Feed aggregator

mBio. 2024 Apr 29:e0058124. doi: 10.1128/mbio.00581-24. Online ahead of print.

ABSTRACT

Recombination of short DNA fragments via horizontal gene transfer (HGT) can introduce beneficial alleles, create genomic disharmony through negative epistasis, and create adaptive gene combinations through positive epistasis. For non-core (accessory) genes, the negative epistatic cost is likely to be minimal because the incoming genes have not co-evolved with the recipient genome and are frequently observed as tightly linked cassettes with major effects. By contrast, interspecific recombination in the core genome is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma, we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and C. coli that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings, indirect evidence of negative epistasis. However, multiple HGT events enable recovery of the genome's co-adaption between introgressing alleles, even in core metabolism genes (e.g., formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred, and independently reinstated in a new genetic background-facilitating transition between fitness peaks. In this example, the two-step recombinational process is associated with C. coli that are adapted to the agricultural niche.IMPORTANCEGenetic exchange among bacteria shapes the microbial world. From the acquisition of antimicrobial resistance genes to fundamental questions about the nature of bacterial species, this powerful evolutionary force has preoccupied scientists for decades. However, the mixing of genes between species rests on a paradox: 0n one hand, promoting adaptation by conferring novel functionality; on the other, potentially introducing disharmonious gene combinations (negative epistasis) that will be selected against. Taking an interdisciplinary approach to analyze natural populations of the enteric bacteria Campylobacter, an ideal example of long-range admixture, we demonstrate that genes can independently transfer across species boundaries and rejoin in functional networks in a recipient genome. The positive impact of two-gene interactions appears to be adaptive by expanding metabolic capacity and facilitating niche shifts through interspecific hybridization. This challenges conventional ideas and highlights the possibility of multiple-step evolution of multi-gene traits by interspecific introgression.

PMID:38683013 | DOI:10.1128/mbio.00581-24

Stopping the brain from eating itself: endotoxins, sugars & chaperones

Abstract not available

• Speaker: Guy Brown
• Friday 03 May 2024, 15:00-16:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Biochemistry Friday Seminars; organiser: reception.

Add to your calendar or Include in your list

Stopping the brain from eating itself: endotoxins, sugars & chaperones

Abstract not available

• Speaker: Guy Brown
• Friday 03 May 2024, 15:00-16:00
• Venue: Jean Thomas Lecture theatre, Sanger Building, Tennis Court Road.
• Series: Biochemistry Friday Seminars; organiser: reception.

Add to your calendar or Include in your list

The researchers, from the University of Cambridge, combined flexible electronics and soft robotics techniques to develop the devices, which could be used for the diagnosis and treatment of a range of disorders, including epilepsy and chronic pain, or the control of prosthetic limbs.

Current tools for interfacing with the peripheral nerves – the 43 pairs of motor and sensory nerves that connect the brain and the spinal cord – are outdated, bulky and carry a high risk of nerve injury. However, the robotic nerve ‘cuffs’ developed by the Cambridge team are sensitive enough to grasp or wrap around delicate nerve fibres without causing any damage.

Tests of the nerve cuffs in rats showed that the devices only require tiny voltages to change shape in a controlled way, forming a self-closing loop around nerves without the need for surgical sutures or glues.

The researchers say the combination of soft electrical actuators with neurotechnology could be an answer to minimally invasive monitoring and treatment for a range of neurological conditions. The results are reported in the journal Nature Materials.

Electric nerve implants can be used to either stimulate or block signals in target nerves. For example, they might help relieve pain by blocking pain signals, or they could be used to restore movement in paralysed limbs by sending electrical signals to the nerves. Nerve monitoring is also standard surgical procedure when operating in areas of the body containing a high concentration of nerve fibres, such as anywhere near the spinal cord.

These implants allow direct access to nerve fibres, but they come with certain risks. “Nerve implants come with a high risk of nerve injury,” said Professor George Malliaras from Cambridge’s Department of Engineering, who led the research. “Nerves are small and highly delicate, so anytime you put something large, like an electrode, in contact with them, it represents a danger to the nerves.”

“Nerve cuffs that wrap around nerves are the least invasive implants currently available, but despite this they are still too bulky, stiff and difficult to implant, requiring significant handling and potential trauma to the nerve,” said co-author Dr Damiano Barone from Cambridge’s Department of Clinical Neurosciences.

The researchers designed a new type of nerve cuff made from conducting polymers, normally used in soft robotics. The ultra-thin cuffs are engineered in two separate layers. Applying tiny amounts of electricity – just a few hundred millivolts – causes the devices to swell or shrink.

