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Therapeutic manipulations of phosphatases and kinases controlling protein quality control systems: From the bench, to the clinic and back

The deposition of misfolded proteins is a defining feature of many age-dependent human diseases, including the increasingly prevalent neurodegenerative diseases. Why aggregation-prone proteins accumulate in aged cells remains largely unclear. Cells normally strive to ensure that proteins get correctly folded and have powerful and sophisticated mechanisms to maintain protein homeostasis (proteostasis) under adverse conditions. However, with age and in diseases, the cellular defence systems against misfolded proteins are overwhelmed, leading to the accumulation of misfolded proteins with devastating consequences for cells and organism. In principle, improving the cells’ ability to deal with misfolded proteins could represent a generic approach to reduce the pathology in diverse protein misfolding diseases. My lab has identified powerful small drug-like molecules that safely boost a natural defence system against misfolded. These small molecules inhibit serine/threonine phosphatases controlling the termination of a proteostatic pathway, an interesting finding because phosphatases were previously thought to be undruggable. The inhibitors have demonstrated therapeutic effects in various models of neurodegenerative diseases. This work demonstrates that generic approaches aimed at helping cells to survive protein quality control failures can be useful to prevent protein misfolding diseases, including the devastating neurodegenerative diseases. One of these inhibitors, Sephin1, has passed through favourable Phase 1 clinical trials in 2019 and is being now developed for Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. In 2011, Guanabenz was found beneficial in a phase 2 clinical trial in ALS , 10 years after we reported its proteostasis-boosting activity.

The work on these inhibitors has perked our interest in serine/threonine phosphatases, a class of very important yet poorly characterized enzymes. In a recent tour de force, we have deployed a combination of approaches to elucidate the mechanism by which an eIF2 phosphatase recruits its large substrate.

Expanding our toolbox, we recently made the unexpected discovery that broadly used ATP -competitive inhibitors of eIF2 kinases can paradoxically increase eIF2 phosphorylation by directly binding to and activating a sister kinase resulting in functional activation of the pathway rather than the intended inhibition. These findings have broad relevance to kinases.

• Speaker: Anne Bertolotti
• Friday 09 February 2024, 15:00-16:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Therapeutic manipulations of phosphatases and kinases controlling protein quality control systems: From the bench, to the clinic and back

The deposition of misfolded proteins is a defining feature of many age-dependent human diseases, including the increasingly prevalent neurodegenerative diseases. Why aggregation-prone proteins accumulate in aged cells remains largely unclear. Cells normally strive to ensure that proteins get correctly folded and have powerful and sophisticated mechanisms to maintain protein homeostasis (proteostasis) under adverse conditions. However, with age and in diseases, the cellular defence systems against misfolded proteins are overwhelmed, leading to the accumulation of misfolded proteins with devastating consequences for cells and organism. In principle, improving the cells’ ability to deal with misfolded proteins could represent a generic approach to reduce the pathology in diverse protein misfolding diseases. My lab has identified powerful small drug-like molecules that safely boost a natural defence system against misfolded. These small molecules inhibit serine/threonine phosphatases controlling the termination of a proteostatic pathway, an interesting finding because phosphatases were previously thought to be undruggable. The inhibitors have demonstrated therapeutic effects in various models of neurodegenerative diseases. This work demonstrates that generic approaches aimed at helping cells to survive protein quality control failures can be useful to prevent protein misfolding diseases, including the devastating neurodegenerative diseases. One of these inhibitors, Sephin1, has passed through favourable Phase 1 clinical trials in 2019 and is being now developed for Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. In 2011, Guanabenz was found beneficial in a phase 2 clinical trial in ALS , 10 years after we reported its proteostasis-boosting activity.

The work on these inhibitors has perked our interest in serine/threonine phosphatases, a class of very important yet poorly characterized enzymes. In a recent tour de force, we have deployed a combination of approaches to elucidate the mechanism by which an eIF2 phosphatase recruits its large substrate.

Expanding our toolbox, we recently made the unexpected discovery that broadly used ATP -competitive inhibitors of eIF2 kinases can paradoxically increase eIF2 phosphorylation by directly binding to and activating a sister kinase resulting in functional activation of the pathway rather than the intended inhibition. These findings have broad relevance to kinases.

• Speaker: Anne Bertolotti
• Friday 09 February 2024, 15:00-16:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

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.

The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

The international team, led by the University of Cambridge, used the NASA/ESA/CSA James Webb Space Telescope (JWST) to detect the black hole, which dates from 400 million years after the big bang, more than 13 billion years ago. The results, which lead author Professor Roberto Maiolino says are “a giant leap forward”, are reported in the journal Nature.

That this surprisingly massive black hole – a few million times the mass of our Sun – even exists so early in the universe challenges our assumptions about how black holes form and grow. Astronomers believe that the supermassive black holes found at the centre of galaxies like the Milky Way grew to their current size over billions of years. But the size of this newly-discovered black hole suggests that they might form in other ways: they might be ‘born big’ or they can eat matter at a rate that’s five times higher than had been thought possible.

According to standard models, supermassive black holes form from the remnants of dead stars, which collapse and may form a black hole about a hundred times the mass of the Sun. If it grew in an expected way, this newly-detected black hole would take about a billion years to grow to its observed size. However, the universe was not yet a billion years old when this black hole was detected.

