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Results

Characterising metabolic mechanisms conferring deltamethrin resistance in Anopheles albimanus, major malaria vector in Guatemala 22 Nov 2016

Malaria is still a publich health in Guatemala, reportin a total of 4,931 confirmed malaria cases for 2014. The main malaria vector is An. albimanus because is the most abundant and widely distributed species. Insecticide-based vector control strategies are maily used in Guatemala, which includes pyrethroid LLIN's. Unfortunately, the emergence of resistance to insecticides is threatening the continued success of the insecticide-based vector control interventions. Bioassays, molecular and biochemical assays indicated development of pyrethroids resistance in An. albimanus from Guatemala with early evidences suggesting a predominant role of metabolic resistance mechanisms. Therefore, this project aims at elucidatin the metabolic resistance mechanisms involved in the deltamethrin resistance in Guatemalan An. albimanus. So, insecticide resistance profile will be assessed in field populations of An. albimanus throughout Guatemala using CDC bottle bioassays and synergist assays. Resistant mosquitoes will be used to detect key genes conferring metabolic resistance using RNA-seq transcriptomic approach with Illumina and quantitative PCR. In addition, deltamethrin resistance markers will be detected by sequencing of candidate genes between resistant and susceptible mosquitoes. This will allow us to design DNA-based diagnostic tools which will to enhance the sentinel surveillance to detect insecticide resistance at early stage.

Amount: £140,950
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

The role of β-amyloid in cognition in normal and APP knock-in mice 31 Jan 2017

Working hypothesis: modulation of beta-amyloid (Abeta) production (in the absence of APP overexpression) in mice will lead to changes in brain network activity and cognitive function. Our understanding of dementia pathogenesis has been heavily influenced by the amyloid cascade hypothesis. However, progress is hampered by the fact that (1) little is known about the normal function of Abeta and (2) current mouse models of amyloid pathology rely on over-expression of human APP mutations. APP over-expression alone causes synaptic and cognitive changes that are independent of Abeta production. We propose to examine the role of normal Abeta production in synaptic plasticity and cognition and to characterize a novel knock-in mouse model of amyloid pathology (Saito et al., 2014; the NL-F mouse). We will examine cognitive changes in NL-F mice during aging to establish a profile of brain network changes. We will test the effects of steric hindrance of Abeta production on memory by using an antibody (2B3) that binds across the beta-secretase cleavage site in both NL-F and WT mice. Analysis of memory function will be accompanied by assessment of network activity (c-fos expression), brain metabolite profile (MR-Spectroscopy) and APP cleavage products (using standard biochemical assays) in NL-F and WT mice.

Amount: £31,128
Funder: The Wellcome Trust
Recipient: Cardiff University

Raising awareness and interest in biomedical science research in Malawian schools 27 Nov 2016

The host antiviral immune response is relatively effective at recognising and eliminating most HIV-infected cells. However, HIV manipulates resting memory CD4 T cells and persistently resides in them in a latent state, resulting in formation of viral reservoirs. These reservoirs are poorly recognised by antiviral cytotoxic cells and are less susceptible to the effects of the current antiretroviral therapy (ART), leading to incomplete clearance of the infection. In the lung, alveolar macrophages (AM) have a long life span, can harbour HIV and are relatively resistant to the cytopathic effects of HIV, making them an important potential viral reservoir. Recently, we have shown that HIV persists in AM in HIV-infected individuals on long term ART despite undetectable plasma viraemia. This fellowship proposes using bronchoalveolar lavage (BAL) and peripheral blood obtained from HIV-infected and uninfected Malawian adults to address the hypothesis that HIVs ability to hinder immune recognitio n and block the induction of apoptosis leads to its persistence in AM. Specifically, the following questions will be addressed a) How does HIV hinder immune recognition of HIV-infected AM by cytotoxic cells? b) How does HIV block progression to apoptosis in HIV-infected AM? c) Which viral proteins are responsible for modulation of macrophages?