The cuffs are small enough that they could be rolled up into a needle and injected near the target nerve. When activated electrically, the cuffs will change their shape to wrap around the nerve, allowing nerve activity to be monitored or altered.

“To ensure the safe use of these devices inside the body, we have managed to reduce the voltage required for actuation to very low values,” said Dr Chaoqun Dong, the paper’s first author. “What's even more significant is that these cuffs can change shape in both directions and be reprogrammed. This means surgeons can adjust how tightly the device fits around a nerve until they get the best results for recording and stimulating the nerve.”

Tests in rats showed that the cuffs could be successfully placed without surgery, and formed a self-closing loop around the target nerve. The researchers are planning further testing of the devices in animal models, and are hoping to begin testing in humans within the next few years.

“Using this approach, we can reach nerves that are difficult to reach through open surgery, such as the nerves that control, pain, vision or hearing, but without the need to implant anything inside the brain,” said Barone. “The ability to place these cuffs so they wrap around the nerves makes this a much easier procedure for surgeons, and it’s less risky for patients.”

“The ability to make an implant that can change shape through electrical activation opens up a range of future possibilities for highly targeted treatments,” said Malliaras. “In future, we might be able to have implants that can move through the body, or even into the brain – it makes you dream how we could use technology to benefit patients in future.”

The research was supported in part by the Swiss National Science Foundation, the Cambridge Trust, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI).

 

Reference:
Chaoqun Dong et al. ‘Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.’ Nature Materials (2024). DOI: 10.1038/s41563-024-01886-0

Researchers have developed tiny, flexible devices that can wrap around individual nerve fibres without damaging them.

The ability to make an implant that can change shape through electrical activation opens up a range of future possibilities for highly targeted treatmentsGeorge MalliarasXH4D via iStock / Getty Images PlusIllustration of the human nervous system

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

Respir Res. 2024 Apr 25;25(1):180. doi: 10.1186/s12931-024-02800-7.

ABSTRACT

BACKGROUND: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult. Here, we present a platform to produce hiPSC-derived AECs (hiPSC-AECs) including ionocytes and investigate their role in the airway epithelium.

METHODS: hiPSCs were differentiated into lung progenitors, which were expanded as 3D organoids and matured by air-liquid interface culture as polarised hiPSC-AEC epithelia. Using CRISPR/Cas9 technology, we generated a hiPSCs knockout (KO) for FOXI1, a transcription factor that is essential for ionocyte specification. Differences between FOXI1 KO hiPSC-AECs and their wild-type (WT) isogenic controls were investigated by assessing gene and protein expression, epithelial composition, cilia coverage and motility, pH and transepithelial barrier properties.

RESULTS: Mature hiPSC-AEC epithelia contained basal cells, secretory cells, ciliated cells with motile cilia, pulmonary neuroendocrine cells (PNECs) and ionocytes. There was no difference between FOXI1 WT and KO hiPSCs in terms of their capacity to differentiate into airway progenitors. However, FOXI1 KO led to mature hiPSC-AEC epithelia without ionocytes with reduced capacity to produce ciliated cells.

CONCLUSION: Our results suggest that ionocytes could have role beyond transepithelial ion transport by regulating epithelial properties and homeostasis in the airway epithelium.

PMID:38664797 | DOI:10.1186/s12931-024-02800-7

JACC Asia. 2024 Apr 3;4(4):289-291. doi: 10.1016/j.jacasi.2024.02.003. eCollection 2024 Apr.

NO ABSTRACT

PMID:38660106 | PMC:PMC11035929 | DOI:10.1016/j.jacasi.2024.02.003

For the first time, the research has shown that this risk is higher in people living in areas of greater socioeconomic deprivation.

Breast cancer is the most commonly diagnosed cancer in the UK. Around 56,000 people in the UK are diagnosed each year, the vast majority (over 99%) of whom are women. Improvements in earlier diagnosis and in treatments mean that five year survival rates have been increasing over time, reaching 87% by 2017 in England.

People who survive breast cancer are at risk of second primary cancer, but until now the exact risk has been unclear. Previously published research suggested that women and men who survive breast cancer are at a 24% and 27% greater risk of a non-breast second primary cancer than the wider population respectively. There have been also suggestions that second primary cancer risks differ by the age at breast cancer diagnosis.