“It’s very early in the universe to see a black hole this massive, so we’ve got to consider other ways they might form,” said Maiolino, from Cambridge’s Cavendish Laboratory and Kavli Institute for Cosmology. “Very early galaxies were extremely gas-rich, so they would have been like a buffet for black holes.”

Like all black holes, this young black hole is devouring material from its host galaxy to fuel its growth. Yet, this ancient black hole is found to gobble matter much more vigorously than its siblings at later epochs.

The young host galaxy, called GN-z11, glows from such an energetic black hole at its centre. Black holes cannot be directly observed, but instead they are detected by the tell-tale glow of a swirling accretion disc, which forms near the edges of a black hole. The gas in the accretion disc becomes extremely hot and starts to glow and radiate energy in the ultraviolet range. This strong glow is how astronomers are able to detect black holes.

GN-z11 is a compact galaxy, about one hundred times smaller than the Milky Way, but the black hole is likely harming its development. When black holes consume too much gas, it pushes the gas away like an ultra-fast wind. This ‘wind’ could stop the process of star formation, slowly killing the galaxy, but it will also kill the black hole itself, as it would also cut off the black hole’s source of ‘food’.

Maiolino says that the gigantic leap forward provided by JWST makes this the most exciting time in his career. “It’s a new era: the giant leap in sensitivity, especially in the infrared, is like upgrading from Galileo’s telescope to a modern telescope overnight,” he said. “Before Webb came online, I thought maybe the universe isn’t so interesting when you go beyond what we could see with the Hubble Space Telescope. But that hasn’t been the case at all: the universe has been quite generous in what it’s showing us, and this is just the beginning.”

Maiolino says that the sensitivity of JWST means that even older black holes may be found in the coming months and years. Maiolino and his team are hoping to use future observations from JWST to try to find smaller ‘seeds’ of black holes, which may help them untangle the different ways that black holes might form: whether they start out large or they grow fast.

The research was supported in part by the European Research Council, the Royal Society, and the Science and Technology Facilities Council (STFC), part of UK Research and Innovation (UKRI).

 

Reference:
Roberto Maiolino et al. ‘A small and vigorous black hole in the early Universe.’ Nature (2024). DOI: 10.1038/s41586-024-07052-5

Researchers have discovered the oldest black hole ever observed, dating from the dawn of the universe, and found that it is ‘eating’ its host galaxy to death.

It’s a new era: the giant leap in sensitivity, especially in the infrared, is like upgrading from Galileo’s telescope to a modern telescope overnightRoberto MaiolinoNASA, ESA, and P. Oesch (Yale University)The GN-z11 galaxy, taken by the Hubble Space Telescope

The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

YesLicence type: Public Domain

Large-scale genetic analysis has helped researchers uncover the interplay between cancer-driving genetic mutations and inherited genetic variants in a rare type of blood cancer.

Researchers from the University of Cambridge, Wellcome Sanger Institute, and collaborators, combined various comprehensive data sets to understand the impact of both cancer-driving spontaneous mutations and inherited genetic variation on the risk of developing myeloproliferative neoplasms (MPN).

The study, published today in the journal Nature Genetics, describes how inherited genetic variants can influence whether a spontaneous mutation in a particular gene increases the risk of developing this rare blood cancer.

This analysis has an impact on current clinical predictions of disease development in individuals. Further research is required to understand the biological mechanisms behind how these inherited genetic variants influence the chances of developing rare blood cancer. In the future, this knowledge could aid drug development and interventions that reduce the risk of disease.

Myeloproliferative neoplasms, MPNs, are a group of rare, chronic, blood cancers. There are around 4,000 cases of MPN in the UK each year. These occur when the bone marrow overproduces blood cells, which can result in blood clots and bleeding. MPNs can also progress into other forms of blood cancer, such as leukaemia.

In the population, there is a large amount of natural variation between individuals’ blood cells, which can affect the amount of blood cells a person has and their particular traits. This is because multiple different genes can influence blood cell features in an individual. During routine blood tests, researchers take known information about these genes and analyse the variation to give a genetic risk score, which is how likely that individual is to develop a disease over their lifetime.  

MPNs have been linked to random somatic mutations in certain genes including in a gene called JAK2. However, mutated JAK2 is commonly found in the global population, and the vast majority of these individuals do not have or go on to develop MPN.

Whilst previous studies have identified over a dozen associated inherited genetic variants that increase the risk of MPN, these studies insufficiently explain why most individuals in the population do not go on to develop MPN.

This new study, from the Wellcome Sanger Institute and collaborators, combined information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN.

They found that the inherited variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will go on to cause MPN.  They also found that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, thus, mimicking disease.

Dr Jing Guo, from the University of Cambridge and the Wellcome Sanger Institute and first author of the study, said: “Our large-scale statistical study has helped fill the knowledge gaps in how variants in DNA, both inherited and somatic, interact to influence complex disease risk. By combining these three different types of datasets we were able to get a more complete picture of how these variants combine to cause blood disorders.”

Professor Nicole Soranzo, co-senior author from the University of Cambridge, the Wellcome Sanger Institute, and Human Technopole, Italy, said: “There has been increasing realisation that human diseases have complex causes involving a combination of common and rare inherited genetic variants with different severity.

