Imaging African trypanosomes

Trypanosoma brucei are extracellular kinetoplastid parasites transmitted by the blood-sucking tsetse fly. They are responsible for the fatal disease human African trypanosomiasis (HAT), also known as sleeping sickness. In late-stage infection, trypanosomes cross the blood–brain barrier (BBB) and invade the central nervous system (CNS) invariably leading to coma and death if untreated. There is no available vaccine and current late-stage HAT chemotherapy consists of either melarsoprol, which is highly toxic causing up to 8% of deaths, or nifurtimox–eflornithine combination therapy (NECT), which is costly and difficult to administer. There is therefore an urgent need to identify new late-stage HAT drug candidates. Here, we review how current imaging tools, ranging from fluorescent confocal microscopy of live immobilized cells in culture to whole-animal imaging, are providing insight into T. brucei biology, parasite-host interplay, trypanosome CNS invasion and disease progression. We also consider how imaging tools can be used for candidate drug screening purposes that could lead to new chemotherapies

Global Potato Yields Increase Under Climate Change With Adaptation and CO2 Fertilisation

The contribution of potatoes to the global food supply is increasing—consumption more than doubled in developing countries between 1960 and 2005. Understanding climate change impacts on global potato yields is therefore important for future food security. Analyses of climate change impacts on potato compared to other major crops are rare, especially at the global scale. Of two global gridded potato modeling studies published at the time of this analysis, one simulated the impacts of temperature increases on potential potato yields; the other did not simulate the impacts of farmer adaptation to climate change, which may offset negative climate change impacts on yield. These studies may therefore overestimate negative climate change impacts on yields as they do not simultaneously include CO2 fertilisation and adaptation to climate change. Here we simulate the abiotic impacts of climate change on potato to 2050 using the GLAM crop model and the ISI-MIP ensemble of global climate models. Simulations include adaptations to climate change through varying planting windows and varieties and CO2 fertilisation, unlike previous global potato modeling studies. Results show significant skill in reproducing observed national scale yields in Europe. Elsewhere, correlations are generally positive but low, primarily due to poor relationships between national scale observed yields and climate. Future climate simulations including adaptation to climate change through changing planting windows and crop varieties show that yields are expected to increase in most cases as a result of longer growing seasons and CO2 fertilisation. Average global yield increases range from 9 to 20% when including adaptation. The global average yield benefits of adaptation to climate change range from 10 to 17% across climate models. Potato agriculture is associated with lower green house gas emissions relative to other major crops and therefore can be seen as a climate smart option given projected yield increases with adaptation

Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase to direct macrophage polarization.

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment

Global burden of human brucellosis : a systematic review of disease frequency

BACKGROUND: This report presents a systematic review of scientific literature published between 1990-2010 relating to the frequency of human brucellosis, commissioned by WHO. The objectives were to identify high quality disease incidence data to complement existing knowledge of the global disease burden and, ultimately, to contribute towards the calculation of a Disability-Adjusted Life Years (DALY) estimate for brucellosis.METHODS/PRINCIPAL FINDINGS: Thirty three databases were searched, identifying 2,385 articles relating to human brucellosis. Based on strict screening criteria, 60 studies were selected for quality assessment, of which only 29 were of sufficient quality for data analysis. Data were only available from 15 countries in the regions of Northern Africa and Middle East, Western Europe, Central and South America, Sub-Saharan Africa, and Central Asia. Half of the studies presented incidence data, six of which were longitudinal prospective studies, and half presented seroprevalence data which were converted to incidence rates. Brucellosis incidence varied widely between, and within, countries. Although study biases cannot be ruled out, demographic, occupational, and socioeconomic factors likely play a role. Aggregated data at national or regional levels do not capture these complexities of disease dynamics and, consequently, at-risk populations or areas may be overlooked. In many brucellosis-endemic countries, health systems are weak and passively-acquired official data underestimate the true disease burden.CONCLUSIONS: High quality research is essential for an accurate assessment of disease burden, particularly in Eastern Europe, the Asia-Pacific, Central and South America and Africa where data are lacking. Providing formal epidemiological and statistical training to researchers is essential for improving study quality. An integrated approach to disease surveillance involving both human health and veterinary services would allow a better understand of disease dynamics at the animal-human interface, as well as a more cost-effective utilisation of resources

Primary non-Hodgkin's breast lymphoma: Surgical approach

We report the case of a 38-year old woman affected by primary lymphoma of the right breast, with disease progression after chemotherapy and subsequent radiotherapy, successfully treated with a modified radical mastectomy. The literature of primary breast lymphomas has been reviewed and discussed in relation to our case. Our experience stresses the importance of a radical surgical approach in a locally advanced non-Hodgkin's lymphoma of the breast unresponsive to radio and chemotherapy

Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us

Supernova remnants (SNRs) arise from the interaction between the ejecta of a supernova (SN) explosion and the surrounding circumstellar and interstellar medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However, to understand SNRs as a whole, large samples of SNRs must be assembled and studied. Here, we describe the radio, optical, and X-ray techniques which have been used to identify and characterize almost 300 Galactic SNRs and more than 1200 extragalactic SNRs. We then discuss which types of SNRs are being found and which are not. We examine the degree to which the luminosity functions, surface-brightness distributions and multi-wavelength comparisons of the samples can be interpreted to determine the class properties of SNRs and describe efforts to establish the type of SN explosion associated with a SNR. We conclude that in order to better understand the class properties of SNRs, it is more important to study (and obtain additional data on) the SNRs in galaxies with extant samples at multiple wavelength bands than it is to obtain samples of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdin. Final version available at https://doi.org/10.1007/978-3-319-20794-0_90-

Renal artery stenosis-when to screen, what to stent?

