The PTEN Phosphatase Functions Cooperatively with the Fanconi Anemia Proteins in DNA Crosslink Repair

Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and increased cancer risk. The FA proteins function primarily in DNA interstrand crosslink (ICL) repair. Here, we have examined the role of the PTEN phosphatase in this process. We have established that PTEN-deficient cells, like FA cells, exhibit increased cytotoxicity, chromosome structural aberrations, and error-prone mutagenic DNA repair following exposure to ICL-inducing agents. The increased ICL sensitivity of PTEN-deficient cells is caused, in part, by elevated PLK1 kinase-mediated phosphorylation of FANCM, constitutive FANCM polyubiquitination and degradation, and the consequent inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci. We also establish that PTEN function in ICL repair is dependent on its protein phosphatase activity and ability to be SUMOylated, yet is independent of its lipid phosphatase activity. Finally, via epistasis analysis, we demonstrate that PTEN and FANCD2 function cooperatively in ICL repair

Evaluating the taxa that provide shared pollination services across multiple crops and regions

Many pollinator species visit multiple crops in multiple regions, yet we know little about their pollination service provisioning at local and regional scales. We investigated the floral visitors (n = 13,200), their effectiveness (n = 1718 single visits) and response to landscape composition across three crops avocado, mango and macadamia within a single growing region (1 year), a single crop (3 years) and across different growing regions in multiple years. In total, eight wild visitor groups were shared across all three crops. The network was dominated by three pollinators, two bees (Apis mellifera and Tetragonula spp.) and a fly, Stomorhina discolor. The visitation network for the three crops was relatively generalised but with the addition of pollen deposition data, specialisation increased. Sixteen managed and wild taxa were consistently present across three years in avocado, yet their contribution to annual network structure varied. Node specialisation (d’) analyses indicated many individual orchard sites across each of the networks were significantly more specialised compared to that predicted by null models, suggesting the presence of site-specific factors driving these patterns. Identifying the taxa shared across multiple crops, regions and years will facilitate the development of specific pollinator management strategies to optimize crop pollination services in horticultural systems

Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

Introduction Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4-positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity. Methods Flow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13). Results The frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17-producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFα) was significantly increased in SFMC (P = 0.0068). The frequency of IFNγ-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNγ. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression. Conclusions These findings demonstrate a modest enrichment of IL-17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFα than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients

Patterns of predation and meat-eating by chacma baboons in an Afromontane environment

Meat-eating among non-human primates has been well documented but its prevalence among Afromontane baboons is understudied. In this study we report the predatory and meat-eating behaviours of a habituated group of gray-footed chacma baboons (Papio ursinus griseipes) living in an Afromontane environment in South Africa. We calculated a vertebrate-eating rate of 1 every 78.5 hours, increasing to 58.1 hours when unsuccessful predation attempts were included. A key food source was young antelopes, particularly bushbuck (Tragelaphus scriptus), which were consumed once every 115 observation hours. Similar to other baboon research sites, predations seemed mostly opportunistic, adult males regularly scrounged and monopolised prey, there was no evidence they used an active kill bite, and active sharing was absent. This is the first baboon study to report predation of rock python (Python sebae) eggs and likely scavenging of a leopard (Panthera pardus) kill (bushbuck) cached in a tree. We also describe several scramble kleptoparasitism events, tolerating active defence from antelope parents, and the baboons inhibiting public information about predations. In the latter case, baboons with meat often hid beyond the periphery of the group, reducing the likelihood of scrounging by competitors. This often led to prey carcasses being discarded without being fully exploited and potentially providing resources to scavengers. We also highlight the absence of encounters with numerous species, suggesting the baboons are a key component of several species’ landscapes of fear. Given these findings it seems likely that their ecological role in the Soutpansberg has been undervalued, and such conclusions may also hold for other baboon populations

PL-016 Endurance training, muscle fibre type composition and the maximal capacity for fat oxidation

Objective A greater capacity for fat oxidation in endurance trained athletes is linked to greater utilisation of intramuscular lipid (IMCL). IMCL breakdown occurs only in type I muscle fibres yet little is known about the fibre type specific abundance of lipid regulatory proteins. We explored the impact of endurance training on the maximal rate fat oxidation, muscle fibre type and muscle fibre type specific abundance of proteins regulating IMCL metabolism. Methods Endurance trained (n=7, 28 ± 3 years, VO2max62.6 ± 1.6 ml·min-1·kg-1) and untrained (n=8, 25 ± 1 years, VO2max44.9 ± 1.9 ml·min-1·kg-1) males performed an incremental exercise test to determine maximal fat oxidation rate. Muscle fibre type composition and fibre type-specific IMCL content was assessed with immunofluorescence microscopy and protein abundance was analysed with immunoblotting on pooled single muscle fibres and whole muscle. Results Endurance trained individuals displayed a higher peak fat oxidation rate (0.49 ± 0.05 vs. 0.20 ± 0.03 g·min-1, P<0.05), which correlated with type I fibre percentage (R = 0.83, P < 0.01) and VO2max (R = 0.78, P < 0.01). Type I muscle fibres from endurance trained individuals had a greater abundance of ATGL. In whole muscle, the endurance trained group had greater abundance of PLIN2, PLIN5 and ATGL compared to the untrained group (P < 0.05). Furthermore, autophagy flux measured as LC3-II/I ratio was higher in type I muscle fibres and LC3-II/I, lysosomal markers (LAMP2) and chaperone-mediated autophagy markers (LAMP2A) were all higher in whole muscle of endurance trained individuals (P < 0.05). Conclusions These results demonstrate that the maximal rate of fat oxidation is related to the proportion of type I muscle fibres. Furthermore, IMCL storage and the abundance of key proteins regulating lipid metabolism is fibre type specific and greater in endurance trained individuals. Muscle fibre type composition should be considered when investigating the regulation of IMCL utilisation and markers of autophagy