“We have previously shown that variation in blood cell parameters and function has complex genetic variability by highlighting thousands of genetic changes that affect different gene functions. Here, we show for the first time that common variants in these genes also affect blood cancers, independent of causative somatic mutations. This confirms a new important contribution of normal variability beyond complex disease, contributing to our understanding of myeloproliferative neoplasms and blood cancer more generally.”

Dr Jyoti Nangalia, co-senior author from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, and the Wellcome Sanger Institute, said: “We have a good understanding of the genetic causes of myeloproliferative neoplasms. In fact, many of these genetic mutations are routine diagnostic tests in the clinic. However, these mutations can often be found in healthy individuals without the disease.

“Our study helps us understand how inherited DNA variation from person to person can interact with cancer-causing mutations to determine whether disease occurs in the first place, and how this can alter the type of any subsequent disease that emerges. Our hope is that this information can be incorporated into future disease prediction efforts.”  

This research was funded by Cancer Research UK and Wellcome.

Reference

J. Guo, K. Walter, P. M. Quiros, et al. ‘Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.’ Jan 2024,  Nature Genetics. DOI: 10.1038/s41588-023-01638-x

Adapted from a press release by the Wellcome Sanger Institute

Combining three different sources of genetic information has allowed researchers to further understand why only some people with a common mutation go on to develop rare blood cancer

Our hope is that this information can be incorporated into future disease prediction effortsJyoti NangaliaPhoto by Sangharsh Lohakare on UnsplashDNA

The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

YesLicence type: Attribution-Noncommerical

The findings, published today in The Lancet, suggest that more than 7,000 hospitalisations and deaths might have been averted in summer 2022 if the UK had had better vaccine coverage.

With COVID-19 cases on the rise and a new variant strain recently identified, this research provides a timely insight into vaccine uptake and hesitancy and could inform policy-makers.

The research relied on secure access to anonymised health data for everyone in all four nations of the UK, an advance which has only become possible during the pandemic.

Co-author Angela Wood, Professor of Health Data Science at the Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge and Associate Director of the British Heart Foundation Data Science Centre said: “This is the first epidemiological study to use individual-level anonymised health data covering the entire UK population. We have created a detailed, UK-wide picture of who is under-vaccinated against COVID-19 and the associated risks of under-vaccination.

“These results can be used to help create health policy and public health interventions to improve vaccine uptake. This approach could be extended to many other areas of medicine with great potential for new discoveries in the understanding and treatment of disease.”

Early COVID-19 vaccine rollout began strongly in the UK, with over 90% of the population over the age of 12 vaccinated with at least one dose by January 2022. However, rates of subsequent booster doses across the UK were not fully understood until now.

Scientists from England, Scotland, Northern Ireland and Wales – led by Health Data Research UK (HDR UK) and the University of Edinburgh – studied securely-held, routinely collected NHS data from everyone over five years of age during 1 June to 30 September 2022. All data was de-identified and available only to approved researchers.

Data from across the four countries was then pooled and harmonised, a feat that was not possible until now. People were grouped by vaccine status, with under-vaccination defined as not having had all doses of a vaccine for which that a person was eligible.

The findings reveal that the proportion of people who were under-vaccinated on 1 June 2022 ranged between one third and one half of the population – 45.7% for England, 49.8% for Northern Ireland, 34.2% for Scotland and 32.8% Wales.

Mathematical modelling indicated that 7,180 hospitalisations and deaths out of around 40,400 severe COVID-19 outcomes during four months in summer 2022 might have been averted, if the UK population was fully vaccinated.

Under-vaccination was related to significantly more hospitalisations and deaths across all age groups studied, with under-vaccinated people over 75 more than twice as likely to have a severe COVID-19 outcome than those who were fully protected.

The highest rates of under-vaccination were found in younger people, men, people in areas of higher deprivation, and people of non-white ethnicity.

Researchers say the study – the largest ever study carried out in the UK – also ushers in a new era for UK science by overcoming challenges in uniting NHS data that is gathered and stored in different ways between devolved nations.

Professor Cathie Sudlow, Chief Scientist at Health Data Research UK and Director of the British Heart Foundation (BHF) Data Science Centre, said: “The infrastructure now exists to make full use of the potential of routinely collected data in the NHS across the four nations of the UK. We believe that we could and should extend these approaches to many other areas of medicine, such as cancer, heart disease and diabetes to search for better understanding, prevention and treatment of disease."

Professor Sir Aziz Sheikh, Director of the Usher Institute at the University of Edinburgh, HDR UK Research Director and study co-lead, said: “Large-scale data studies have been critical to pandemic management, allowing scientists to make policy-relevant findings at speed. COVID-19 vaccines save lives. As new variants emerge, this study will help to pinpoint groups of our society and areas of the country where public health campaigns should be focused and tailored for those communities.”

Reference
HDR UK COALESCE Consortium. Undervaccination and severe COVID-19 outcomes: meta-analysis of national cohort studies in England, Northern Ireland, Scotland, and Wales. Lancet; 16 Jan 2024; DOI: 0.1016/S0140-6736(23)02622-3

Adapted from a release from HDR-UK

Between a third and a half of the populations of the four UK nations had not had the recommended number of COVID vaccinations and boosters by summer 2022, according to the first research study to look at COVID-19 vaccine coverage of the entire UK population.

