Unlocking the potential of anti-CD33 therapy in adult and childhood acute myeloid leukaemia

Acute Myeloid Leukaemia (AML) develops when there is a block in differentiation and uncontrolled proliferation of myeloid precursors, resulting in bone marrow failure. AML is a heterogeneous disease clinically, morphologically, and genetically, and biological differences between adult and childhood AML have been identified. AML comprises 15-20% of all children less than fifteen years diagnosed with acute leukaemia. Relapse occurs in up to 40% of children with AML and is the commonest cause of death.1,2 Relapse arises from leukaemic stem cells (LSCs) that persist after conventional chemotherapy. The treatment of AML is challenging and new strategies to target LSCs are required. The cell surface marker CD33 has been identified as a therapeutic target, and novel anti-CD33 immunotherapies are promising new agents in the treatment of AML. This review will summarise recent developments emphasising the genetic differences in adult and childhood AML, while highlighting the rationale for CD33 as a target for therapy, in all age groups

Basal rot of narcissus : understanding pathogenicity in fusarium oxysporum f. sp. narcissi

Fusarium oxysporum is a globally distributed soilborne fungal pathogen causing root rots, bulb rots, crown rots and vascular wilts on a range of horticultural plants. Pathogenic F. oxysporum isolates are highly host specific and are classified as formae speciales. Narcissus is an important ornamental crop and both the quality and yield of flowers and bulbs can be severely affected by a basal rot caused by F. oxysporum f. sp. narcissi (FON); 154 Fusarium isolates were obtained from different locations and Narcissus cultivars in the United Kingdom, representing a valuable resource. A subset of 30 F. oxysporum isolates were all found to be pathogenic and were therefore identified as FON. Molecular characterisation of isolates through sequencing of three housekeeping genes, suggested a monophyletic origin with little divergence. PCR detection of 14 Secreted in Xylem (SIX) genes, previously shown to be associated with pathogenicity in other F. oxysporum f. spp., revealed different complements of SIX7, SIX9, SIX10, SIX12 and SIX13 within FON isolates which may suggest a race structure. SIX gene sequences were unique to FON and SIX10 was present in all isolates, allowing for molecular identification of FON for the first time. The genome of a highly pathogenic isolate was sequenced and lineage specific (LS) regions identified which harboured putative effectors including the SIX genes. Real-time RT-PCR, showed that SIX genes and selected putative effectors were expressed in planta with many significantly upregulated during infection. This is the first study to characterise molecular variation in FON and provide an analysis of the FON genome. Identification of expressed genes potentially associated with virulence provides the basis for future functional studies and new targets for molecular diagnostics

Subregional Hippocampal Thickness Abnormalities in Older Adults with a History of Heavy Cannabis Use.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p<0.0001], and in the entire HC averaged over all subregions [F(1,42)=8.49, p=0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: ClinicalTrials.gov # NCT01874886

Electrical output of bryophyte microbial fuel cell systems is sufficient to power a radio or an environmental sensor

Plant microbial fuel cells (PMFCs) are a recently developed technology that exploits photosynthesis in vascular plants by harnessing solar energy and generating electrical power. In the present study the model moss species Physcomitrella patens, and other environmental samples of mosses, have been used to develop a non-vascular bryophyte microbial fuel cell (bryoMFC). A novel 3-dimensional anodic matrix was successfully created and characterized, and was further tested in a bryoMFC to determine the capacity of mosses to generate electrical power. The importance of anodophilic microorganisms in the bryoMFC was also determined. It was found that the non-sterile bryoMFCs operated with P. patens delivered over an order of magnitude higher peak power output (2.6±0.6 μW m-2) than bryoMFCs kept in near sterile conditions (0.2±0.1 μW m-2). These results confirm the importance of the microbial populations for delivering electrons to the anode in a bryoMFC. When thebryoMFCs were operated with environmental samples of moss (non-sterile) the peak power output reached 6.7±0.6 mW m-2. The bryoMFCs operated with environmental samples of moss were able to power a commercial radio receiver or an environmental sensor (LCD desktop weather station)

Urban Resilience Thinking for Municipalities

This document was prepared as a contribution to the Department of Science and Technology’s (DST’s) Grand Challenge on Global Change and as a complement to flagship initiatives such as the South African Risk and Vulnerability Atlas project (Archer, et al., 2010). The Global Change Grand Challenge is aimed at “supporting knowledge generation and technological innovation that will enable South Africa, Africa, and the world, to respond to global environmental change, including climate change” (Archer, et al., 2010, p. ii). While the Grand Challenge highlights the importance of science in supporting South Africa’s response to global change, it extends beyond a purely biophysical focus to acknowledge the importance of the social sciences. There is a clear understanding that the most compelling responses to global change will come through the combined efforts of the natural and social sciences. The DST therefore supports a number of research programmes across South Africa that draw on a wide range of scientific and academic fields in responding to specific challenges of global change across rural and urban –South Africa. One of the key thematic areas supported through the Grand Challenge is “urban resilience”. This is not at the expense of work on rural areas, as there are also a number of research programmes targeting rural South Africa, but it is recognition of both the threats posed by poorly managed urban areas and of the opportunities that towns and cities offer for greater resilience and sustainability.Global Change and Sustainability Research Institute at the University of the Witwatersrand, the Department of Science and Technology, and the National Research Foundation, South Afric

MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity

Background—Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Methods and Results—Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4–/flox bone marrow transplanted into Ldlr–/– mice. Compared with control Ldlr–/– chimeric mice, CD11c-Cre × Tcf4–/flox mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr–/– mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100–specific CD4+ T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell–derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4+ T cell–depleted animals. Conclusions—This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity

Identification of pathogenicity-related genes in Fusarium oxysporum f. sp. cepae

Pathogenic isolates of Fusarium oxysporum, distinguished as formae speciales (f. spp.) based on their host specificity, cause crown rots, root rots and vascular wilts on many important crops worldwide. F. oxysporum f. sp. cepae (FOC) is particularly problematic to onion growers worldwide and is increasing in prevalence in the UK. We characterised 31 F. oxysporum isolates collected from UK onions using pathogenicity tests, sequencing of housekeeping genes and identification of effectors. In onion seedling and bulb tests, 21 isolates were pathogenic while 10 were non-pathogenic. Molecular characterisation of these isolates, and 21 additional isolates comprising other f. spp. and different Fusarium species, was carried out by sequencing three housekeeping genes. A concatenated tree separated the F. oxysporum isolates into six clades but did not distinguish pathogenic and non-pathogenic isolates. Ten putative effectors were identified within FOC, including seven Secreted in Xylem (SIX) genes first reported in F. oxysporum f. sp. lycopersici. Two highly homologous proteins with signal peptides and RxLR motifs (CRX1/CRX2) and a gene with no previously characterised domains (C5) were also identified. The presence/absence of nine of these genes was strongly related to pathogenicity against onion and all were shown to be expressed in planta. Different SIX gene complements were identified in other f. spp. but none were identified in three other Fusarium species from onion. Although the FOC SIX genes had a high level of homology with other f. spp. there were clear differences in sequence which were unique to FOC while CRX1 and C5 genes appear to be largely FOC specific. This article is protected by copyright. All rights reserved

Electrical output of bryophyte microbial fuel cell systems is sufficient to power a radio or an environmental sensor.

Plant microbial fuel cells are a recently developed technology that exploits photosynthesis in vascular plants by harnessing solar energy and generating electrical power. In this study, the model moss species Physcomitrella patens, and other environmental samples of mosses, have been used to develop a non-vascular bryophyte microbial fuel cell (bryoMFC). A novel three-dimensional anodic matrix was successfully created and characterized and was further tested in a bryoMFC to determine the capacity of mosses to generate electrical power. The importance of anodophilic microorganisms in the bryoMFC was also determined. It was found that the non-sterile bryoMFCs operated with P. patens delivered over an order of magnitude higher peak power output (2.6 ± 0.6 µW m-2) than bryoMFCs kept in near-sterile conditions (0.2 ± 0.1 µW m-2). These results confirm the importance of the microbial populations for delivering electrons to the anode in a bryoMFC. When the bryoMFCs were operated with environmental samples of moss (non-sterile) the peak power output reached 6.7 ± 0.6 mW m-2. The bryoMFCs operated with environmental samples of moss were able to power a commercial radio receiver or an environmental sensor (LCD desktop weather station).The authors are grateful for funding provided by the UK Engineering and Physical Sciences Research Council (EPSRC) (P.B., A.G.S. and C.J. Howe), EnAlgae (http://www.enalgae.eu/, INTERREG IVB NWE) (P.B. and C.J. Howe), the Royal Society URF (C.J. Harrison), the Gatsby Charitable Foundation (Fellowship GAT2962) (C.J. Harrison), the Leverhulme Trust (P.B. and C.J. Howe), the Shuttleworth Foundation (P.B.) and the Department of Science and Technology and the National Research Foundation of South Africa through the South African Research Chair Initiative Chair in Bioprocess Engineering (UID 64778) (S.T.L.H. and D.M.R.I.).This is the final version of the article. It first appeared from the Royal Society Publishing via https://doi.org/10.1098/rsos.16024

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

Assessing the use of hospital staff influenza-like absence (ILA) for enhancing hospital preparedness and national surveillance

BACKGROUND: Early warning and robust estimation of influenza burden are critical to inform hospital preparedness and operational, treatment, and vaccination policies. Methods to enhance influenza-like illness (ILI) surveillance are regularly reviewed. We investigated the use of hospital staff ‘influenza-like absences’ (hospital staff-ILA), i.e. absence attributed to colds and influenza, to improve capture of influenza dynamics and provide resilience for hospitals. METHODS: Numbers and rates of hospital staff-ILA were compared to regional surveillance data on ILI primary-care presentations (15–64 years) and to counts of laboratory confirmed cases among hospitalised patients from April 2008 to April 2013 inclusive. Analyses were used to determine comparability of the ILI and hospital-ILA and how systems compared in early warning and estimating the burden of disease. RESULTS: Among 20,021 reported hospital-ILA and 4661 community ILI cases, correlations in counts were high and consistency in illness measurements was observed. In time series analyses, both hospital-ILA and ILI showed similar timing of the seasonal component. Hospital-ILA data often commenced and peaked earlier than ILI according to a Bayesian prospective alarm algorithm. Hospital-ILA rates were more comparable to model-based estimates of ‘true’ influenza burden than ILI. CONCLUSIONS: Hospital-ILA appears to have the potential to be a robust, yet simple syndromic surveillance method that could be used to enhance estimates of disease burden and early warning, and assist with local hospital preparedness. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-015-0789-z) contains supplementary material, which is available to authorized users