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European experts caring for young patients with a specific type of brain cancer have – for the first time – agreed and published freely available guidance outlining how best to treat them. The guidance looks at current treatments for patients with a rare type of tumour called Central Nervous System Germ Cell Tumours – or...

Host manipulation by the parasite _Cryptosporidium_

Infection by the parasite Cryptosporidium is a leading cause of child mortality, no vaccine is available and the current drug treatment against this diarrheal pathogen is inefficient. The disease is transmitted through food or water contaminated with oocysts, the chlorine-resistant parasite stage. The parasite infects the epithelial cells of the small intestine in which it replicates intracellularly. Invasion and intracellular development require extensive modifications of the host cell that remain largely unknown at the molecular level. We recently showed that parasite secreted proteins play an important role in this process, however, our knowledge remains limited. Modifications of the enterocytes as well as persistent inflammation will alter the physiology of the gut and have long lasting impact on the children. In collaboration with Ross Waller laboratory, we conducted a proteomic experiment, hyperLOPIT, on fractionated Cryptosporidium sporozoites to identify the content of the various secretory organelles. This list of potential Cryptosporidium virulence factors will help fill important gaps in our knowledge of the host/parasite interplay.

• Speaker: Dr Amandine Guérin - Assistant Professor, Department of Microbiology and Molecular Medicine, University of Geneva, Switzerland
• Wednesday 24 April 2024, 14:00-15:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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Adrian Liston, Professor of Pathology at the University of Cambridge, talks about our extraordinary immune system ahead of his event, Diversity in the immune system on 20th March.

Cutting back malaria: CRISPR-based approaches for antimalarial target discovery

The repeated emergence of antimalarial resistance underscores the importance of identifying new drug targets, as well as understanding the genetic architecture of current resistance pathways and any associated fitness costs. We have developed several genomics-based approaches that leverage CRISPR editing of the Plasmodium falciparum genome to validate causal resistance mutations and explore the essentiality and biological function of gene families as antimalarial targets. To more efficiently determine if compounds kill the parasite via known modes-of-action, we have generated a panel of barcoded parasite lines that encompass a wide spectrum of the known Plasmodium resistome, and have miniaturised a compound-screening assay to allow semi-automated liquid handling of parasite cultures. Competitive growth of drug-resistant lines also reveals the fitness cost of resistance. To overcome a bottleneck in evolution of resistance in the lab, we have also developed “mutator” parasite lines with an elevated mutation rate to increase the genetic complexity of parasite cultures. Finally, we are exploring whether non-coding mutations, specifically in lncRNAs, might also contribute to the parasite resistome. Collectively these approaches aim to accelerate the identification and validation of potential new targets, as well as understand the breadth of the parasite response to antimalarial challenge.

• Speaker: Professor Marcus Lee - Biological Chemistry and Drug Discovery, University of Dundee
• Wednesday 20 March 2024, 14:00-15:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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Karolinska Institutet has decided to award honorary doctorates to Ashley Moffett, professor emerita at the University of Cambridge, UK, for her significant contributions to science and KI, respectively. The formal ceremony will occur at the conferment ceremony in Stockholm City Hall on 26 April. Professor Ashley Moffet is...

Expanding BioID: the nuclear pore complex of trypanosomes

Proximity labelling by a biotin ligase combined with mass spectrometry of biotin-affinity purified proteins (BioID) has become a powerful tool to investigate protein interactions in vivo in a range of organisms, including trypanosomes. We recently discovered an interesting off-label application of BioID for protein imaging by fluorescent streptavidin. We found streptavidin imaging superior to classical antibody labelling because it (i) provides a stronger signal with no loss in resolution (ii) can image proteins in phase-separated regions that are not accessible to antibodies and (iii) provides information on localization dynamics, since “historic” interactions are preserved. We have used the method, in combination with expansion microscopy, classical BioID, neural-network based in silico predictions and reverse genetics to reinvestigate the trypanosome nuclear pore complex.

• Speaker: Dr Susanne Kramer - Universität Wüerzburg - Germany.
• Wednesday 06 March 2024, 14:00-15:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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The complexed relationships of African Schistosoma species

Abstract not available

• Speaker: Dr Bonnie Webster - Natural History Museum - London
• Wednesday 28 February 2024, 14:00-15:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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Cambridge researchers will discuss their pioneering work as part of events focusing on cancer and the University’s work to help end the death and disease it causes.