To provide more accurate estimates, a team led by researchers at the University of Cambridge analysed data from over 580,000 female and over 3,500 male breast cancer survivors diagnosed between 1995 and 2019 using the National Cancer Registration Dataset. The results of their analysis are published today in Lancet Regional Health – Europe.

First author Isaac Allen from the Department of Public Health and Primary Care at the University of Cambridge said: “It’s important for us to understand to what extent having one type of cancer puts you at risk of a second cancer at a different site. The female and male breast cancer survivors whose data we studied were at increased risk of a number of second cancers. Knowing this can help inform conversations with their care teams to look out for signs of potential new cancers.”

The researchers found significantly increased risks of cancer in the contralateral (that is, unaffected) breast and for endometrium and prostate cancer in females and males, respectively. Females who survived breast cancer were at double the risk of contralateral breast cancer compared to the general population and at 87% greater risk of endometrial cancer, 58% greater risk of myeloid leukaemia and 25% greater risk of ovarian cancer.

Age of diagnosis was important, too – females diagnosed with breast cancer under the age of 50 were 86% more likely to develop a second primary cancer compared to the general population of the same age, whereas women diagnosed after age 50 were at a 17% increased risk. One potential explanation is that a larger number of younger breast cancer survivors may have inherited genetic alterations that increase risk for multiple cancers. For example, women with inherited changes to the BRCA1 and BRCA2 genes are at increased risk of contralateral breast cancer, ovarian and pancreatic cancer.

Females from the most socioeconomically deprived backgrounds were at 35% greater risk of a second primary cancer compared to females from the least deprived backgrounds. These differences were primarily driven by non-breast cancer risks, particularly for lung, kidney, head and neck, bladder, oesophageal and stomach cancers. This may be because smoking, obesity, and alcohol consumption – established risk factors for these cancers – are more common among more deprived groups.

Allen, a PhD student at Clare Hall, added: “This is further evidence of the health inequalities that people from more deprived backgrounds experience. We need to fully understand why they are at greater risk of second cancers so that we can intervene and reduce this risk.”

Male breast cancer survivors were 55 times more likely than the general male population to develop contralateral breast cancer – though the researchers stress that an individual’s risk was still very low. For example, for every 100 men diagnosed with breast cancer at age 50 or over, about three developed contralateral breast cancer during a 25 year period.  Male breast cancer survivors were also 58% more likely than the general male population to develop prostate cancer.

Professor Antonis Antoniou from the Department of Public Health and Primary Care at the University of Cambridge, the study’s senior author, said: “This is the largest study to date to look at the risk in breast cancer survivors of developing a second cancer. We were able to carry this out and calculate more accurate estimates because of the outstanding data sets available to researchers through the NHS.”

The research was funded by Cancer Research UK with support from the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Cancer Research UK’s senior cancer intelligence manager, Katrina Brown, said: “This study shows us that the risk of second primary cancers is higher in people who have had breast cancer, and this can differ depending on someone’s socioeconomic background. But more research is needed to understand what is driving this difference and how to tackle these health inequalities.”

People who are concerned about their cancer risk should contact their GP for advice. If you or someone close to you have been affected by cancer and you’ve got questions, you can call Cancer Research UK nurses on freephone 0808 800 4040, Monday to Friday.

Reference
Allen, I, et al. Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort study. Lancet Regional Health – Europe; 24 April 2024: DOI: 10.1016/j.lanepe.2024.100903

Survivors of breast cancer are at significantly higher risk of developing second cancers, including endometrial and ovarian cancer for women and prostate cancer for men, according to new research studying data from almost 600,000 patients in England.

It’s important for us to understand to what extent having one type of cancer puts you at risk of a second cancer at a different site. Knowing this can help inform conversations with their care teams to look out for signs of potential new cancersIsaac AllenNational Cancer InstituteDoctor standing near woman patient doing breast cancer

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

The researchers, led by the University of Cambridge, are developing low-cost light-harvesting semiconductors that power devices for converting water into clean hydrogen fuel, using just the power of the sun. These semiconducting materials, known as copper oxides, are cheap, abundant and non-toxic, but their performance does not come close to silicon, which dominates the semiconductor market.

However, the researchers found that by growing the copper oxide crystals in a specific orientation so that electric charges move through the crystals at a diagonal, the charges move much faster and further, greatly improving performance. Tests of a copper oxide light harvester, or photocathode, based on this fabrication technique showed a 70% improvement over existing state-of-the-art oxide photocathodes, while also showing greatly improved stability.

The researchers say their results, reported in the journal Nature, show how low-cost materials could be fine-tuned to power the transition away from fossil fuels and toward clean, sustainable fuels that can be stored and used with existing energy infrastructure.

