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Intraflagellar transport proteins (IFTs) are mostly known for their role in cilia assembly and maintenance. The cilial protein IFT88 is now found to transport microtubule clusters containing microtubule-nucleating proteins to spindle poles to promote astral microtubule formation and correct spindle orientation. Cilia dysfunction has long been associated with cyst formation and ciliopathies 1 . More recently, misoriented cell division has been observed in cystic kidneys 2 , but the molecular mechanism leading to this abnormality remains unclear. Proteins of the intraflagellar transport (IFT) machinery are linked to cystogenesis and are required for cilia formation in non-cycling cells 3 , 4 . Several IFT proteins also localize to spindle poles in mitosis 5 , 6 , 7 , 8 , indicating uncharacterized functions for these proteins in dividing cells. Here, we show that IFT88 depletion induces mitotic defects in human cultured cells, in kidney cells from the IFT88 mouse mutant Tg737 o r p k and in zebrafish embryos. In mitosis, IFT88 is part of a dynein1-driven complex that transports peripheral microtubule clusters containing microtubule-nucleating proteins to spindle poles to ensure proper formation of astral microtubule arrays and thus proper spindle orientation. This work identifies a mitotic mechanism for a cilia protein in the orientation of cell division and has important implications for the etiology of ciliopathies.

Background Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. Methods and results Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. Conclusions Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia, and elucidating its genetic underpinnings is critical. FTLD research centers typically recruit patient cohorts that are limited by the center's specialty and the ways in which its geographic location affects the ethnic makeup of research participants. Novel sources of data are needed to get population estimates of the contribution of variants in known FTLD-associated genes. We compared FLTD-associated genetic variants in microtubule-associated protein tau ( ), progranulin ( ), and chromosome nine open reading frame 72 ( ) from an academic research cohort and a commercial clinical genetics laboratory. Pathogenicity was assessed using guidelines of the American College of Medical Genetics and Genomics and a rule-based DNA variant assessment system. We conducted chart reviews on patients with novel or rare disease-associated variants. A total of 387 cases with FTLD-associated variants from the commercial (n=2,082) and 78 cases from the academic cohort (n=2,089) were included for analysis. In the academic cohort, the most frequent pathogenic variants were expansions (63%, n=49), followed by (26%, n=20) and (11%, n=9). Each gene's contribution to disease was similarly ranked in the commercial laboratory but differed in magnitude: (89%, n=345), (6%, n=24), and (5%, n=19). Of the 37 unique / variants identified, only six were found in both cohorts. Clinicopathological data from patients in the academic cohort strengthened classification of two novel variant as pathogenic (p.Pro166Leufs*2, p.Gln406*) and one variant of unknown significance as a possible rare risk variant (p.Cys139Arg). Differences in gene frequencies and identification of unique pathogenic alleles in each cohort demonstrate the importance of data sharing between academia and community laboratories. Using shared data sources with well-characterized clinical phenotypes for individual variants can enhance interpretation of variant pathogenicity and inform clinical management of at-risk patients and families.

This study examines how graduate teaching assistants of composition and peer and professional tutors of writing develop their identities as teacher and tutors in preparation programs. Research in teacher education programs indicates that when preparatory sessions highlight the concept of teacher identity in the preparation of K-12 teacher candidates, teacher candidates have higher levels of teacher efficacy, job satisfaction, and retention in the field (Danielewicz, 2001; Alsup, 2006; McKinney et al., 2008). Because writing TAs and tutors account for much of the composition instruction and support of undergraduate writers, the preparation programs of these two groups would greatly benefit from the same attention to teacher identity as in the preparation of K-12 teachers. This study considers three central issues: first, it investigates the types of identities that are encouraged and/or fostered in the preparation of TAs and undergraduate tutors of writing at two sites, referred to as The University and The Community College. Second, it examines whether or not the identities promoted in the preparation modes at The University and The Community College reflect the philosophies of the preparation programs. Third, it considers how the construction of identity affects the tutoring or teaching practices of the participants. These questions provide a framework through which the development and presence of teaching or tutoring identities in the study’s participants are examined. Three case studies of preparation programs were observed preparing either TAs or tutors. Data were drawn from fourteen self-selected participants across three cases: four undergraduate students from a four-year university; four professional writing tutors from a community college; and six graduate TAs all teaching composition. All preparatory sessions were observed across the three cases. Each subject’s teaching or tutoring practices were observed two times, and within a week of each observation, the subjects were interviewed regarding the observation. These data were analyzed as individual cases and in parallel. The resulting themes are presented as a heuristic of teacher identity characteristics along a novice-to-expert spectrum focusing on four characteristics: content knowledge and behaviors; flexibility in theory and practice, membership in a peer community, and engagement in reflective practices. The majority of the participants developed teacher or tutor identities consistent with the goals of the program in which they were prepared and displayed evidence of the teacher identity characteristics in their practices. Among those not included in the majority, one subset developed identities that were not aligned with the preparation program; another developed identities reflecting the goals of the preparation program but were not aligned with best practices in the field.