These results can be used to help create health policy and public health interventions to improve vaccine uptakeAngela WoodKoldoyChris (Getty Images)Girl being injected with COVID-19 vaccine

The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Airway Biology at the Nanoscale

A significant frontier in Spatial Biology is the construction of an integrated view of tissue function within its native environment at the cellular and molecular levels. In this seminar, we will explore how the combination of nanometre-scale imaging modalities, AI segmentation algorithms, and protein-protein interaction mapping in human tissue models is providing a novel perspective on airway biology and creating opportunities for translational medicine research. The primary focus will be on the respiratory epithelium, a critical tissue that safeguards our lungs by serving as the first line of defence against bacteria, viruses, and particulate matter. We will provide examples illustrating how this multimodal spatial biology approach is revealing the molecular mechanisms underlying airway protection from pathogens.

• Speaker: Vito Mannella
• Tuesday 06 February 2024, 12:00-13:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Airway Biology at the Nanoscale

A significant frontier in Spatial Biology is the construction of an integrated view of tissue function within its native environment at the cellular and molecular levels. In this seminar, we will explore how the combination of nanometre-scale imaging modalities, AI segmentation algorithms, and protein-protein interaction mapping in human tissue models is providing a novel perspective on airway biology and creating opportunities for translational medicine research. The primary focus will be on the respiratory epithelium, a critical tissue that safeguards our lungs by serving as the first line of defence against bacteria, viruses, and particulate matter. We will provide examples illustrating how this multimodal spatial biology approach is revealing the molecular mechanisms underlying airway protection from pathogens.

• Speaker: Vito Mannella
• Tuesday 06 February 2024, 12:00-13:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Reciprocal gut/body interactions in health and disease

The adult intestine is a major barrier epithelium and coordinator of multi-organ functions. Stem cells constantly repair the intestinal epithelium by adjusting their proliferation and differentiation to tissue intrinsic as well as micro- and macro-environmental signals. How these signals integrate to control intestinal and whole-body homeostasis is largely unknown. Addressing this gap in knowledge is central to an improved understanding of intestinal pathophysiology and its systemic consequences. Combining Drosophila and mammalian model systems my laboratory studies fundamental mechanisms driving intestinal regeneration and tumourigenesis including complex inter-organ signaling, which I will discuss during my seminar including: 1- Interactions between the intestine and its microenvironment influencing intestinal regeneration and tumourigenesis. 2- Impact of changes in intestinal homeostasis to whole-body physiology.

• Speaker: Julia Cordero
• Tuesday 30 January 2024, 12:00-13:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Reciprocal gut/body interactions in health and disease

The adult intestine is a major barrier epithelium and coordinator of multi-organ functions. Stem cells constantly repair the intestinal epithelium by adjusting their proliferation and differentiation to tissue intrinsic as well as micro- and macro-environmental signals. How these signals integrate to control intestinal and whole-body homeostasis is largely unknown. Addressing this gap in knowledge is central to an improved understanding of intestinal pathophysiology and its systemic consequences. Combining Drosophila and mammalian model systems my laboratory studies fundamental mechanisms driving intestinal regeneration and tumourigenesis including complex inter-organ signaling, which I will discuss during my seminar including: 1- Interactions between the intestine and its microenvironment influencing intestinal regeneration and tumourigenesis. 2- Impact of changes in intestinal homeostasis to whole-body physiology.

• Speaker: Julia Cordero
• Tuesday 30 January 2024, 12:00-13:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Adaptation of the cytoskeleton for pathogenicity in the malaria parasite

To ensure disease transmission, the malaria parasite undergoes multiple rounds of metamorphosis, as it entirely alters its cell morphology to promote uptake and establishment in the mosquito vector and human host. Two cytoskeletal components play essential roles in this process: microtubules and actin.

Within each new ecological niche, microtubules drive the single-celled parasite’s successive cellular transformations. Microtubules have been studied extensively and their architecture and composition are established to be highly conserved. Using focussed ion beam milling and electron cryo tomography, we recently studied distinct stages in the Plasmodium falciparum life cycle. This revealed that the parasite has microtubules which are evolved to undertake specific roles in each life cycle stage with structures that are strikingly different from the well-studied canonical microtubules in vertebrates.

While unique microtubules drive cellular transformations, filamentous actin ensures several parasite stages can migrate between different niches. These stages utilise a unique form of motility, termed gliding motility, which relies on a specialised actomyosin motor system. Our recent work on actively gliding parasites sheds light on this process and highlights novel roles of parasite actin in other cellular locations. Together, this work provides unanticipated insights into adaptations of the parasite’s cytoskeleton, highlighting areas of novelty where the parasite has diverged from the biology of the host.

• Speaker: Josie Ferreira
• Tuesday 23 January 2024, 12:00-13:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Adaptation of the cytoskeleton for pathogenicity in the malaria parasite

To ensure disease transmission, the malaria parasite undergoes multiple rounds of metamorphosis, as it entirely alters its cell morphology to promote uptake and establishment in the mosquito vector and human host. Two cytoskeletal components play essential roles in this process: microtubules and actin.

Within each new ecological niche, microtubules drive the single-celled parasite’s successive cellular transformations. Microtubules have been studied extensively and their architecture and composition are established to be highly conserved. Using focussed ion beam milling and electron cryo tomography, we recently studied distinct stages in the Plasmodium falciparum life cycle. This revealed that the parasite has microtubules which are evolved to undertake specific roles in each life cycle stage with structures that are strikingly different from the well-studied canonical microtubules in vertebrates.