Copper (I) oxide, or cuprous oxide, has been touted as a cheap potential replacement for silicon for years, since it is reasonably effective at capturing sunlight and converting it into electric charge. However, much of that charge tends to get lost, limiting the material’s performance.

“Like other oxide semiconductors, cuprous oxide has its intrinsic challenges,” said co-first author Dr Linfeng Pan from Cambridge’s Department of Chemical Engineering and Biotechnology. “One of those challenges is the mismatch between how deep light is absorbed and how far the charges travel within the material, so most of the oxide below the top layer of material is essentially dead space.”

“For most solar cell materials, it’s defects on the surface of the material that cause a reduction in performance, but with these oxide materials, it’s the other way round: the surface is largely fine, but something about the bulk leads to losses,” said Professor Sam Stranks, who led the research. “This means the way the crystals are grown is vital to their performance.”

To develop cuprous oxides to the point where they can be a credible contender to established photovoltaic materials, they need to be optimised so they can efficiently generate and move electric charges – made of an electron and a positively-charged electron ‘hole’ – when sunlight hits them.

One potential optimisation approach is single-crystal thin films – very thin slices of material with a highly-ordered crystal structure, which are often used in electronics. However, making these films is normally a complex and time-consuming process.

Using thin film deposition techniques, the researchers were able to grow high-quality cuprous oxide films at ambient pressure and room temperature. By precisely controlling growth and flow rates in the chamber, they were able to ‘shift’ the crystals into a particular orientation. Then, using high temporal resolution spectroscopic techniques, they were able to observe how the orientation of the crystals affected how efficiently electric charges moved through the material.

“These crystals are basically cubes, and we found that when the electrons move through the cube at a body diagonal, rather than along the face or edge of the cube, they move an order of magnitude further,” said Pan. “The further the electrons move, the better the performance.”

“Something about that diagonal direction in these materials is magic,” said Stranks. “We need to carry out further work to fully understand why and optimise it further, but it has so far resulted in a huge jump in performance.” Tests of a cuprous oxide photocathode made using this technique showed an increase in performance of more than 70% over existing state-of-the-art electrodeposited oxide photocathodes.

“In addition to the improved performance, we found that the orientation makes the films much more stable, but factors beyond the bulk properties may be at play,” said Pan.

The researchers say that much more research and development is still needed, but this and related families of materials could have a vital role in the energy transition.

“There’s still a long way to go, but we’re on an exciting trajectory,” said Stranks. “There’s a lot of interesting science to come from these materials, and it’s interesting for me to connect the physics of these materials with their growth, how they form, and ultimately how they perform.”

The research was a collaboration with École Polytechnique Fédérale de Lausanne, Nankai University and Uppsala University. The research was supported in part by the European Research Council, the Swiss National Science Foundation, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI). Sam Stranks is Professor of Optoelectronics in the Department of Chemical Engineering and Biotechnology, and a Fellow of Clare College, Cambridge.

 

Reference:
Linfeng Pan, Linjie Dai et al. ‘High carrier mobility along the [111] orientation in Cu2O photoelectrodes.’ Nature (2024). DOI: 10.1038/s41586-024-07273-8

For more information on energy-related research in Cambridge, please visit the Energy IRC, which brings together Cambridge’s research knowledge and expertise, in collaboration with global partners, to create solutions for a sustainable and resilient energy landscape for generations to come. 

Researchers have found a way to super-charge the ‘engine’ of sustainable fuel generation – by giving the materials a little twist.

orange via Getty ImagesAbstract orange swirls

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

Elife. 2024 Apr 24;12:RP88960. doi: 10.7554/eLife.88960.

ABSTRACT

African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.

PMID:38655765 | DOI:10.7554/eLife.88960

Cell Rep. 2024 Apr 22;43(5):114122. doi: 10.1016/j.celrep.2024.114122. Online ahead of print.

ABSTRACT

DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.

PMID:38652659 | DOI:10.1016/j.celrep.2024.114122

The virtual centres, supported by the charity LifeArc, will focus on areas where there are significant unmet needs. They will tackle barriers that ordinarily prevent new tests and treatments reaching patients with rare diseases and speed up the delivery of rare disease treatment trials.

The centres will bring together leading scientists and rare disease clinical specialists from across the UK for the first time, encouraging new collaborations across different research disciplines and providing improved access to facilities and training.