Amount: £30,800
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Assessing the anticancer properties of Biocyanin SLH 31 May 2018

Haemocyanins are oxygen-carrying proteins found in the haemolymph of molluscs and gastropods. They are of interest to biotech and medical research as strongly immunogenic carrier proteins, for making antibodies to conjugated peptides and for use as cancer vaccines. In addition, direct application of haemocyanin to tumours has been shown to produce an anticancer effect, and haemocyanins from several species including keyhole limpet have shown promise in the treatment of bladder cancer, colon cancer and melanoma. Particularly striking are their lack of toxicity and adverse effects. Recently, Mikota PLC have developed protocols for the purification of a new haemocyanin, Biocyanin SLH, from the slipper limpet Crepidula fornicata. The main aim of our proposal is to test the potential of Biocyanin SLH as an anticancer agent, by incubating it with a panel of cancer cell lines and assessing its ability to induce cell death. In addition, we will investigate the signalling pathways involved in the anticancer action of Biocyanin SLH, determining whether cell death occurs via apoptosis or necrosis, and analysing cellular production of stress molecules. Finally, we will label Biocyanin SLH with a fluorescent dye to track its interaction with cells using confocal microscopy. Keywords: haemocyanin, cancer, cell death.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Investigating the relationship between the cerebellum and cognition in both health and disease 30 Sep 2018

The cerebellum is traditionally ascribed only a role in motor coordination. With it containing more neurones than the rest of the central nervous system combined and with connections with almost every other area of the brain concerned with cognition, this seems exceptionally unlikely. Indeed, studies utilising magnetic resonance imaging (MRI) increasingly show strong cerebellar activity associated with cognitive processes. This is still a greatly understudied area with only a few groups researching this. We, therefore, wish to investigate the role of the cerebellum in cognition using large imaging datasets, our own high-field imaging capabilities at Cardiff and various cerebellar-specific MRI processing tools which have not yet been applied to this question. This will allow us to see how well peoples’ cognitive performance in various domains correlates with cerebellar activity and structural differences. Additionally, recent evidence suggests cerebellar structural differences in schizophrenic patients. We wish, therefore, to also investigate if schizophrenia diagnosis and genetic risk for schizophrenia similarly alters cerebellar structure and, if so, at what time during development, if certain cognitive domains are particularly affected and if cerebellar metabolite levels differ in schizophrenic patients compared to non-schizophrenic controls.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Influence of Sleep on Human Brain Structure 08 Nov 2017

Sleep is essential to brain functioning and its loss greatly impairs cognition, yet the brain mechanisms underlying the cognitive benefits of sleep remain largely unclear. During sleep, the brain’s functional networks break down, with different brain regions showing decoupled activities. I hypothesize that this decoupling of brain regions will facilitate the remodeling and optimization of brain structural networks, leading to improved brain functioning and cognitive performances after sleep. I will test my hypothesis in human participants by combining measures of brain structure, function, cognition, with brain stimulation during sleep. First, I will study how the structure of inter-regional connections change after sleep, whether these changes improve the network properties, and how these changes are reflected in the function of inter-regional communications. Then, I will study how the post-sleep changes in brain function correlate with brain activity in sleep, and whether these functional changes can be modulated by brain stimulation during sleep. Last, I will study how the post-sleep changes in brain structure differ across different inter-regional connections, and whether these structural changes can predict the selective influences of sleep on different cognitive performances. Overall, this project aims to explore how sleep benefits cognition by improving brain structure for higher functionality.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £81,092
Funder: The Wellcome Trust
Recipient: Cardiff University

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £40,930
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Vacation Scholarships 2017 - Liverpool School of Tropical Medicine 16 Jun 2017

Vacation Scholarships 2017 - Liverpool School of Tropical Medicine

Developing a universal antivenom to treat snake venom-induced consumption coagulopathy 24 Feb 2016

Snakebite is a neglected tropical disease that causes ~100,000 deaths each year. Venom-induced consumption coagulopathy (VICC) is the most common, clinically important, pathology associated with snakebite. Existing antivenom treatments exhibit limited paraspecific efficacy, poor levels of antibody specificity and high incidences of adverse reactions. The aim of this project is to develop a single, pathology-specific, antivenom to be used throughout the world for treating venom-induced consumption coagulopathy caused by snakebite. The specific goals are: To identify the venom constituents that cause procoagulant bioactivities induced by different snake venoms To determine whether a panel of murine monoclonal antibodies can neutralise procoagulation irrespective of snake species To demonstrate proof of concept for humanising murine monoclonal antibodies specific to venom toxins To do so, I will first characterise the specific venom toxins found in different snake species that cause VICC using small-scale proteomics and biochemical assays. Next, I will design epitope-string immunogens to stimulate the production of antibodies specific to those toxins. I will then use a monoclonal antibody approach to generate a first of its kind, pathology specific, antivenom that will be validated pre-clinically for future worldwide use for treating VICC. Key words: snakebite, antivenom, protein, toxins, pathology, antibody

Amount: £817,821
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Integrative Neuroscience. 14 Jul 2014