While unique microtubules drive cellular transformations, filamentous actin ensures several parasite stages can migrate between different niches. These stages utilise a unique form of motility, termed gliding motility, which relies on a specialised actomyosin motor system. Our recent work on actively gliding parasites sheds light on this process and highlights novel roles of parasite actin in other cellular locations. Together, this work provides unanticipated insights into adaptations of the parasite’s cytoskeleton, highlighting areas of novelty where the parasite has diverged from the biology of the host.

• Speaker: Josie Ferreira
• Tuesday 23 January 2024, 12:00-13:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Department of Biochemistry - Tea Club Seminars; organiser: reception.

Add to your calendar or Include in your list

Predicting how molecules will react is vital for the discovery and manufacture of new pharmaceuticals, but historically this has been a trial-and-error process, and the reactions often fail. To predict how molecules will react, chemists usually simulate electrons and atoms in simplified models, a process that is computationally expensive and often inaccurate.

Now, researchers from the University of Cambridge have developed a data-driven approach, inspired by genomics, where automated experiments are combined with machine learning to understand chemical reactivity, greatly speeding up the process. They’ve called their approach, which was validated on a dataset of more than 39,000 pharmaceutically relevant reactions, the chemical ‘reactome’.

Their results, reported in the journal Nature Chemistry, are the product of a collaboration between Cambridge and Pfizer.

“The reactome could change the way we think about organic chemistry,” said Dr Emma King-Smith from Cambridge’s Cavendish Laboratory, the paper’s first author. “A deeper understanding of the chemistry could enable us to make pharmaceuticals and so many other useful products much faster. But more fundamentally, the understanding we hope to generate will be beneficial to anyone who works with molecules.”

The reactome approach picks out relevant correlations between reactants, reagents, and performance of the reaction from the data, and points out gaps in the data itself. The data is generated from very fast, or high throughput, automated experiments.

“High throughput chemistry has been a game-changer, but we believed there was a way to uncover a deeper understanding of chemical reactions than what can be observed from the initial results of a high throughput experiment,” said King-Smith.

“Our approach uncovers the hidden relationships between reaction components and outcomes,” said Dr Alpha Lee, who led the research. “The dataset we trained the model on is massive – it will help bring the process of chemical discovery from trial-and-error to the age of big data.”

In a related paper, published in Nature Communications, the team developed a machine learning approach that enables chemists to introduce precise transformations to pre-specified regions of a molecule, enabling faster drug design.

The approach allows chemists to tweak complex molecules – like a last-minute design change – without having to make them from scratch. Making a molecule in the lab is typically a multi-step process, like building a house. If chemists want to vary the core of a molecule, the conventional way is to rebuild the molecule, like knocking the house down and rebuilding from scratch. However, core variations are important to medicine design.

A class of reactions, known as late-stage functionalisation reactions, attempts to directly introduce chemical transformations to the core, avoiding the need to start from scratch. However, it is challenging to make late-stage functionalisation selective and controlled – there are typically many regions of the molecules that can react, and it is difficult to predict the outcome.

“Late-stage functionalisations can yield unpredictable results and current methods of modelling, including our own expert intuition, isn't perfect,” said King-Smith. “A more predictive model would give us the opportunity for better screening.”

The researchers developed a machine learning model that predicts where a molecule would react, and how the site of reaction vary as a function of different reaction conditions. This enables chemists to find ways to precisely tweak the core of a molecule.

“We trained the model on a large body of spectroscopic data – effectively teaching the model general chemistry – before fine-tuning it to predict these intricate transformations,” said King-Smith. This approach allowed the team to overcome the limitation of low data: there are relatively few late-stage functionalisation reactions reported in the scientific literature. The team experimentally validated the model on a diverse set of drug-like molecules and was able to accurately predict the sites of reactivity under different conditions.

“The application of machine learning to chemistry is often throttled by the problem that the amount of data is small compared to the vastness of chemical space,” said Lee. “Our approach – designing models that learn from large datasets that are similar but not the same as the problem we are trying to solve – resolves this fundamental low-data challenge and could unlock advances beyond late-stage functionalisation.”  

The research was supported in part by Pfizer and the Royal Society.

References:
Emma King-Smith et al. ‘Predictive Minisci Late Stage Functionalization with Transfer Learning.’ Nature Communications (2023). DOI: 10.1038/s41467-023-42145-1

Emma King-Smith et al. ‘Probing the Chemical "Reactome" with High Throughput Experimentation Data.’ Nature Chemistry (2023). DOI: 10.1038/s41557-023-01393-w

Researchers have developed a platform that combines automated experiments with AI to predict how chemicals will react with one another, which could accelerate the design process for new drugs.

A deeper understanding of the chemistry could enable us to make pharmaceuticals and so many other useful products much faster. Emma King-SmithBlackJack3D via Getty ImagesDigital Molecular Structure Concept

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Modelling optimal intervention strategies for animal diseases in data poor settings

Abstract: Emerging diseases of livestock can devastate the agricultural industry and have a severe impact upon livestock exports. It is therefore vital to provide tools to assess the risk associated with infectious diseases and establish surveillance and intervention protocols that will reduce the cost of such outbreaks in the future. In this presentation, I will discuss the role of infectious disease models in supporting contingency planning for livestock disease outbreaks. These models typically require data on locations, sizes and species compositions of farms, as well as detailed information on any animals that are infected with the disease. However, in many settings such data are not available. I will therefore demonstrate how models can support infectious disease control in settings where such detailed data are not accessible and how surveillance resources should be targeted to reduce model uncertainty and provide accurate predictions regarding the future spread of disease.

