstruction problem as a bi-level optimization problem in terms of the background and coefficients for the level-set function. To constrain the background reconstruction we impose smoothness through Tikhonov regularization. The bi-level optimization problem is solved in an alternating fashion; in each iteration we first reconstruct the background and consequently update the level-set function. We test our method on numerical phantoms and show that we can successfully reconstruct the geometry of the anomaly, even from limited data. On these phantoms, our method outperforms Total Variation reconstruction, DART and P-DART.Comment: Paper submitted to 20th International Conference on Discrete Geometry for Computer Imager

Paleo-leaf economics reveal a dramatic shift in ecosystem function associated with the end-Triassic mass extinction event

Climate change is likely to have altered the ecological functioning of past ecosystems, and is likely to alter functioning in the future; however, the magnitude and direction of such changes are difficult to predict. Here we use a deep-time case study to evaluate the impact of a well-constrained CO2-induced global warming event on the ecological functioning of dominant plant communities. We use leaf mass per area (LMA), a widely used trait in modern plant ecology, to infer the palaeoecological strategy of fossil plant taxa. We show that palaeo-LMA can be inferred from fossil leaf cuticles based on a tight relationship between LMA and cuticle thickness observed among extant gymnosperms. Application of this new palaeo-LMA proxy to fossil gymnosperms from East Greenland reveals significant shifts in the dominant ecological strategies of vegetation found across the Triassic–Jurassic transition. Late Triassic forests, dominated by low-LMA taxa with inferred high transpiration rates and short leaf lifespans, were replaced in the Early Jurassic by forests dominated by high-LMA taxa that were likely to have slower metabolic rates. We suggest that extreme CO2-induced global warming selected for taxa with high LMA associated with a stress-tolerant strategy and that adaptive plasticity in leaf functional traits such as LMA contributed to post-warming ecological success

Defining conservation units with enhanced molecular tools to reveal fine scale structuring among Mediterranean green turtle rookeries

This is the final version. Available on open access from Elsevier via the DOI in this recordData accessibility: the data associated with this article is avaiable in the Dryad Digital Repository: https://datadryad.org/stash/dataset/doi:10.5061/dryad.7db01Understanding the connectivity among populations is a key research priority for species of conservation concern. Genetic tools are widely used for this purpose, but the results can be limited by the resolution of the genetic markers in relation to the species and geographic scale. Here, we investigated natal philopatry in green turtles (Chelonia mydas) from four rookeries within close geographic proximity (~200 km) on the Mediterranean island of Cyprus. We genotyped hypervariable mtSTRs, a mtDNA control region sequence (CR) and 13 microsatellite loci to genetically characterise 479 green turtles using markers with different modes of inheritance. We demonstrated matrilineal stock structure for the first time among Mediterranean green turtle rookeries. This result contradicts previous regional assessments and supports a growing body of evidence that green turtles exhibit a more precise level of natal site fidelity than has commonly been recognised. The microsatellites detected weak male philopatry with significant stock structure among three of the six pairwise comparisons. The absence of Atlantic CR haplotypes and mtSTRs amongst these robust sample sizes reaffirms the reproductive isolation of Mediterranean green turtles and supports their status as a subpopulation. A power analysis effectively demonstrated that the mtDNA genetic markers previously employed to evaluate regional stock identity were confounded by an insufficient resolution considering the recent colonisation of this region. These findings improve the regional understanding of stock connectivity and illustrate the importance of using suitable genetic markers to define appropriate units for management and conservation.Natural Environment Research Council (NERC)Ministerio de Economía y Competitividad, Spai

Identification of a variant in NDP associated with X-linked retinal dysplasia in the English cocker spaniel dog.

PURPOSE: Three related male English Cocker Spaniels (ECS) were reported to be congenitally blind. Examination of one of these revealed complete retinal detachment. A presumptive diagnosis of retinal dysplasia (RD) was provided and pedigree analysis was suggestive of an X-linked mode of inheritance. We sought to investigate the genetic basis of RD in this family of ECS. METHODS: Following whole genome sequencing (WGS) of the one remaining male RD-affected ECS, two distinct investigative approaches were employed: a candidate gene approach and a whole genome approach. In the candidate gene approach, COL9A2, COL9A3, NHEJ1, RS1 and NDP genes were investigated based on their known associations with RD and retinal detachment in dogs and humans. In the whole genome approach, affected WGS was compared with 814 unaffected canids to identify candidate variants, which were filtered based on appropriate segregation and predicted pathogenic effects followed by subsequent investigation of gene function. Candidate variants were tested for appropriate segregation in the ECS family and association with disease was assessed using samples from a total of 180 ECS. RESULTS: The same variant in NDP (c.653_654insC, p.Met114Hisfs*16) that was predicted to result in 15 aberrant amino acids before a premature stop in norrin protein, was identified independently by both approaches and was shown to segregate appropriately within the ECS family. Association of this variant with X-linked RD was significant (P = 0.0056). CONCLUSIONS: For the first time, we report a variant associated with canine X-linked RD. NDP variants are already known to cause X-linked RD, along with other abnormalities, in human Norrie disease. Thus, the dog may serve as a useful large animal model for research