Not available

Amount: £149,985
Funder: The Wellcome Trust
Recipient: Cardiff University

The functions of postsynaptic density implicated in psychiatric disorders in associative memory formation. 10 Feb 2014

Variants in the genes coding for postsynaptic density (PSD) proteins Homer1, DLG1 and DLG2 have been linked to psychopathology and schizophrenia. These proteins are functionally linked to postsynaptic glutamate receptors such asAMPA, NMDA and metabotropic glutamate receptors, and are thought to be key mediators of synaptic plasticity. Since associative learning is dependent on NMDA receptor-mediated synaptic plasticity and is impaired in several psychiatric disorders, we aim to determine the roles that PSD proteins including Homer1, DLG1 and DLG2 have in associative learning, with a view to shedding light on their part in psychiatric pathology To do this, we will a) use in situ hybridization to measure the expression of Homer1 transcription variants, Homer1a and Ania-3, DLG1 and DLG2 during key components of associative learning, including memory consolidation, recall andinhibitory learning, through the fear conditioning of adult rats. b) Use antisense­mediated knockdown of these PSD proteins before consolidation, recall and inhibitory learning, as well as knockout rodent models, to evaluate their function in processes required for associative learning. c) Administer mGiu and AMPA receptor-acting drugs to transgenic animals to investigate gene dependence in associative learning processes.

Amount: £38,873
Funder: The Wellcome Trust
Recipient: Cardiff University

Professional decision making around next generation clinical genetics. 30 Sep 2016

Over the past couple of years new genomic technologies, such as DNA microarrays and high throughout genomic sequencing, have begun to enter clinical practice in a range of conditions. While the promise of such approaches - as heralded by the NHSs 100,000 genomes project - is considerable, the challenges raised by integrating these technologies into the clinic are no less great. To a considerable extent, these challenges centre on professional decision making: these technologies produce large amounts of data, some of which is clinically relevant, some of which is not, but large amounts of which - for example so called VUSs, variants of unknown significance - are uncertain. It is this uncertainty - whether or not a specific stretch of DNA is clinically relevant - and the decision making processes that surround it, that this project will examine. The method used will be ethnographic observation and interviews with laboratory staff, clinical geneticists and other members of the mu ltidisciplinary teams that create, review and interpret this genomic data. While some similar work is taking place in the US, and some UK studies are exploring the impact of this kind of data, particularly around informing patients, there are no current studies focusing on the way professionals generate and interpret this kind of data.

Amount: £145,915
Funder: The Wellcome Trust
Recipient: Cardiff University

Neural correlates of retrieval control in human episodic memory 19 Nov 2014

It is widely assumed that control processes help to extract task-relevant information from episodic memory. Preparatory control processes are thought to facilitate this by influencing the way in which retrieval cues are processed. Neural correlates of preparatory control processes will be obtained by contrasting brain activity elicited by cues directing participants to prepare to retrieve different types of episodic information. Neural correlates of retrieval cue processing will be obtained by c ontrasting brain activity elicited by unstudied items across different episodic memory tasks. The overarching aim of the proposed research is to investigate the extent to which retrieval control processes directly impact upon successful episodic retrieval, thus extending the study of retrieval control from the correlational to the causal. Key goals will include: i) separating EEG correlates of preparatory control processes according to the accuracy of the subsequent memory judgment, then asking whether this neural activity predicts retrieval accuracy, ii) observing whether a resource depletion manipulation decreases both EEG correlates of retrieval control processes and episodic retrieval accuracy, and iii) employing EEG source localisation to identify possible neural generators of retrieval control processes, then targeting these cortical regions with transcranial magnetic stimulation (TMS) and observing the effects on episodic retrieval accuracy.

Amount: £219,932
Funder: The Wellcome Trust
Recipient: Cardiff University

Development of a model to image Plasmodium falciparum cytoadherence in vivo 08 Apr 2015

The outcome of this work will be to have tested the primary hypothesis that the efficiency of recruitment to endothelium at the vessel wall is a major component of disease in P. falciparum malaria. In addition we will understand how different endothelial receptors contribute to this recruitment and retention of IE. This research will also provide information on the impact of cytoadherence on the circulation, the local endothelial response (inflammation and signalling) and effects at the level of the tissue. Our intention is to use this data to identify specific adhesion-based therapies that target recruitment and retention of IE in the brain and develop them into products that will reduce the mortality of cerebral malaria.