LifeArc Centre for Rare Mitochondrial Diseases

Professor Patrick Chinnery will lead the LifeArc Centre for Rare Mitochondrial Diseases, a national partnership with the Lily Foundation and Muscular Dystrophy UK, together with key partners at UCL, Newcastle University and three other centres (Oxford, Birmingham and Manchester).

Mitochondrial diseases are genetic disorders affecting 1 in 5,000 people. They often cause progressive damage to the brain, eyes, muscles, heart and liver, leading to severe disability and a shorter life. There is currently have no cure for most conditions, however, new opportunities to treat mitochondrial diseases have been identified in the last five years, meaning that it’s a critical time for research development. The £7.5M centre will establish a national platform that will connect patient groups, knowledge and infrastructure in order to accelerate new treatments getting to clinical trial.

Professor Chinnery said: “The new LifeArc centre unites scientific and clinical strengths from across the UK. For the first time we will form a single team, focussed on developing new treatments for mitochondrial diseases which currently have no cure.”

Adam Harraway has Mitochondrial Disease and says he lives in constant fear of what might go wrong next with his condition. “With rare diseases such as these, it can feel like the questions always outweigh the answers. The news of this investment from LifeArc fills me with hope for the future. To know that there are so many wonderful people and organisations working towards treatments and cures makes me feel seen and heard. It gives a voice to people who often have to suffer in silence, and I'm excited to see how this project can help Mito patients in the future."

LifeArc Centre for Rare Respiratory Diseases

Professor Stefan Marciniak will co-lead the LifeArc Centre for Rare Respiratory Diseases, a UK wide collaborative centre co-created in partnership with patients and charities. This Centre is a partnership between Universities and NHS Trusts across the UK, co-led by Edinburgh with Nottingham, Dundee, Cambridge, Southampton, University College London and supported by six other centres (Belfast, Cardiff, Leeds, Leicester, Manchester and Royal Brompton).

For the first time ever, it will provide a single ‘go to’ centre that will connect children and adults with rare respiratory disease with clinical experts, researchers, investors and industry leaders across the UK. The £9.4M centre will create a UK-wide biobank of patient samples and models of disease that will allow researchers to advance pioneering therapies and engage with industry and regulatory partners to develop innovative human clinical studies.

Professor Marciniak said: “There are many rare lung diseases, and together those affected constitute a larger underserved group of patients. The National Translational Centre for Rare Respiratory Diseases brings together expertise from across the UK to find effective treatments and train the next generation of rare disease researchers.”

Former BBC News journalist and presenter, Philippa Thomas, has the rare incurable lung disease, Lymphangioleiomyomatosis (LAM). Her condition has stabilised but for many people, the disease can be severely life-limiting. Philippa said: “There is so little research funding for rare respiratory diseases, that getting treatment - let alone an accurate diagnosis - really does feel like a lottery. It is also terrifying being diagnosed with something your GP will never have heard of.”

Globally, there are more than 300 million people living with rare diseases. However, rare disease research can be fragmented. Researchers can lack access to specialist facilities, as well as advice on regulation, trial designs, preclinical regulatory requirements, and translational project management, which are vital in getting new innovations to patients.

Dr Catriona Crombie, Head of Rare Disease at LifeArc, says: “We’re extremely proud to be launching four new LifeArc Translational Centres for Rare Diseases. Each centre has been awarded funding because it holds real promise for delivering change for people living with rare diseases. These centres also have the potential to create a blueprint for accelerating improvements across other disease areas, including common diseases.”

Adapted from a press release from LifeArc

Cambridge researchers will play key roles in two new centres dedicated to developing improved tests, treatments and potentially cures for thousands of people living with rare medical conditions.

The new LifeArc centre unites scientific and clinical strengths from across the UKPatrick ChinneryAlexander_Safonov (Getty)Woman inhaling from a mask nebulizer

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

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 20:167193. doi: 10.1016/j.bbadis.2024.167193. Online ahead of print.

ABSTRACT

SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.

PMID:38648902 | DOI:10.1016/j.bbadis.2024.167193

BMC Biol. 2024 Apr 22;22(1):89. doi: 10.1186/s12915-024-01886-1.

ABSTRACT

BACKGROUND: Innate immune responses can be activated by pathogen-associated molecular patterns (PAMPs), danger signals released by damaged tissues, or the absence of self-molecules that inhibit immunity. As PAMPs are typically conserved across broad groups of pathogens but absent from the host, it is unclear whether they allow hosts to recognize parasites that are phylogenetically similar to themselves, such as parasitoid wasps infecting insects.

