Subject preferences of fifth-grade children.

Thesis (Ed.M.)--Boston University N.B.:Pages 155 and 309 are missing from original thesis

Representing kidney development using the gene ontology.

Gene Ontology (GO) provides dynamic controlled vocabularies to aid in the description of the functional biological attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org). Here we describe collaboration between the renal biomedical research community and the GO Consortium to improve the quality and quantity of GO terms describing renal development. In the associated annotation activity, the new and revised terms were associated with gene products involved in renal development and function. This project resulted in a total of 522 GO terms being added to the ontology and the creation of approximately 9,600 kidney-related GO term associations to 940 UniProt Knowledgebase (UniProtKB) entries, covering 66 taxonomic groups. We demonstrate the impact of these improvements on the interpretation of GO term analyses performed on genes differentially expressed in kidney glomeruli affected by diabetic nephropathy. In summary, we have produced a resource that can be utilized in the interpretation of data from small- and large-scale experiments investigating molecular mechanisms of kidney function and development and thereby help towards alleviating renal disease

A national-scale assessment of climate change impacts on species: assessing the balance of risks and opportunities for multiple taxa

It is important for conservationists to be able to assess the risks that climate change poses to species, in order to inform decision making. Using standardised and repeatable methods, we present a national-scale assessment of the risks of range loss and opportunities for range expansion, that climate change could pose for over 3,000 plants and animals that occur in England. A basic risk assessment that compared projected future changes in potential range with recently observed changes classified 21% of species as being at high risk and 6% at medium risk of range loss under a B1 climate change scenario. A greater number of species were classified as having a medium (16%) or high (38%) opportunity to potentially expand their distribution. A more comprehensive assessment, incorporating additional ecological information, including potentially confounding and exacerbating factors, was applied to 402 species, of which 35 % were at risk of range loss and 42 % may expand their range extent. This study covers a temperate region with a significant proportion of species at their poleward range limit. The balance of risks and opportunities from climate change may be different elsewhere. The outcome of both risk assessments varied between taxonomic groups, with bryophytes and vascular plants containing the greatest proportion of species at risk from climate change. Upland habitats contained more species at risk than other habitats. Whilst the overall pattern was clear, confidence was generally low for individual assessments, with the exception of well-studied taxa such as birds. In response to climate change, nature conservation needs to plan for changing species distributions and increasing uncertainty of the future

Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting.Methods 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey.Results 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD.Conclusion We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting

Utility of polygenic risk scores in UK cancer screening:a modelling analysis

This work was funded by a Wellcome Trust Clinical Research Fellowship. CH is supported by a Wellcome Trust Clinical Research Training Fellowship (203924/Z/16/Z). RSH acknowledges grant support from Cancer Research UK (C1298/A8362) and the Wellcome Trust (214388). AS is in receipt of a National Institute for Health Research (NIHR) Academic Clinical Lectureship, funding from the Royal Marsden Biomedical Research Centre, and is recipient of the Whitney-Wood Scholarship from the Royal College of Physicians. CT, CFR, HH, KS, RW, and BT acknowledge grant support from Cancer Research UK (C8620/A8372). MEJ receives funding from Breast Cancer Now.It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer). For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016-18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types. For each of five PRS-defined high-risk quantiles (ie, the top 50%, 20%, 10%, 5%, and 1%) and according to each of the three PRS tools (ie, current, future, and optimised) for the eight cancers, we calculated the relative proportion of cancers arising, the odds ratios of a cancer arising compared with the UK population average, and the lifetime cancer risk. We examined maximal attainable rates of cancer detection by age stratum from combining PRS-based stratification with cancer screening tools and modelled the maximal impact on cancer-specific survival of hypothetical new UK programmes of PRS-stratified screening. The PRS-defined high-risk quintile (20%) of the population was estimated to capture 37% of breast cancer cases, 46% of prostate cancer cases, 34% of colorectal cancer cases, 29% of pancreatic cancer cases, 26% of ovarian cancer cases, 22% of renal cancer cases, 26% of lung cancer cases, and 47% of testicular cancer cases. Extending UK screening programmes to a PRS-defined high-risk quintile including people aged 40-49 years for breast cancer, 50-59 years for colorectal cancer, and 60-69 years for prostate cancer has the potential to avert, respectively, a maximum of 102, 188, and 158 deaths annually. Unstratified screening of the full population aged 48-49 years for breast cancer, 58-59 years for colorectal cancer, and 68-69 years for prostate cancer would use equivalent resources and avert, respectively, an estimated maximum of 80, 155, and 95 deaths annually. These maximal modelled numbers will be substantially attenuated by incomplete population uptake of PRS profiling and cancer screening, interval cancers, non-European ancestry, and other factors. Under favourable assumptions, our modelling suggests modest potential efficiency gain in cancer case detection and deaths averted for hypothetical new PRS-stratified screening programmes for breast, prostate, and colorectal cancer. Restriction of screening to high-risk quantiles means many or most incident cancers will arise in those assigned as being low-risk. To quantify real-world clinical impact, costs, and harms, UK-specific cluster-randomised trials are required.Publisher PDFPeer reviewe