Bio: Prof. Mike Tildesley is a Professor of Infectious Disease Modelling at the University of Warwick. He has an interest in the predictive power of models in the early stages of emerging disease outbreaks and in communicating modelling results to policy advisors. He has extensive experience of modelling livestock disease systems, including Foot-and-Mouth Disease (FMD) and Highly Pathogenic Avian Influenza (HPAI). Prof. Tildesley has advised the UK Government’s Department for the Environment, Food and Rural Affairs, the US Department of Agriculture and the Food and Agriculture Organisation of the United Nations about strategies for control of livestock diseases including FMD and HPAI . From March 2020 to March 2022, He was a member of the Scientific Pandemic Influenza Modelling Operational group (SPI-M-O), and worked extensively on COVID -19, providing policy advice to the UK government.

This talk will be streamed and will be accessible remotely once it has started, with raven login here: https://cambridgelectures.cloud.panopto.eu/Panopto/Pages/Sessions/List.aspx#folderID=%220c72d750-7bc0-4938-88f2-ae7c00b8c25d%22

• Speaker: Professor Mike Tildesley, Professor of Infectious Disease Modelling, University of Warwick
• Friday 19 January 2024, 12:00-13:00
• Venue: LT2.
• Series: Departmental Seminar Programme, Department of Veterinary Medicine; organiser: Fiona Roby.

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Modelling optimal intervention strategies for animal diseases in data poor settings

Abstract: Emerging diseases of livestock can devastate the agricultural industry and have a severe impact upon livestock exports. It is therefore vital to provide tools to assess the risk associated with infectious diseases and establish surveillance and intervention protocols that will reduce the cost of such outbreaks in the future. In this presentation, I will discuss the role of infectious disease models in supporting contingency planning for livestock disease outbreaks. These models typically require data on locations, sizes and species compositions of farms, as well as detailed information on any animals that are infected with the disease. However, in many settings such data are not available. I will therefore demonstrate how models can support infectious disease control in settings where such detailed data are not accessible and how surveillance resources should be targeted to reduce model uncertainty and provide accurate predictions regarding the future spread of disease.

Bio: Prof. Mike Tildesley is a Professor of Infectious Disease Modelling at the University of Warwick. He has an interest in the predictive power of models in the early stages of emerging disease outbreaks and in communicating modelling results to policy advisors. He has extensive experience of modelling livestock disease systems, including Foot-and-Mouth Disease (FMD) and Highly Pathogenic Avian Influenza (HPAI). Prof. Tildesley has advised the UK Government’s Department for the Environment, Food and Rural Affairs, the US Department of Agriculture and the Food and Agriculture Organisation of the United Nations about strategies for control of livestock diseases including FMD and HPAI . From March 2020 to March 2022, He was a member of the Scientific Pandemic Influenza Modelling Operational group (SPI-M-O), and worked extensively on COVID -19, providing policy advice to the UK government.

This talk will be streamed and will be accessible remotely once it has started, with raven login here: https://cambridgelectures.cloud.panopto.eu/Panopto/Pages/Sessions/List.aspx#folderID=%220c72d750-7bc0-4938-88f2-ae7c00b8c25d%22

• Speaker: Professor Mike Tildesley, Professor of Infectious Disease Modelling, University of Warwick
• Friday 19 January 2024, 12:00-13:00
• Venue: LT2.
• Series: Departmental Seminar Programme, Department of Veterinary Medicine; organiser: Fiona Roby.

Add to your calendar or Include in your list

Lancet Microbe. 2024 Feb;5(2):e151-e163. doi: 10.1016/S2666-5247(23)00297-5. Epub 2024 Jan 11.

ABSTRACT

BACKGROUND: DNA sequencing could become an alternative to in vitro antibiotic susceptibility testing (AST) methods for determining antibiotic resistance by detecting genetic determinants associated with decreased antibiotic susceptibility. Here, we aimed to assess and improve the accuracy of antibiotic resistance determination from Enterococcus faecium genomes for diagnosis and surveillance purposes.

METHODS: In this retrospective diagnostic accuracy study, we first conducted a literature search in PubMed on Jan 14, 2021, to compile a catalogue of genes and mutations predictive of antibiotic resistance in E faecium. We then evaluated the diagnostic accuracy of this database to determine susceptibility to 12 different, clinically relevant antibiotics using a diverse population of 4382 E faecium isolates with available whole-genome sequences and in vitro culture-based AST phenotypes. Isolates were obtained from various sources in 11 countries worldwide between 2000 and 2018. We included isolates tested with broth microdilution, Vitek 2, and disc diffusion, and antibiotics with at least 50 susceptible and 50 resistant isolates. Phenotypic resistance was derived from raw minimum inhibitory concentrations and measured inhibition diameters, and harmonised primarily using the breakpoints set by the European Committee on Antimicrobial Susceptibility Testing. A bioinformatics pipeline was developed to process raw sequencing reads, identify antibiotic resistance genetic determinants, and report genotypic resistance. We used our curated database, as well as ResFinder, AMRFinderPlus, and LRE-Finder, to assess the accuracy of genotypic predictions against phenotypic resistance.

