New vaccine effective against coronaviruses that haven’t even emerged yet
This is a new approach to vaccine development called ‘proactive vaccinology’, where scientists build a vaccine before the disease-causing pathogen even emerges.
The new vaccine works by training the body’s immune system to recognise specific regions of eight different coronaviruses, including SARS-CoV-1, SARS-CoV-2, and several that are currently circulating in bats and have potential to jump to humans and cause a pandemic.
Key to its effectiveness is that the specific virus regions the vaccine targets also appear in many related coronaviruses. By training the immune system to attack these regions, it gives protection against other coronaviruses not represented in the vaccine – including ones that haven’t even been identified yet.
For example, the new vaccine does not include the SARS-CoV-1 coronavirus, which caused the 2003 SARS outbreak, yet it still induces an immune response to that virus.
“Our focus is to create a vaccine that will protect us against the next coronavirus pandemic, and have it ready before the pandemic has even started,” said Rory Hills, a graduate researcher in the University of Cambridge’s Department of Pharmacology and first author of the report.
He added: “We’ve created a vaccine that provides protection against a broad range of different coronaviruses – including ones we don’t even know about yet.”
The results are published today in the journal Nature Nanotechnology.
“We don’t have to wait for new coronaviruses to emerge. We know enough about coronaviruses, and different immune responses to them, that we can get going with building protective vaccines against unknown coronaviruses now,” said Professor Mark Howarth in the University of Cambridge’s Department of Pharmacology, senior author of the report.
He added: “Scientists did a great job in quickly producing an extremely effective COVID vaccine during the last pandemic, but the world still had a massive crisis with a huge number of deaths. We need to work out how we can do even better than that in the future, and a powerful component of that is starting to build the vaccines in advance.”
The new ‘Quartet Nanocage’ vaccine is based on a structure called a nanoparticle – a ball of proteins held together by incredibly strong interactions. Chains of different viral antigens are attached to this nanoparticle using a novel ‘protein superglue’. Multiple antigens are included in these chains, which trains the immune system to target specific regions shared across a broad range of coronaviruses.
This study demonstrated that the new vaccine raises a broad immune response, even in mice that were pre-immunised with SARS-CoV-2.
The new vaccine is much simpler in design than other broadly protective vaccines currently in development, which the researchers say should accelerate its route into clinical trials.
The underlying technology they have developed also has potential for use in vaccine development to protect against many other health challenges.
The work involved a collaboration between scientists at the University of Cambridge, the University of Oxford, and Caltech. It improves on previous work, by the Oxford and Caltech groups, to develop a novel all-in-one vaccine against coronavirus threats. The vaccine developed by Oxford and Caltech should enter Phase 1 clinical trials in early 2025, but its complex nature makes it challenging to manufacture which could limit large-scale production.
Conventional vaccines include a single antigen to train the immune system to target a single specific virus. This may not protect against a diverse range of existing coronaviruses, or against pathogens that are newly emerging.
The research was funded by the Biotechnology and Biological Sciences Research Council.
Reference: Hills, R.A. et al: ‘Proactive vaccination using multiviral Quartet Nanocages to elicit broad anti-coronavirus responses.’ Nature Nanotechnology, May 2024. DOI: 10.1038/s41565-024-01655-9
Researchers have developed a new vaccine technology that has been shown in mice to provide protection against a broad range of coronaviruses with potential for future disease outbreaks - including ones we don’t even know about
Our focus is to create a vaccine that will protect us against the next coronavirus pandemic, and have it ready before the pandemic has even started.Rory HillsStefan Cristian Cioata on GettySyringe and vaccine bottle
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shaPRS: Leveraging shared genetic effects across traits or ancestries improves accuracy of polygenic scores
Am J Hum Genet. 2024 Apr 27:S0002-9297(24)00124-1. doi: 10.1016/j.ajhg.2024.04.009. Online ahead of print.
