Characterisation of a Human tRNA Gene Cluster

Prior to the start of this project, several recombinants had been selected from a library of human genomic DNA cloned in lambdaCharon 4A using a mixed tRNA probe (Goddard et al., 1983). One such clone was termed lambdaHt363. Restriction digests of DNA from this recombinant were transferred to nitrocellulose membranes and hybridised to the mixed tRNA probe used in the original cloning. Several fragments from each digest hybridised to the probe, indicating the possible presence of a tRNA gene cluster. The cluster was partially characterised (McLaren and Goddard, 1986) and found to contain a 4.2 kb Bam HI fragment carrying three tRNA genes, coding for tRNA Lys, tRNA Gln and tRNA Leu. The partial sequence of a fourth gene, coding for tRNA Gly, was found at one end of an 800 bp Eco RI fragment, thought to originate from close to the right hand arm of the lambda recombinant

The Giant Tortoise Population of Aldabra (Cryptodira: Testudinidae)

The preliminary results of a study of the endemic giant tortoise population of Aldabra Atoll in the Indian Ocean (Geochelone gigatea Schweiger) are briefly described. Their number would appear to have increased dramatically since the turn of the century to their present level of some 141 000 individuals. Crude estimates of mortality and reproductive rates are also given

Pms2 suppresses large expansions of the (GAA·TTC)n sequence in neuronal tissues

Copyright @ 2012 Bourn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Expanded trinucleotide repeat sequences are the cause of several inherited neurodegenerative diseases. Disease pathogenesis is correlated with several features of somatic instability of these sequences, including further large expansions in postmitotic tissues. The presence of somatic expansions in postmitotic tissues is consistent with DNA repair being a major determinant of somatic instability. Indeed, proteins in the mismatch repair (MMR) pathway are required for instability of the expanded (CAG·CTG)(n) sequence, likely via recognition of intrastrand hairpins by MutSβ. It is not clear if or how MMR would affect instability of disease-causing expanded trinucleotide repeat sequences that adopt secondary structures other than hairpins, such as the triplex/R-loop forming (GAA·TTC)(n) sequence that causes Friedreich ataxia. We analyzed somatic instability in transgenic mice that carry an expanded (GAA·TTC)(n) sequence in the context of the human FXN locus and lack the individual MMR proteins Msh2, Msh6 or Pms2. The absence of Msh2 or Msh6 resulted in a dramatic reduction in somatic mutations, indicating that mammalian MMR promotes instability of the (GAA·TTC)(n) sequence via MutSα. The absence of Pms2 resulted in increased accumulation of large expansions in the nervous system (cerebellum, cerebrum, and dorsal root ganglia) but not in non-neuronal tissues (heart and kidney), without affecting the prevalence of contractions. Pms2 suppressed large expansions specifically in tissues showing MutSα-dependent somatic instability, suggesting that they may act on the same lesion or structure associated with the expanded (GAA·TTC)(n) sequence. We conclude that Pms2 specifically suppresses large expansions of a pathogenic trinucleotide repeat sequence in neuronal tissues, possibly acting independently of the canonical MMR pathway.IDB was supported by a postdoctoral fellowship from the National Ataxia Foundation. RMP was supported by Ataxia UK. SA was supported by The Wellcome Trust. This research was made possible by grants from the National Institutes of Health (NIH/NINDS) and the Muscular Dystrophy Association to S.I.B

Atypical Haemolytic Uraemic Syndrome Associated with a Hybrid Complement Gene

BACKGROUND: Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1–5; aliases CFHR1–5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS. METHODS AND FINDINGS: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1–21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS. CONCLUSIONS: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene

Nf2/Merlin controls spinal cord neural progenitor function in a Rac1/ErbB2-dependent manner

Objective: Individuals with the neurofibromatosis type 2 (NF2) cancer predisposition syndrome develop spinal cord glial tumors (ependymomas) that likely originate from neural progenitor cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural progenitor cells (NPCs). Methods: To identify potential therapeutic targets for these tumors, we leveraged primary mouse Nf2-deficient spinal cord neural progenitor cells. Results: We demonstrate that the Nf2 protein, merlin, negatively regulates spinal neural progenitor cell survival and glial differentiation in an ErbB2-dependent manner, and that NF2-associated spinal ependymomas exhibit increased ErbB2 activation. Moreover, we show that Nf2-deficient SC NPC ErbB2 activation results from Rac1-mediated ErbB2 retention at the plasma membrane. Significance: Collectively, these findings establish ErbB2 as a potential rational therapeutic target for NF2-associated spinal ependymoma

Implementing and operationalising integrative approaches to sustainability in Higher Education: The role of project-oriented learning.

Higher education institutions across the world are increasingly placing an emphasis on students’ acquisition of a broader range of skills or attributes within the taught curriculum, which should lead to a widening of their chances of academic success, in particular in the employment market. Among other issues, matters related to sustainable development are playing a key role, but many universities do not yet cater for integrative approaches, which may help them to approach sustainability issues in a transformative way. It is therefore necessary to develop new approaches and methods, which may address this gap. Based on the importance of meeting this perceived research need, this paper defines the role of project-oriented learning, also designated as Project Based Learning, as a tool to support integrative approaches to sustainability in a higher education context. The scientific value of the paper lies in the provision of some examples of successful approaches to Project Based Learning and the identification of some of the trends that characterise it. The paper makes clear why project-oriented learning should be more widely used in support of integrative approaches to sustainability, and why it needs to become part of the routine of higher education institutions. The outline of some of the initiatives recently and currently being undertaken may inspire others and assist in the implementation of Project Based Learning

Overcoming the challenges of public data archiving for citizen science biodiversity recording and monitoring schemes

1. Public data archiving (PDA) is widely advocated as a means of achieving open data standards, leading to improved data preservation, increased scientific reproducibility, and transparency, as well as additional data use. 2. Public data archiving was primarily conceived to archive data from short‐term, single‐purpose scientific studies. It is now more widely applied, including to large‐scale citizen science biodiversity recording and monitoring schemes which combine the efforts of volunteers with professional scientists. 3. This may affect the financial security of such schemes by reducing income from data and analytical services. Communication between scheme organizers and researchers may be disrupted, reducing scientific quality and impeding scheme development. It may also have an impact on the participation of some volunteers. 4. Synthesis and applications. In response to the challenges of public data archiving for citizen science biodiversity recording and monitoring schemes, the archive function of scheme organizations should be better recognized by those promoting open data principles. Increased financial support from the public sector or from commercial or academic data users may offset financial risk. Those in favour of public data archiving should do more to facilitate communication between nonscheme users and the originating schemes, while a more flexible approach to data archiving may be required to address potential impacts on volunteer participation

Lack of NF1 expression in a sporadic schwannoma from a patient without neurofibromatosis

The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, neurofibromin, which is expressed at high levels in Schwann cells and other adult tissues. Loss of NF1 expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 and its loss is associated with increased proliferation of these cells. In this report, we describe downregulation of NF1 expression in a single spinal schwannoma from an individual without clinical features of neurofibromatosis type 1 or 2. Barely detectable expression of NF1 RNA was found in this tumor by in situ hybridization using an NF1 -specific riboprobe as well as by Northern blot and reverse-transcribed (RT)-PCR analysis. In Schwann cells cultured from this schwannoma, abundant expression of NF1 RNA could be detected by Northern blot and RT-PCR analysis. These results suggest that, in some tumors, expression of NF1 may be downregulated by factors produced within the tumor and may represent a novel mechanism for inactivating these growth suppressing genes and allowing for increased cell proliferation in tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45383/1/11060_2005_Article_BF01057754.pd

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year