Guidance on providing the best care possible for patients with a rare tumour affecting their ovaries will now be freely available to doctors worldwide. Led by Cambridge University Hospitals NHS Foundation Trust (CUH), the guidance will, for the first time, recommend the best treatment options for patients with a type of...

What is still so fascinating about the trypanosome coat?

The cell surface coat of African trypanosomes has been studied for a long time. So you could assume that all the essentials are known. However, this is not the case. In my talk, I focus on the fabric from which this coat is woven (the VGSs) and their incredible dynamics. We’ve known for 20 years that the VSG coat can be recycled quickly, and we have a good idea of why. However, how the underlying biological processes can take place at such high speeds is only gradually coming to light. We’re trying to put the puzzle together step by step. In doing so, we sometimes come across surprising insights that can shed new light on basic cell biology. That’s what I’m going to tell you about. In addition, I would like to make my talk a plea for continuing research into parasitic protozoa, whose extreme adaptations can expand our reductionist perspective on cell biology.

• Speaker: Prof Markus Engstler - Universität Wüerzburg - Germany
• Wednesday 07 February 2024, 14:00-15:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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A goat milk company is examining customers' gut health through its poo post-box scheme. Ceredigion-based Chuckling Goat has gone from selling its goat milk-based Kefir to launching a microbiome test kit with the University of Cambridge. "We basically examine everything that's happening inside the microbiome," said co-...

The recent preprint from the Atomic Virology Lab presents a fascinating discovery about how viruses can impersonate cellular proteins to aid their replication. The focus is on human cytomegalovirus (HCMV), a common virus that can cause severe disease in babies and people with weakened immune systems. For instance, if a...

Reassessing red blood cell invasion in malaria parasites

Malaria parasites rely on cycles of cellular invasion and intracellular growth to proliferate within the blood stream, a process which underpins symptoms of the disease. The cycles of cellular invasion and intracellular growthThe adaptation of P. knowlesi (Pk) to culture in human erythrocytes presents exciting opportunities to study erythrocyte invasion biology. Two major protein families have been studied extensively in P. falciparum (Pf): the erythrocyte binding-like proteins (EBPs/EBAs) and the reticulocyte binding-like proteins (RBLs/RHs). These proteins are hypothesized to have overlapping but critical roles during the invasion process. The zoonotic malaria parasite P. knowlesi, has a smaller repertoire of these proteins, and much larger and polarised invasive stages known as merozoites.

Employing a conditional knockout approach, we’ve demonstrated distinct roles for the two families at different invasion stages, including a specific role for RBL proteins in the initial identification and deformation of target host erythrocytes. Furthermore, we’ve unearthed new features that prompt a significant reassessment of invasion. Notably, we’ve discovered that Pk merozoites can engage in productive gliding motility prior to invasion, and we’ve corrected a longstanding assumption in merozoite topology – the merozoite apex is actually located in the wider end of the cell, contrary to prior beliefs. These findings unveil new aspects of this complex process and introduce fresh tools and techniques to deepen our understanding of invasion across all malaria parasite species. Finally, we will demonstrate how the new genetic tools emerging from studies in basic biology of malaria parasite can be readily adapted to facilitate vaccine, drug and diagnostics targeting a broader range of malaria parasite species.

Please note 16:00 start time for this seminar

• Speaker: Dr Robert Moon - LSHTM
• Wednesday 31 January 2024, 16:00-17:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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TBC

Abstract not available

Please note 16:00 start time for this seminar

• Speaker: Dr Robert Moon - LSHTM
• Wednesday 31 January 2024, 16:00-17:00
• Venue: Seminar Room, Tennis Court Road, Dept of Pathology..
• Series: Parasitology Seminars; organiser: Anna Protasio.

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The study, published today in Cell Stem Cell, shows that it is possible to experiment on a developing human placenta, rather than merely observe specimens, in order to study major disorders of pregnancy.

Successful pregnancy depends on the development of the placenta in the first few weeks of gestation. During this period, the placenta implants itself into the endometrium – the mucosal lining of the mother’s uterus.

Interactions between the cells of the endometrium and the cells of the placenta are critical to whether a pregnancy is successful. In particular, these interactions are essential to increase the maternal blood supply to the placenta, necessary for fetal growth and development.