FINDINGS: We curated a catalogue of 228 genetic markers involved in resistance to 12 antibiotics in E faecium. Very accurate genotypic predictions were obtained for ampicillin (sensitivity 99·7% [95% CI 99·5-99·9] and specificity 97·9% [95·8-99·0]), ciprofloxacin (98·0% [96·4-98·9] and 98·8% [95·9-99·7]), vancomycin (98·8% [98·3-99·2] and 98·8% [98·0-99·3]), and linezolid resistance (after re-testing false negatives: 100·0% [90·8-100·0] and 98·3% [97·8-98·7]). High sensitivity was obtained for tetracycline (99·5% [99·1-99·7]), teicoplanin (98·9% [98·4-99·3]), and high-level resistance to aminoglycosides (97·7% [96·6-98·4] for streptomycin and 96·8% [95·8-97·5] for gentamicin), although at lower specificity (60-90%). Sensitivity was expectedly low for daptomycin (73·6% [65·1-80·6]) and tigecycline (38·3% [27·1-51·0]), for which the genetic basis of resistance is not fully characterised. Compared with other antibiotic resistance databases and bioinformatic tools, our curated database was similarly accurate at detecting resistance to ciprofloxacin and linezolid and high-level resistance to streptomycin and gentamicin, but had better sensitivity for detecting resistance to ampicillin, tigecycline, daptomycin, and quinupristin-dalfopristin, and better specificity for ampicillin, vancomycin, teicoplanin, and tetracycline resistance. In a validation dataset of 382 isolates, similar or improved diagnostic accuracies were also achieved.

INTERPRETATION: To our knowledge, this work represents the largest published evaluation to date of the accuracy of antibiotic susceptibility predictions from E faecium genomes. The results and resources will facilitate the adoption of whole-genome sequencing as a tool for the diagnosis and surveillance of antimicrobial resistance in E faecium. A complete characterisation of the genetic basis of resistance to last-line antibiotics, and the mechanisms mediating antibiotic resistance silencing, are needed to close the remaining sensitivity and specificity gaps in genotypic predictions.

FUNDING: Wellcome Trust, UK Department of Health, British Society for Antimicrobial Chemotherapy, Academy of Medical Sciences and the Health Foundation, Medical Research Council Newton Fund, Vietnamese Ministry of Science and Technology, and European Society of Clinical Microbiology and Infectious Disease.

PMID:38219758 | DOI:10.1016/S2666-5247(23)00297-5

Lancet Microbe. 2024 Feb;5(2):e142-e150. doi: 10.1016/S2666-5247(23)00292-6. Epub 2024 Jan 11.

ABSTRACT

BACKGROUND: The effect of antibiotic usage on the success of multidrug-resistant (MDR) clones in a population remains unclear. With this genomics-based molecular epidemiology study, we aimed to investigate the contribution of antibiotic use to Escherichia coli clone success, relative to intra-strain competition for colonisation and infection.

METHODS: We sequenced all the available E coli bloodstream infection isolates provided by the British Society for Antimicrobial Chemotherapy (BSAC) from 2012 to 2017 (n=718) and combined these with published data from the UK (2001-11; n=1090) and Norway (2002-17; n=3254). Defined daily dose (DDD) data from the European Centre for Disease Prevention and Control (retrieved on Sept 21, 2021) for major antibiotic classes (β-lactam, tetracycline, macrolide, sulfonamide, quinolone, and non-penicillin β-lactam) were used together with sequence typing, resistance profiling, regression analysis, and non-neutral Wright-Fisher simulation-based modelling to enable systematic comparison of resistance levels, clone success, and antibiotic usage between the UK and Norway.

FINDINGS: Sequence type (ST)73, ST131, ST95, and ST69 accounted for 892 (49·3%) of 1808 isolates in the BSAC collection. In the UK, the proportion of ST69 increased between 2001-10 and 2011-17 (p=0·0004), whereas the proportions of ST73 and ST95 did not vary between periods. ST131 expanded quickly after its emergence in 2003 and its prevalence remained consistent throughout the study period (apart from a brief decrease in 2009-10). The extended-spectrum β-lactamase (ESBL)-carrying, globally disseminated MDR clone ST131-C2 showed overall greater success in the UK (154 [56·8%] of 271 isolates in 2003-17) compared with Norway (51 [18·3%] of 278 isolates in 2002-17; p<0·0001). DDD data indicated higher total use of antimicrobials in the UK, driven mainly by the class of non-penicillin β-lactams, which were used between 2·7-times and 5·1-times more in the UK per annum (ratio mean 3·7 [SD 0·8]). This difference was associated with the higher success of the MDR clone ST131-C2 (pseudo-R2 69·1%). A non-neutral Wright-Fisher model replicated the observed expansion of non-MDR and MDR sequence types under higher DDD regimes.

INTERPRETATION: Our study indicates that resistance profiles of contemporaneously successful clones can vary substantially, warranting caution in the interpretation of correlations between aggregate measures of resistance and antibiotic usage. Our study further suggests that in countries with low-to-moderate use of antibiotics, such as the UK and Norway, the extent of non-penicillin β-lactam use modulates rather than determines the success of widely disseminated MDR ESBL-carrying E coli clones. Detailed understanding of underlying causal drivers of success is important for improved control of resistant pathogens.