RESULTS: Parasitoids must penetrate the cuticle of Drosophila larvae to inject their eggs. In line with previous results, we found that the danger signal of wounding triggers the differentiation of specialized immune cells called lamellocytes. However, using oil droplets to mimic infection by a parasitoid wasp egg, we found that this does not activate the melanization response. This aspect of the immune response also requires exposure to parasite molecules. The unidentified factor enhances the transcriptional response in hemocytes and induces a specific response in the fat body.

CONCLUSIONS: We conclude that a combination of danger signals and the recognition of nonself molecules is required to activate Drosophila's immune response against parasitic insects.

PMID:38644510 | PMC:PMC11034056 | DOI:10.1186/s12915-024-01886-1

Lancet Microbe. 2024 Apr 17:S2666-5247(24)00072-7. doi: 10.1016/S2666-5247(24)00072-7. Online ahead of print.

NO ABSTRACT

PMID:38642566 | DOI:10.1016/S2666-5247(24)00072-7

Bradford Hill seminar - Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice

All are welcome to our next hybrid Bradford Hill Seminar by Prof Cath Mercer of the UCL Institute for Global Health, who will discuss:

‘Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice’.

This will be a hybrid event

No registration required to attend in person at:

Large Seminar Room, East Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SRT .

Registration required to attend online

Please register in Teams in advance at https://rb.gy/4svy5i

About this talk

Poor sexual and reproductive health causes significant morbidity. Last year, nearly 400,000 new sexually transmitted infections were diagnosed in England alone. Additionally, there is increasing awareness of sexual rights, the role of sexual pleasure and wellbeing, and what these mean for a satisfying sex life and our general health and wellbeing.

Yet this critical aspect of our lives is highly sensitive and sometimes stigmatised making sexual behaviour, its drivers and consequences difficult to research. Methods are required that maximise response and minimise bias so that the resulting evidence is of sufficient quality, including for informing policy and practice.

Such methodological rigour is neither cheap nor quick, and since the COVID -19 pandemic shifted expectations around both the timelines for acquiring evidence and the public’s willingness to participate in research, do we need to re-think how we do research in challenging fields such as sexual and reproductive health? Do we need to revise in our definition of what is ‘good enough’?

About Professor Cath Mercer

Cath Mercer is Professor of Sexual Health Science at University College London. A statistician and demographer by training, Cath is internationally recognised as an expert in developing and employing robust methods that advance the scientific study of sexual behaviour, one of the most socially-sensitive disciplines, leading studies that work for – and with – marginalised communities through to the general population, in a variety of settings, employing a range of study designs and research methods.

• Speaker: Professor Cath Mercer, UCL Institute for Global Health
• Wednesday 15 May 2024, 13:00-14:00
• Venue: Large Seminar Room, East Forvie Building, Forvie Site Robinson Way Cambridge CB2 0SR..
• Series: Bradford Hill Seminars; organiser: Paul Browne.

Add to your calendar or Include in your list

Bradford Hill seminar - Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice

All are welcome to our next hybrid Bradford Hill Seminar by Prof Cath Mercer of the UCL Institute for Global Health, who will discuss:

‘Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice’.

This will be a hybrid event

No registration required to attend in person at:

Large Seminar Room, East Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SRT .

Registration required to attend online

Please register in Teams in advance at https://rb.gy/4svy5i

About this talk

Poor sexual and reproductive health causes significant morbidity. Last year, nearly 400,000 new sexually transmitted infections were diagnosed in England alone. Additionally, there is increasing awareness of sexual rights, the role of sexual pleasure and wellbeing, and what these mean for a satisfying sex life and our general health and wellbeing.

Yet this critical aspect of our lives is highly sensitive and sometimes stigmatised making sexual behaviour, its drivers and consequences difficult to research. Methods are required that maximise response and minimise bias so that the resulting evidence is of sufficient quality, including for informing policy and practice.

Such methodological rigour is neither cheap nor quick, and since the COVID -19 pandemic shifted expectations around both the timelines for acquiring evidence and the public’s willingness to participate in research, do we need to re-think how we do research in challenging fields such as sexual and reproductive health? Do we need to revise in our definition of what is ‘good enough’?

About Professor Cath Mercer

Cath Mercer is Professor of Sexual Health Science at University College London. A statistician and demographer by training, Cath is internationally recognised as an expert in developing and employing robust methods that advance the scientific study of sexual behaviour, one of the most socially-sensitive disciplines, leading studies that work for – and with – marginalised communities through to the general population, in a variety of settings, employing a range of study designs and research methods.