When these interactions do not work properly, they can lead to complications, such as pre-eclampsia, a condition that causes high blood pressure during pregnancy. Pre-eclampsia occurs in around six in 100 first pregnancies and can put at risk the health of both the mother and the baby.

Professor Ashley Moffett from the Department of Pathology at the University of Cambridge said: “Most of the major disorders of pregnancy – pre-eclampsia, still birth, growth restriction, for example – depend on failings in the way the placenta develops in the first few weeks. This is a process that is incredibly difficult to study – the period after implantation, when the placenta embeds itself into the endometrium, is often described as a ‘black box of human development’.

“Over the past few years, many scientists – including several at Cambridge – have developed embryo-like models to help us understand early pre-implantation development. But further development is impeded because we understand so little about the interactions between the placenta and the uterus.”

Professor Moffett and colleagues at the Friedrich Miescher Institute, Switzerland, and the Wellcome Sanger Institute, Cambridge, have used ‘mini-placentas’ – a cellular model of the early stages of the placenta – to provide a window into early pregnancy and help improve our understanding of reproductive disorders. Known as ‘trophoblast organoids’, these are grown from placenta cells and model the early placenta so closely that they have previously been shown to record a positive response on an over-the-counter pregnancy test.

In previous work, Professor Moffett and colleagues identified genes that increase the risk of or protect against conditions such as pre-eclampsia. These highlighted the important role of immune cells uniquely found in the uterus, known as ‘uterine natural killer cells’, which cluster in the lining of the womb at the site where the placenta implants. These cells mediate the interactions between the endometrium and the cells of the placenta.

In their new study, her team applied proteins secreted by the uterine natural killer cells to the trophoblast organoids so that they could mimic the conditions where the placenta implants itself. They identified particular proteins that were crucial to helping the organoids develop. These proteins will contribute to successful implantation, allowing the placenta to invade the uterus and transform the mother’s arteries.

“This is the only time that we know of where a normal cell invades and transforms an artery, and these cells are coming from another individual, the baby,” said Professor Moffett, who is also a Fellow at King’s College, Cambridge.

“If the cells aren’t able to invade properly, the arteries in the womb don’t open up and so the placenta – and therefore the baby – are starved of nutrients and oxygen. That's why you get problems later on in pregnancy, when there just isn't enough blood to feed the baby and it either dies or is very tiny.”

The researchers also found several genes that regulate blood flow and help with this implantation, which Professor Moffett says provide pointers for future research to better understand pre-eclampsia and similar disorders.

Dr Margherita Turco, from the Friedrich Miescher Institute in Switzerland and co-lead of this work, added: “Despite affecting millions of women a year worldwide, we still understand very little about pre-eclampsia. Women usually present with pre-eclampsia at the end of pregnancy, but really to understand it – to predict it and prevent it – we have to look at what's happening in the first few weeks.

“Using ‘mini-placentas’, we can do just that, providing clues as to how and why pre-eclampsia occurs. This has helped us unpick some of the key processes that we should now focus on far more. It shows the power of basic science in helping us understand our fundamental biology, something that we hope will one day make a major difference to the health of mothers and their babies.”

The research was supported by Wellcome, the Royal Society, European Research Council and Medical Research Council.

Reference
Li, Q et al. Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell; 17 Jan 2024; DOI: doi.org/10.1016/j.stem.2023.12.013

Scientists have grown ‘mini-placentas’ in the lab and used them to shed light on how the placenta develops and interacts with the inner lining of the womb – findings that could help scientists better understand and, in future, potentially treat pre-eclampsia.

Most of the major disorders of pregnancy – pre-eclampsia, still birth, growth restriction, for example – depend on failings in the way the placenta develops in the first few weeks. This is a process that is incredibly difficult to study.Ashley MoffettFriedrich Miescher Institute/University of CambridgePlacental organoid (circle in the centre). Trophoblast cells are invading out of the organoid, mimicking placental cells invading the uterus in the early weeks of pregnancy.

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Scientists have grown ‘mini-placentas’ in the lab and used them to shed light on how the placenta develops and interacts with the inner lining of the womb – findings that could help scientists better understand and, in future, potentially treat pre-eclampsia. The study , published today in Cell Stem Cell by Professor...