FUNDING: Trond Mohn Foundation, Marie Skłodowska-Curie Actions, European Research Council, Royal Society, and Wellcome Trust.

PMID:38219757 | DOI:10.1016/S2666-5247(23)00292-6

Nat Commun. 2024 Jan 12;15(1):494. doi: 10.1038/s41467-023-43854-3.

ABSTRACT

Carbapenem-resistant Escherichia coli (CREC) ST410 has recently emerged as a major global health problem. Here, we report a shift in CREC prevalence in Chinese hospitals between 2017 and 2021 with ST410 becoming the most commonly isolated sequence type. Genomic analysis identifies a hypervirulent CREC ST410 clone, B5/H24RxC, which caused two separate outbreaks in a children's hospital. It may have emerged from the previously characterised B4/H24RxC in 2006 and has been isolated in ten other countries from 2015 to 2021. Compared with B4/H24RxC, B5/H24RxC lacks the blaOXA-181-bearing X3 plasmid, but carries a F-type plasmid containing blaNDM-5. Most of B5/H24RxC also carry a high pathogenicity island and a novel O-antigen gene cluster. We find that B5/H24RxC grew faster in vitro and is more virulent in vivo. The identification of this newly emerged but already globally disseminated hypervirulent CREC clone, highlights the ongoing evolution of ST410 towards increased resistance and virulence.

PMID:38216585 | PMC:PMC10786849 | DOI:10.1038/s41467-023-43854-3

EBioMedicine. 2024 Jan 11;100:104965. doi: 10.1016/j.ebiom.2023.104965. Online ahead of print.

ABSTRACT

BACKGROUND: Simian immunodeficiency viruses (SIV) have been jumping between non-human primates in West/Central Africa for thousands of years and yet, the HIV-1 epidemic only originated from a primate lentivirus over 100 years ago.

METHODS: This study examined the replicative fitness, transmission, restriction, and cytopathogenicity of 22 primate lentiviruses in primary human lymphoid tissue and both primary human and chimpanzee peripheral blood mononuclear cells.

FINDINGS: Pairwise competitions revealed that SIV from chimpanzees (cpz) had the highest replicative fitness in human or chimpanzee peripheral blood mononuclear cells, even higher fitness than HIV-1 group M strains responsible for worldwide epidemic. The SIV strains belonging to the "HIV-2 lineage" (including SIVsmm, SIVmac, SIVagm) had the lowest replicative fitness. SIVcpz strains were less inhibited by human restriction factors than the "HIV-2 lineage" strains. SIVcpz efficiently replicated in human tonsillar tissue but did not deplete CD4+ T-cells, consistent with the slow or nonpathogenic disease observed in most chimpanzees. In contrast, HIV-1 isolates and SIV of the HIV-2 lineage were pathogenic to the human tonsillar tissue, almost independent of the level of virus replication.

INTERPRETATION: Of all primate lentiviruses, SIV from chimpanzees appears most capable of infecting and replicating in humans, establishing HIV-1. SIV from other Old World monkeys, e.g. the progenitor of HIV-2, replicate slowly in humans due in part to restriction factors. Nonetheless, many of these SIV strains were more pathogenic than SIVcpz. Either SIVcpz evolved into a more pathogenic virus while in humans or a rare SIVcpz, possibly extinct in chimpanzees, was pathogenic immediately following the jump into human.

FUNDING: Support for this study to E.J.A. was provided by the NIH/NIAID R01 AI49170 and CIHR project grant 385787. Infrastructure support was provided by the NIH CFAR AI36219 and Canadian CFI/Ontario ORF 36287. Efforts of J.A.B. and N.J.H. was provided by NIH AI099473 and for D.H.C., by VA and NIH AI AI080313.

PMID:38215691 | PMC:PMC10827413 | DOI:10.1016/j.ebiom.2023.104965

How the Cultural Revolution still shapes China

The Cultural Revolution is everywhere and nowhere in modern China. It is impossible to make sense of China without understanding what happened in this decade of political fanaticism, brutal violence and chaos, which saw perhaps two million die and tens of millions hounded. But it also seems impossible to truly understand this era, with its constant changes and contradictions. Discussion has been suppressed by both political diktat and personal trauma. Even so, its memory persists.

While many remain deeply scarred by the horrors, there is now a surprising nostalgia for the era. It speaks in large part to concerns about the present day but also reflects the appeal of powerful possibilities for transformation which existed in the era, however briefly and marginally.

What exactly are people remembering when they remember the Cultural Revolution? And how has an era which turned the nation upside down come to be an essential part of the party-state’s maintenance of the political status quo?

Tania Branigan is foreign leader writer at the Guardian and spent seven years as its China correspondent. Her book Red Memory: The Afterlives of China’s Cultural Revolution won the Cundill History Prize 2023 and was shortlisted for the Baillie Gifford prize, the British Academy Book Prize for Global Cultural Understanding and the Kirkus non-fiction prize. It was named as one of the Wall Street Journal’s ten best books of 2023 and TIME ’s 100 must-read books of 2023.

• Speaker: Ms Tania Branigan
• Friday 08 March 2024, 17:30-18:30
• Venue: Lady Mitchell Hall, Sidgwick Avenue.
• Series: Darwin College Lecture Series; organiser: Janet Gibson.

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