• Speaker: Professor Cath Mercer, UCL Institute for Global Health
• Wednesday 15 May 2024, 13:00-14:00
• Venue: Large Seminar Room, East Forvie Building, Forvie Site Robinson Way Cambridge CB2 0SR..
• Series: Bradford Hill Seminars; organiser: Paul Browne.

Add to your calendar or Include in your list

Bradford Hill seminar - Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice

All are welcome to our next hybrid Bradford Hill Seminar by Prof Cath Mercer of the UCL Institute for Global Health, who will discuss:

‘Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice’.

This will be a hybrid event

No registration required to attend in person at:

Large Seminar Room, East Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SRT .

Registration required to attend online

Please register in Teams in advance at https://rb.gy/4svy5i

About this talk

Poor sexual and reproductive health causes significant morbidity. Last year, nearly 400,000 new sexually transmitted infections were diagnosed in England alone. Additionally, there is increasing awareness of sexual rights, the role of sexual pleasure and wellbeing, and what these mean for a satisfying sex life and our general health and wellbeing.

Yet this critical aspect of our lives is highly sensitive and sometimes stigmatised making sexual behaviour, its drivers and consequences difficult to research. Methods are required that maximise response and minimise bias so that the resulting evidence is of sufficient quality, including for informing policy and practice.

Such methodological rigour is neither cheap nor quick, and since the COVID -19 pandemic shifted expectations around both the timelines for acquiring evidence and the public’s willingness to participate in research, do we need to re-think how we do research in challenging fields such as sexual and reproductive health? Do we need to revise in our definition of what is ‘good enough’?

About Professor Cath Mercer

Cath Mercer is Professor of Sexual Health Science at University College London. A statistician and demographer by training, Cath is internationally recognised as an expert in developing and employing robust methods that advance the scientific study of sexual behaviour, one of the most socially-sensitive disciplines, leading studies that work for – and with – marginalised communities through to the general population, in a variety of settings, employing a range of study designs and research methods.

• Speaker: Professor Cath Mercer, UCL Institute for Global Health
• Wednesday 15 May 2024, 13:00-14:00
• Venue: Large Seminar Room, East Forvie Building, Forvie Site Robinson Way Cambridge CB2 0SR..
• Series: Bradford Hill Seminars; organiser: Paul Browne.

Add to your calendar or Include in your list

Bradford Hill seminar - Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice

All are welcome to our next hybrid Bradford Hill Seminar by Prof Cath Mercer of the UCL Institute for Global Health, who will discuss:

‘Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice’.

This will be a hybrid event

No registration required to attend in person at:

Large Seminar Room, East Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SRT .

Registration required to attend online

Please register in Teams in advance at https://rb.gy/4svy5i

About this talk

Poor sexual and reproductive health causes significant morbidity. Last year, nearly 400,000 new sexually transmitted infections were diagnosed in England alone. Additionally, there is increasing awareness of sexual rights, the role of sexual pleasure and wellbeing, and what these mean for a satisfying sex life and our general health and wellbeing.

Yet this critical aspect of our lives is highly sensitive and sometimes stigmatised making sexual behaviour, its drivers and consequences difficult to research. Methods are required that maximise response and minimise bias so that the resulting evidence is of sufficient quality, including for informing policy and practice.

Such methodological rigour is neither cheap nor quick, and since the COVID -19 pandemic shifted expectations around both the timelines for acquiring evidence and the public’s willingness to participate in research, do we need to re-think how we do research in challenging fields such as sexual and reproductive health? Do we need to revise in our definition of what is ‘good enough’?

About Professor Cath Mercer

Cath Mercer is Professor of Sexual Health Science at University College London. A statistician and demographer by training, Cath is internationally recognised as an expert in developing and employing robust methods that advance the scientific study of sexual behaviour, one of the most socially-sensitive disciplines, leading studies that work for – and with – marginalised communities through to the general population, in a variety of settings, employing a range of study designs and research methods.

• Speaker: Professor Cath Mercer, UCL Institute for Global Health
• Wednesday 15 May 2024, 13:00-14:00
• Venue: Large Seminar Room, East Forvie Building, Forvie Site Robinson Way Cambridge CB2 0SR..
• Series: Bradford Hill Seminars; organiser: Paul Browne.

Add to your calendar or Include in your list

Bradford Hill seminar - Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice

All are welcome to our next hybrid Bradford Hill Seminar by Prof Cath Mercer of the UCL Institute for Global Health, who will discuss:

‘Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice’.

This will be a hybrid event

No registration required to attend in person at:

Large Seminar Room, East Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SRT .