Human occupation of northern Australia by 65,000 years ago

The time of arrival of people in Australia is an unresolved question. It is relevant to debates about when modern humans first dispersed out of Africa and when their descendants incorporated genetic material from Neanderthals, Denisovans and possibly other hominins. Humans have also been implicated in the extinction of Australia's megafauna. Here we report the results of new excavations conducted at Madjedbebe, a rock shelter in northern Australia. Artefacts in primary depositional context are concentrated in three dense bands, with the stratigraphic integrity of the deposit demonstrated by artefact refits and by optical dating and other analyses of the sediments. Human occupation began around 65,000 years ago, with a distinctive stone tool assemblage including grinding stones, ground ochres, reflective additives and ground-edge hatchet heads. This evidence sets a new minimum age for the arrival of humans in Australia, the dispersal of modern humans out of Africa, and the subsequent interactions of modern humans with Neanderthals and Denisovans

An OBO-Edit ‘Ontology Tree Editor’ view showing the relationship and position of the new GO term ‘<i>branching involved in ureteric bud morphogenesis</i>’.

<p>By placing the new term ‘<i>branching involved in ureteric bud morphogenesis</i>’ as a sub-type of ‘<i>morphogenesis of a branching structure’</i>, it puts the renal branching into the context of other types of branching morphogenesis within the Gene Ontology (using the Gene Ontology file from March 19^th 2012). The [+] icon beside each term denotes that there are further child terms that can be viewed; the [−] icon denotes no further child terms; (P) denotes a <i>part_of</i> relationship; (I) denotes an <i>is_a</i> relationship.</p

An OBO-Edit ‘Ontology Tree Editor’ view demonstrating the improved Gene Ontology representing ‘kidney development’ after a focused expansion.

<p>The Gene Ontology representing kidney development was enriched after a focused expansion with an additional 522 new terms, and as an example (using the Gene Ontology file from March 19^th 2012) the expanded node of the ‘<i>pronephros development</i>’ term shows it’s immediate child terms. The [+] icon beside each term denotes that there are further child terms that can be viewed; the [−] icon denotes no further child terms; (P) denotes a <i>part_of</i> relationship; (I) denotes an <i>is_a</i> relationship; (R) denotes a <i>regulates</i> relationship.</p

Summary of the number of GO terms significantly enriched in the differentially expressed gene dataset from glomeruli affected by Diabetic Nephropathy (DN) by both Ontologizer and GO-Elite enrichment analysis tools.

<p>A summary of the number of GO terms that were significantly enriched (having a p-value of <0.1) in the Baelde groups’ differentially expressed gene dataset from glomeruli affected by DN <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099864#pone.0099864-Baelde1" target="_blank">[29]</a> by both Ontologizer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099864#pone.0099864-Bauer1" target="_blank">[28]</a> and GO-Elite <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099864#pone.0099864-Zambon1" target="_blank">[27]</a> term enrichment tools, using the pre-annotation (2009) and post-annotation (2012) GO annotation datasets.</p

UniProtKB accession numbers for 29 homologous proteins using data from <i>in-situ</i> hybridisation expression in murine loop of Henle.

<p>Uniprot accession numbers are listed for homologues of the 29 proteins expressed in the murine loop of Henle structure (data provided by the GUDMAP Consortium via <a href="http://www.gudmap.org" target="_blank">www.gudmap.org</a>) as determined by BLAST (run via the uniprot.org website). The <i>Drosophila</i> proteins in parentheses are homologous to multiple mammalian proteins. (n/a = not applicable).</p