Non-linearity of the collagen triple helix in solution and implications for collagen function

Collagen adopts a characteristic supercoiled triple helical conformation which requires a repeating (Xaa-Yaa-Gly)n sequence. Despite the abundance of collagen, a combined experimental and atomistic modelling approach has not so far quantitated the degree of flexibility seen experimentally in the solution structures of collagen triple helices. To address this question, we report an experimental study on the flexibility of varying lengths of collagen triple helical peptides, composed of six, eight, ten and twelve repeats of the most stable Pro-Hyp-Gly (POG) units. In addition, one unblocked peptide, (POG)10unblocked, was compared with the blocked (POG)10 as a control for the significance of end effects. Complementary analytical ultracentrifugation and synchrotron small angle X-ray scattering data showed that the conformations of the longer triple helical peptides were not well explained by a linear structure derived from crystallography. To interpret these data, molecular dynamics simulations were used to generate 50 000 physically realistic collagen structures for each of the helices. These structures were fitted against their respective scattering data to reveal the best fitting structures from this large ensemble of possible helix structures. This curve fitting confirmed a small degree of non-linearity to exist in these best fit triple helices, with the degree of bending approximated as 4–17° from linearity. Our results open the way for further studies of other collagen triple helices with different sequences and stabilities in order to clarify the role of molecular rigidity and flexibility in collagen extracellular and immune function and disease

Complement C3 variant and the risk of age-related macular degeneration

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.Methods: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.Results: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9 x 10(sup -5)) and the Scottish group (244 cases and 351 controls, P=5.0 x 10(sup -5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.Conclusions: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease

Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis

Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used CRISPR/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas

Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels

This is the final version. Available from BMC via the DOI in this record.All variants in the final dataset are included in Additional file 2. The publicly available variant datasets are available from gnomAD [22] or ClinVar [10]. Genomic datasets from the DDD Study are available under managed access for research into developmental disorders via the European Genome-phenome Archive (EGAS00001000775). Individual pathogenic/likely pathogenic variants are openly accessible with phenotypes via DECIPHER [38].Background: The use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied. Methods: We created a dataset of 3964 small (< 100 bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1–5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2021, PROVEAN, SIFT-indel, VEST-indel and VVP. Results: Our dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n = 809), ClinVar (n = 2882) and, DDD (n = 273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81–0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools’ training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64–0.87. Several of the tools performed similarly however, VEST-indel had the highest AUCs of 0.93 (full dataset) and 0.87 (DDD subset). Conclusions: Algorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools.Medical Research Council (MRC)Health Innovation Challenge FundWellcome Trust Sanger Institut

Passive phloem loading and long-distance transport in a synthetic tree-on-a-chip

Vascular plants rely on differences of osmotic pressure to export sugars from regions of synthesis (mature leaves) to sugar sinks (roots, fruits). In this process, known as M\"unch pressure flow, the loading of sugars from photosynthetic cells to the export conduit (the phloem) is crucial, as it sets the pressure head necessary to power long-distance transport. Whereas most herbaceous plants use active mechanisms to increase phloem concentration above that of the photosynthetic cells, in most tree species, for which transport distances are largest, loading seems to occur via passive symplastic diffusion from the mesophyll to the phloem. Here, we use a synthetic microfluidic model of a passive loader to explore the nonlinear dynamics that arise during export and determine the ability of passive loading to drive long-distance transport. We first demonstrate that in our device, phloem concentration is set by the balance between the resistances to diffusive loading from the source and convective export through the phloem. Convection-limited export corresponds to classical models of M\"unch transport, where phloem concentration is close to that of the source; in contrast, diffusion-limited export leads to small phloem concentrations and weak scaling of flow rates with the hydraulic resistance. We then show that the effective regime of convection-limited export is predominant in plants with large transport resistances and low xylem pressures. Moreover, hydrostatic pressures developed in our synthetic passive loader can reach botanically relevant values as high as 10 bars. We conclude that passive loading is sufficient to drive long-distance transport in large plants, and that trees are well suited to take full advantage of passive phloem loading strategies