Registration required to attend online

Please register in advance at https://teams.microsoft.com/registration/W-89URffB0G1Uj26AJ5ZkA,4gqNqQyPO0ORfyzDfqnrLQ,NG69L_hHNkePrbS1cdRxLA,_0aT3zeTQEa1NGghd-e_mw,nYZuQfjZLEW7X-eoyDoKsw,3BREDUKldEemm90D0KOMUQ

About this talk

Poor sexual and reproductive health causes significant morbidity. Last year, nearly 400,000 new sexually transmitted infections were diagnosed in England alone. Additionally, there is increasing awareness of sexual rights, the role of sexual pleasure and wellbeing, and what these mean for a satisfying sex life and our general health and wellbeing.

Yet this critical aspect of our lives is highly sensitive and sometimes stigmatised making sexual behaviour, its drivers and consequences difficult to research. Methods are required that maximise response and minimise bias so that the resulting evidence is of sufficient quality, including for informing policy and practice.

Such methodological rigour is neither cheap nor quick, and since the COVID -19 pandemic shifted expectations around both the timelines for acquiring evidence and the public’s willingness to participate in research, do we need to re-think how we do research in challenging fields such as sexual and reproductive health? Do we need to revise in our definition of what is ‘good enough’?

About Professor Cath Mercer

Cath Mercer is Professor of Sexual Health Science at University College London. A statistician and demographer by training, Cath is internationally recognised as an expert in developing and employing robust methods that advance the scientific study of sexual behaviour, one of the most socially-sensitive disciplines, leading studies that work for – and with – marginalised communities through to the general population, in a variety of settings, employing a range of study designs and research methods.

• Speaker: Professor Cath Mercer, UCL Institute for Global Health
• Wednesday 15 May 2024, 13:00-14:00
• Venue: Large Seminar Room, East Forvie Building, Forvie Site Robinson Way Cambridge CB2 0SR..
• Series: Bradford Hill Seminars; organiser: Paul Browne.

Add to your calendar or Include in your list

Bradford Hill seminar - Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice

All are welcome to our next hybrid Bradford Hill Seminar by Prof Cath Mercer of the UCL Institute for Global Health, who will discuss:

‘Is perfection the enemy of good? Challenges and opportunities for building the evidence-base to inform sexual and reproductive health policy and practice’.

This will be a hybrid event

No registration required to attend in person at:

Large Seminar Room, East Forvie Building, Forvie Site, Robinson Way, Cambridge CB2 0SRT .

Registration required to attend online

Please register in advance at https://teams.microsoft.com/registration/W-89URffB0G1Uj26AJ5ZkA,4gqNqQyPO0ORfyzDfqnrLQ,NG69L_hHNkePrbS1cdRxLA,_0aT3zeTQEa1NGghd-e_mw,nYZuQfjZLEW7X-eoyDoKsw,3BREDUKldEemm90D0KOMUQ

About this talk

Poor sexual and reproductive health causes significant morbidity. Last year, nearly 400,000 new sexually transmitted infections were diagnosed in England alone. Additionally, there is increasing awareness of sexual rights, the role of sexual pleasure and wellbeing, and what these mean for a satisfying sex life and our general health and wellbeing.

Yet this critical aspect of our lives is highly sensitive and sometimes stigmatised making sexual behaviour, its drivers and consequences difficult to research. Methods are required that maximise response and minimise bias so that the resulting evidence is of sufficient quality, including for informing policy and practice.

Such methodological rigour is neither cheap nor quick, and since the COVID -19 pandemic shifted expectations around both the timelines for acquiring evidence and the public’s willingness to participate in research, do we need to re-think how we do research in challenging fields such as sexual and reproductive health? Do we need to revise in our definition of what is ‘good enough’?

About Professor Cath Mercer

Cath Mercer is Professor of Sexual Health Science at University College London. A statistician and demographer by training, Cath is internationally recognised as an expert in developing and employing robust methods that advance the scientific study of sexual behaviour, one of the most socially-sensitive disciplines, leading studies that work for – and with – marginalised communities through to the general population, in a variety of settings, employing a range of study designs and research methods.

• Speaker: Professor Cath Mercer, UCL Institute for Global Health
• Wednesday 15 May 2024, 13:00-14:00
• Venue: Large Seminar Room, East Forvie Building, Forvie Site Robinson Way Cambridge CB2 0SR..
• Series: Bradford Hill Seminars; organiser: Paul Browne.

Add to your calendar or Include in your list