Amount: £122,177
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

Supported by ISSF funding, LSTM has offered a number of competitive challenge grants to LSTM based research projects in the general area of resistance (with a focus on drugs and insecticides – RDI). These projects will need to be completed within two years (Oct 2016).The research will focus on an area relevant to RDI, will involve PIs from more than one discipline (including external partnerships with NHS Trusts, other academic groups and industry partners), and will have the potential to generate data that can leverage further competitive research funding on completion. Funding: Renewal of Gates-funded IVCC and AWOL programmes, the latter with a major component using a novel mouse model for basic and translational research Reachout consortium. funded by EU to look at strengthening health systems through close-to-community services Cookstove project in Malawi funded by MRC MRC New Investigator Award – "Is targeting vascular remodelling by filarial parasites a viable anti-morbidity solution" CouNTDown programme for NTD implementation research funded by DFID (Adams, Reimer) Health Impact: Development of innovative ‘tiny target’ control systems for tsetse flies (Torr) Discovery of a previously unidentified reservoir of Schistosoma infection in pre-school children (Adams). Introduction of intermittent preventive therapy during pregnancy as a WHO policy recommendation (Terlouw). Development and validation of a human challenge model for Streptococcus pneumonia (Glennie). Development of new monitoring and evaluation systems for malaria surveillance (Terlouw) LSTM’s improving and rapidly growing media visibility and social media presence are beneficial in creating attention for our various PE initiatives

Amount: £1,050,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Professional decision making around next generation clinical genetics. 23 Jul 2015

Over the past couple of years new genomic technologies, such as DNA microarrays and high throughout genomic sequencing, have begun to enter clinical practice in a range of conditions. While the promise of such approaches - as heralded by the NHSs 100,000 genomes project - is considerable, the challenges raised by integrating these technologies into the clinic are no less great. To a considerable extent, these challenges centre on professional decision making: these technologies produce large amounts of data, some of which is clinically relevant, some of which is not, but large amounts of which - for example so called VUSs, variants of unknown significance - are uncertain. It is this uncertainty - whether or not a specific stretch of DNA is clinically relevant - and the decision making processes that surround it, that this project will examine. The method used will be ethnographic observation and interviews with laboratory staff, clinical geneticists and other members of the mu ltidisciplinary teams that create, review and interpret this genomic data. While some similar work is taking place in the US, and some UK studies are exploring the impact of this kind of data, particularly around informing patients, there are no current studies focusing on the way professionals generate and interpret this kind of data.

Amount: £232,876
Funder: The Wellcome Trust
Recipient: Cardiff University

Conjugated Polymeric-Based Prodrug to enhance steroidal delivery into cartilages 25 Aug 2015

Osteoarthritis (OA) is the key disease focus of the project, mainly through an improvement of the currently available drugs uptake. Additionally, a more selective distribution of the drug in the cartilage will reduce the required dose; both factors contributing to a reduction of the side effects associated with the drugs. The prevalence rate for OA is 11.3% or approximately 85 million people globally. It is expected to increase from 85 million in 2009 to 122 million in 2017. The main reason for this is the high incidence rate in the elderly population and the aging population trend. In addition, a rapid increase in the obese population will also contribute to an increase of the incidence of OA.

Amount: £73,028
Funder: The Wellcome Trust
Recipient: Cardiff University

Cardiff, Integrative Neuroscience. 29 May 2015

Not available

Amount: £150,321
Funder: The Wellcome Trust
Recipient: Cardiff University

Investigating the dysregulation of gene expression in 22q11.2 deletion syndrome with human IPS and ES cells and its link to schizophrenia 30 Jan 2015

We hypothesise that 22q11.2 deletion syndrome (22q11.2DS) has an increased risk to schizophrenia and Parkinsons disease (PD) due to abnormal dopaminergic(DA) neuronal development and/or function, which is the consequence of a global dysregulation of gene expression triggered by the haploinsufficiency ofDGCR8. We will perform a comprehensive analysis of the phenotypes of DA and MSN neurons derived from 22q11.2DS induced pluripotent stem cells (iPSC), DGCR8 knock-out human embryonic stem cells (ESC), and if time permit, 22q11.2DS iPSCs overexpressing transgenic DGCR8. Moreover, we will seek further support that DGCR8 has a primary role in 22q11.2DS by analysing the dopaminergic neuron system of DGCR8 conditional knockout mice. This will provide us a unique understanding of the abnormalities caused by thedeletion and by cross-referencing our results and previous genomic studies this study will provide valuable insight to how these deficits may confer riskto schizophrenia and PD.

Amount: £34,290
Funder: The Wellcome Trust
Recipient: Cardiff University