In this article, a group of inservice providers and beginning researchers describe their experiences in learning to conduct evaluation research on a long-term school-university partnership program. We offer the practical lessons we learned in how to undertake such a study, and we share the immediate and powerful effects that the process of conducting the research had on the way we envisionand enact our inservice work. As the director of the inservice program noted, the problem we were addressing changed from “How can we convince others that we do good work?” to “How canwe make our work better?” This is a question at the heart of professional learning communities.

While inklings of the movement to professionalize science can be seen in Britain in the eighteenth century, the real push came around 1830 with the creation of the British Association for the Advancement of Science. Subsequent changes in the social position of science over the course of the century were dramatic. Using examples drawn from popular, genre, and \"literary\" fiction, as well as commentary from scientists, this dissertation examines the public reaction to the process of professionalization in nineteenth century Britain by studying how scientists were portrayed in fiction. What emerges is a dynamic conversation between scientists and authors. The emphasis put on public funding and support necessitated that scientists engage in a dialogue with popular attitudes towards science. Fiction not only responded to science, it could be written by scientists, and furthermore had power to shape both science's position in society and the way scientists presented themselves to the public at large. Focusing on the foundation of professional science in the nineteenth century, this work examines the interplay between science and fiction by examining the image of scientists in representative works from four overlapping periods, covering the early 1800s through World War I. The results of strategies to improve the public image of science and foster government spending on scientific research are then briefly examined by a look at changes in fiction during the post-war period, up to the early 1930s. Major authors discussed include Mary Shelley, Elizabeth Gaskell, Anthony Trollope, Charles Kingsley, George Eliot, Wilkie Collins, Robert Louis Stevenson, H. Rider Haggard, George Gissing, H. G. Wells, Bram Stoker, Arthur Conan Doyle, M. R. James, George Griffith, and Aldous Huxley. Scientists discussed as part of the professionalization movement include Humphrey Davy, Charles Babbage, David Brewster, Charles Darwin, T. H. Huxley, John Tyndall, Karl Pearson, and J. B. S. Haldane.

Though it is now difficult to imagine any language arts teacher at any grade level not knowing about “the writing process,” many of the teaching practices employed in classrooms in the name of said writing process suggest that teachers may have different understandings about what the writing process entails as a model of writing and learning to write, conceptually or epistemologically.

SHAKESPEARE IN LOVE, the critically acclaimed film based on the early life of the Bard, will be shown free to thousands of schoolchildren tomorrow as part of a national campign to interest children in classic literature. Every school in the country has been offered free tickets for screenings of the film, starring Gwyneth Paltrow and Joseph Fiennes. It will be shown at 28 cinemas nationwide and followed in February with special screenings of Trevor Nunn's version of Twelfth Night. The claims are backed by research from King's College, London, which shows that the reading age of children working with screen adaptations of classics can be boosted by as much as two years. Researchers working on the project in inner-city schools in London found that children who worked with film and TV versions of books made remarkable progress while children who worked with texts alone stood still.

Campaigns to get councils to build new comprehensives in areas of high demand have sprung up at Kingston upon Thames in Surrey, Dulwich in south London, and Bristol. In each case, parents say they are being forced to send their children to state schools up to 20 miles away or to go private. In Bristol, one inner-city junior school sends its children on to 15 secondary schools. From Dulwich, children go on to about 40 secondaries across the capital. 'All we want is a continuation of what we have at primary level - a school for all children no matter what their background or ability. Our demands are simple: a good, local comprehensive,' said Marianne Kavanagh, a mother of three primary-age children who founded the Dulwich Area Secondary School Campaign (DASSC) with other parents six weeks ago. More than 1,000 people have since signed a petition calling for a new school.

We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1–2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77–0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45–0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72–0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.