Human immunodeficiency virus seroconversion presenting with acute inflammatory demyelinating polyneuropathy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Acute Human Immunodeficiency Virus infection is associated with a range of neurological conditions. Guillain-Barré syndrome is a rare presentation; acute inflammatory demyelinating polyneuropathy is the commonest form of Guillain-Barré syndrome. Acute inflammatory demyelinating polyneuropathy has occasionally been reported in acute Immunodeficiency Virus infection but little data exists on frequency, management and outcome.</p> <p>Case presentation</p> <p>We describe an episode of Guillain-Barré syndrome presenting as acute inflammatory demyelinating polyneuropathy in a 30-year-old man testing positive for Immunodeficiency Virus, probably during acute seroconversion. Clinical suspicion was confirmed by cerebrospinal fluid analysis and nerve conduction studies. Rapid clinical deterioration prompted intravenous immunoglobulin therapy and early commencement of highly active anti-retroviral therapy. All symptoms resolved within nine weeks.</p> <p>Conclusion</p> <p>Unusual neurological presentations in previously fit patients are an appropriate indication for Immunodeficiency-Virus testing. Highly active anti-retroviral therapy with adequate penetration of the central nervous system should be considered as an early intervention, alongside conventional therapies such as intravenous immunoglobulin.</p

Detection of Aβ plaque-associated astrogliosis in Alzheimer’s disease brain by spectroscopic imaging and immunohistochemistry

Recent work using micro-Fourier transform infrared (μFTIR) imaging has revealed that a lipid-rich layer surrounds many plaques in post-mortem Alzheimer’s brain. However, the origin of this lipid layer is not known, nor is its role in the pathogenesis of Alzheimer’s disease (AD). Here, we studied the biochemistry of plaques in situ using a model of AD. We combined FTIR, Raman and immunofluorescence images, showing that astrocyte processes co-localise with the lipid-ring surrounding many plaques. We used μFTIR imaging to rapidly measure chemical signatures of plaques over large fields of view, and selected plaques for higher resolution analysis with Raman. Raman maps showed similar lipid-rings and dense protein cores as in FTIR images, but also revealed cell bodies. We confirmed the presence of plaques using amylo-glo staining, and measured astrocytes using immunohistochemistry, revealing astrocyte colocalisation with lipid-rings. This work is important because it correlates biochemically changes surrounding the plaque with the biological process of astrogliosis

Proportionate and disproportionate policy responses to climate change: core concepts and empirical applications

A fresh perspective on policy-making and planning has emerged which views disproportionate policy as an intentional policy response. A disproportionate policy response is understood to be a lack of‘fit’or balance between the costs of a public policy and the benefits that are derived from this policy, and between policy ends and means. This paper applies this new perspective on the proportionality of policy-making to the area of climate change. The first part of the paper discusses the underlying causes of disproportionate policy responses in broad terms and then applies the theoretical reasoning to understand the conditions in which they are likely to appear in relation to climate change. These conditions are hypothesized to relate to four main factors: economic considerations; levels of public demand; focusing events; and strategic considerations. It concludes with the suggestion that societal actors may be able to manipulate these four factors to encourage politicians to adopt policies that mitigate climate change more rapidly than is currently the case in most countries

Genome analysis of the necrotrophic fungal pathogens Sclerotinia sclerotiorum and Botrytis cinerea

Sclerotinia sclerotiorum and Botrytis cinerea are closely related necrotrophic plant pathogenic fungi notable for their wide host ranges and environmental persistence. These attributes have made these species models for understanding the complexity of necrotrophic, broad host-range pathogenicity. Despite their similarities, the two species differ in mating behaviour and the ability to produce asexual spores. We have sequenced the genomes of one strain of S. sclerotiorum and two strains of B. cinerea. The comparative analysis of these genomes relative to one another and to other sequenced fungal genomes is provided here. Their 38–39 Mb genomes include 11,860–14,270 predicted genes, which share 83% amino acid identity on average between the two species. We have mapped the S. sclerotiorum assembly to 16 chromosomes and found large-scale co-linearity with the B. cinerea genomes. Seven percent of the S. sclerotiorum genome comprises transposable elements compared t

Production Perspectives of Heavy Metal Record Producers

The study of the recorded artefact from a musicological perspective continues to unfold through contemporary research. Whilst an understanding of the scientific elements of recorded sound is well documented, the exploration of the production and the artistic nature of this endeavour is still developing. This article explores phenomenological aspects of producing heavy metal music from the perspective of seven renowned producers working within the genre. Through a series of interviews and subsequent in-depth analysis, particular sonic qualities are identified as key within the production of this work: Impact; energy; precision; and extremity. A conceptual framework is then put forward for understanding the production methodology of recorded heavy metal music, and how developing technology has influenced the production of the genre