Renal artery stensosis (RAS) continues to be a problem for clinicians, with no clear consensus on how to investigate and assess the clinical significance of stenotic lesions and manage the findings. RAS caused by fibromuscular dysplasia is probably commoner than previously appreciated, should be actively looked for in younger hypertensive patients and can be managed successfully with angioplasty. Atheromatous RAS is associated with increased incidence of cardiovascular events and increased cardiovascular mortality, and is likely to be seen with increasing frequency. Evidence from large clinical trials has led clinicians away from recommending interventional revascularisation towards aggressive medical management. There is now interest in looking more closely at patient selection for intervention, with focus on intervening only in patients with the highest-risk presentations such as flash pulmonary oedema, rapidly declining renal function and severe resistant hypertension. The potential benefits in terms of improving hard cardiovascular outcomes may outweigh the risks of intervention in this group, and further research is needed

Antiviral resistance during pandemic influenza: implications for stockpiling and drug use

<p>Abstract</p> <p>Background</p> <p>The anticipated extent of antiviral use during an influenza pandemic can have adverse consequences for the development of drug resistance and rationing of limited stockpiles. The strategic use of drugs is therefore a major public health concern in planning for effective pandemic responses.</p> <p>Methods</p> <p>We employed a mathematical model that includes both sensitive and resistant strains of a virus with pandemic potential, and applies antiviral drugs for treatment of clinical infections. Using estimated parameters in the published literature, the model was simulated for various sizes of stockpiles to evaluate the outcome of different antiviral strategies.</p> <p>Results</p> <p>We demonstrated that the emergence of highly transmissible resistant strains has no significant impact on the use of available stockpiles if treatment is maintained at low levels or the reproduction number of the sensitive strain is sufficiently high. However, moderate to high treatment levels can result in a more rapid depletion of stockpiles, leading to run-out, by promoting wide-spread drug resistance. We applied an antiviral strategy that delays the onset of aggressive treatment for a certain amount of time after the onset of the outbreak. Our results show that if high treatment levels are enforced too early during the outbreak, a second wave of infections can potentially occur with a substantially larger magnitude. However, a timely implementation of wide-scale treatment can prevent resistance spread in the population, and minimize the final size of the pandemic.</p> <p>Conclusion</p> <p>Our results reveal that conservative treatment levels during the early stages of the outbreak, followed by a timely increase in the scale of drug-use, will offer an effective strategy to manage drug resistance in the population and avoid run-out. For a 1918-like strain, the findings suggest that pandemic plans should consider stockpiling antiviral drugs to cover at least 20% of the population.</p

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

Protein S-palmitoylation, a hydrophobic post-translational modification, is performed by protein acyltransferases that have a common DHHC Cys-rich domain (DHHC proteins), and provides a regulatory switch for protein membrane association. In this work, we analyzed the presence of DHHC proteins in the protozoa parasite Giardia lamblia and the function of the reversible S-palmitoylation of proteins during parasite differentiation into cyst. Two specific events were observed: encysting cells displayed a larger amount of palmitoylated proteins, and parasites treated with palmitoylation inhibitors produced a reduced number of mature cysts. With bioinformatics tools, we found nine DHHC proteins, potential protein acyltransferases, in the Giardia proteome. These proteins displayed a conserved structure when compared to different organisms and are distributed in different monophyletic clades. Although all Giardia DHHC proteins were found to be present in trophozoites and encysting cells, these proteins showed a different intracellular localization in trophozoites and seemed to be differently involved in the encystation process when they were overexpressed. dhhc transgenic parasites showed a different pattern of cyst wall protein expression and yielded different amounts of mature cysts when they were induced to encyst. Our findings disclosed some important issues regarding the role of DHHC proteins and palmitoylation during Giardia encystation.Fil: Merino, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Zamponi, Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Touz, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Ropolo, Andrea Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

Unprecedented climate extremes in South Africa and implications for maize production

This is the final version. Available on open access from IOP Publishing via the DOI in this recordData availability statement: Any data that support the findings of this study are included within the article.Maize is the most important crop grown in South Africa, but yields can be severely reduced by extreme high summer average temperatures and low precipitation, potentially adversely affecting both domestic consumption and regional food security exports. To help understand and manage climate risks to food security in Southern Africa it is essential to quantify the present-day likelihood and magnitude of climate extremes in South Africa’s maize-growing region and explore the potential for unprecedented climate conditions which would likely result in record low maize yields. We analyse a large ensemble of initialised climate model simulations, which provides almost 100 times as many plausible present-day summers as the equivalent observational dataset. We quantify the risk of unprecedented climate extremes affecting maize production in South Africa and examine the role of the El Niño-Southern Oscillation. We find that the South African maize region is at risk of experiencing record-breaking hot, cold, dry or wet events under current climatic conditions. We find that the annual chance of unprecedented high temperatures in South Africa is approximately 4%, increasing to 62% during very strong El Niño years. We also find that the chance of exceeding the present day seasonal high temperature record has increased across the 1979-2018 period, being five times more likely now than it was in 1980. These extreme events could result in a record-breaking number of days above the optimum, or even the maximum, temperature for maize production, and lead to more severe floods or droughts. Under climate change scenarios, the magnitude and frequency of climate extremes is projected to increase meaning that the unprecedented extremes studied here could become commonplace in the future. This suggests that significant investment is needed to develop adaptations that manage the climate-related risks to food systems now and build resilience to the projected impacts of climate change.Biotechnology and Biological Sciences Research Council (BBSRC