Contextual factors among indiscriminate or larger attacks on food or water supplies, 1946-2015

This research updates previous inventories of malicious attacks on food and water to include data from 1946 through mid-2015. A systematic search of news reports, databases and previous inventories of poisoning events was undertaken. Incidents that threatened or were intended to achieve direct harm to humans, and that were either relatively large (number of victims > 4 or indiscriminate in intent or realisation were included. Agents could be chemical, biological or radio-nuclear. Reports of candidate incidents were subjected to systematic inclusion and exclusion criteria as well as validity analysis (not always clearly undertaken in previous inventories of such attacks). We summarise contextual aspects of the attacks that may be important for scenario prioritisation, modelling and defensive preparedness. Opportunity is key to most realised attacks, particularly access to dangerous agents. The most common motives and relative success rate in causing harm were very different between food and water attacks. The likelihood that people were made ill or died also varied by food/water mode, and according to motive and opportunity for delivery of the hazardous agent. Deaths and illness associated with attacks during food manufacture and prior to sale have been fewer than those in some other contexts. Valuable opportunities for food defence improvements are identified in other contexts, especially food prepared in private or community settings

Genetic variants in the MRPS30 region and postmenopausal breast cancer risk

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The Unseeing Eye: Disability and the hauntology of Derrida’s ghost. A story in three parts

Through the employment of the three stanzas of Thomas Hardy’s poem ‘The Self-Unseeing’ this paper seeks to tremble the picture of disability located in the pedagogical materials in English Schools. By mobilising, and then reversing, Derrida’s concept of the visor and the ghost, as well as Bentham’s Panopticon, this story reveals the power of the Them, the Their and the They. In materialising the ghost of the real of disability within a utopia of hope this story deconstructs the power of Their transparent house by revealing disabled people as magnificent beings

Partial Depletion of Natural CD4+CD25+ Regulatory T Cells with Anti-CD25 Antibody Does Not Alter the Course of Acute Influenza A Virus Infection

Foxp3+ CD4+ regulatory T cells represent a T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, and there is emerging evidence to suggest these cells temper pulmonary inflammation in response to acute viral infection. Recent studies have demonstrated treatment with PC61 CD25-depleting antibody potentiates inflammation in a murine model of RSV infection, while paradoxically delaying recruitment of CD8+ T cells to the site of inflammation. The present study therefore sought to examine the role of these cells in a murine model of acute influenza A virus infection through the administration of PC61 CD25-depleting antibody. PC61 antibody is able to partially deplete CD25+Foxp3+ regulatory T cells to a comparable degree as seen within previous work examining RSV, however this does not alter influenza A-virus induced mortality, weight loss, viral clearance and cellularity within the lung. Collectively, these data demonstrate that partial depletion of CD4+CD25+ regulatory T cells with PC61 antibody does not alter the course of influenza A virus infection

Myogenin Regulates Exercise Capacity but Is Dispensable for Skeletal Muscle Regeneration in Adult mdx Mice

Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myogflox/flox mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myogflox/flox mice (mdx), Myogflox/flox mice (wild-type), and mdx:MyogfloxΔ/floxΔ:Cre-ER mice (mdx:Myog-deleted). mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function

Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA

The modified base 5-methylcytosine (m5C) is well studied in DNA, but investigations of its prevalence in cellular RNA have been largely confined to tRNA and rRNA. In animals, the two m5C methyltransferases NSUN2 and TRDMT1 are known to modify specific tRNAs and have roles in the control of cell growth and differentiation. To map modified cytosine sites across a human transcriptome, we coupled bisulfite conversion of cellular RNA with next-generation sequencing. We confirmed 21 of the 28 previously known m5C sites in human tRNAs and identified 234 novel tRNA candidate sites, mostly in anticipated structural positions. Surprisingly, we discovered 10 275 sites in mRNAs and other non-coding RNAs. We observed that distribution of modified cytosines between RNA types was not random; within mRNAs they were enriched in the untranslated regions and near Argonaute binding regions. We also identified five new sites modified by NSUN2, broadening its known substrate range to another tRNA, the RPPH1 subunit of RNase P and two mRNAs. Our data demonstrates the widespread presence of modified cytosines throughout coding and non-coding sequences in a transcriptome, suggesting a broader role of this modification in the post-transcriptional control of cellular RNA function

A KLHL40 3’ UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism

Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). Common features include fetal akinesia, fractures, contractures, dysphagia, respiratory failure, and neonatal death. Here, we describe a man in his 20s with relatively mild NEM8. He presented with hypotonia and bilateral femur fractures at birth, later developing bilateral Achilles’ contractures, scoliosis, and elbow and knee contractures. He had walking difficulties throughout childhood and became wheelchair bound during adolescence after prolonged immobilisation. Muscle MRI during adolescence indicated prominent fat replacement in his pelvic girdle, posterior compartments of thighs, and vastus intermedius. Muscle biopsy revealed nemaline bodies and intranuclear rods. RNA sequencing and western blotting of patient skeletal muscle indicated significant reduction in KLHL40 mRNA and protein respectively. Using gene panel screening, exome sequencing and RNA sequencing, we identified compound heterozygous variants in KLHL40; a truncating 10.9 kb deletion in trans with a likely pathogenic variant (c.*152G>T) in the 3’ untranslated region (UTR). Computational tools SpliceAI and Introme predicted the c.*152G>T variant created a cryptic donor splice site. RNA-seq and in vitro analyses indicated that the c.*152G>T variant induces multiple de novo splicing events that likely provoke nonsense mediated decay of KLHL40 mRNA explaining the loss of mRNA expression and protein abundance in the patient. Analysis of 3’ UTR variants in ClinVar suggests SNPs that introduce aberrant 3’ UTR splicing may be underrecognised in Mendelian disease. We encourage consideration of this mechanism during variant curation.This study was funded by an Australian NHMRC Investigator Grant (APP2007769), Fellowship (APP1117510) and Ideas Grant (APP2002640). The study was supported by an Australian Government Research Training Program (RTP) Scholarship, as well as resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia.N