ABSTRACT
We present shaPRS, a method that leverages widespread pleiotropy between traits or shared genetic effects across ancestries, to improve the accuracy of polygenic scores. The method uses genome-wide summary statistics from two diseases or ancestries to improve the genetic effect estimate and standard error at SNPs where there is homogeneity of effect between the two datasets. When there is significant evidence of heterogeneity, the genetic effect from the disease or population closest to the target population is maintained. We show via simulation and a series of real-world examples that shaPRS substantially enhances the accuracy of polygenic risk scores (PRSs) for complex diseases and greatly improves PRS performance across ancestries. shaPRS is a PRS pre-processing method that is agnostic to the actual PRS generation method, and as a result, it can be integrated into existing PRS generation pipelines and continue to be applied as more performant PRS methods are developed over time.
PMID:38703768 | DOI:10.1016/j.ajhg.2024.04.009
The factor inhibiting HIF regulates T cell differentiation and anti-tumour efficacy
Front Immunol. 2024 Apr 16;15:1293723. doi: 10.3389/fimmu.2024.1293723. eCollection 2024.
ABSTRACT
T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumour suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion in vivo, and improves anti-tumour immunotherapy in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy.
PMID:38690263 | PMC:PMC11058823 | DOI:10.3389/fimmu.2024.1293723
Thyroid disease in ANCA-associated vasculitis: a clinical and epidemiological study
RMD Open. 2024 Apr 30;10(2):e003996. doi: 10.1136/rmdopen-2023-003996.
ABSTRACT
OBJECTIVES: To describe clinical and laboratory characteristics and outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and thyroid disease (TD). We also aimed to calculate incidence and identify predictors of TD in two large cohorts of patients with AAV.
METHODS: The study comprised 644 patients with AAV in a population-based cohort from southern Sweden (n=325) and a cohort from a specialised vasculitis centre in Cambridge, UK (n=319). Diagnosis and classification of AAV and TD were confirmed by medical record review. Person-years (PY) of follow-up were calculated from AAV diagnosis to the earliest of TD, death or the end of study. Cox-regression analysis was employed to study predictors of TD.
RESULTS: At AAV diagnosis, 100 individuals (15.5%, 77 females) had TD, 59 had myeloperoxidase (MPO)-ANCA+ and 34 had proteinase-3 (PR3)-ANCA+. Patients with TD tended to have lower C reactive protein, lower haemoglobin and fewer constitutional symptoms. Survival and renal survival was greater in those patients with AAV with pre-existing TD. During 4522 PY of follow-up, a further 29 subjects developed TD, yielding an incidence rate of 641/100 000 PY. No analysed factor predicted de novo TD in AAV. The prevalence of TD among patients with AAV in southern Sweden was 18%.
CONCLUSION: TD is a common comorbidity in AAV, affecting nearly one in five. While TD diagnosis is more common in females and MPO-ANCA+, these factors do not predict de novo TD after initiation of AAV treatment, necessitating monitoring of all patients with AAV with respect to this comorbidity.
PMID:38688691 | DOI:10.1136/rmdopen-2023-003996
Vitamin D regulates microbiome-dependent cancer immunity
Science. 2024 Apr 26;384(6694):428-437. doi: 10.1126/science.adh7954. Epub 2024 Apr 25.
ABSTRACT
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
PMID:38662827 | DOI:10.1126/science.adh7954
Century of Milestones and Breakthroughs Related to the Immune Mechanisms of Atherosclerosis
Arterioscler Thromb Vasc Biol. 2024 May;44(5):1002-1006. doi: 10.1161/ATVBAHA.124.319397. Epub 2024 Apr 24.
NO ABSTRACT
PMID:38657035 | DOI:10.1161/ATVBAHA.124.319397
Addressing ethnic disparities in neurological research in the United Kingdom: an example from the prospective multicentre COVID-19 Clinical Neuroscience Study
Clin Med (Lond). 2024 Apr 18:100209. doi: 10.1016/j.clinme.2024.100209. Online ahead of print.
ABSTRACT
BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection.
METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment.
RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-white ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups.
CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.
PMID:38642613 | DOI:10.1016/j.clinme.2024.100209
Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine
BMJ Open. 2024 Apr 17;14(4):e073639. doi: 10.1136/bmjopen-2023-073639.
ABSTRACT
INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments.
METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures.
ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk.
TRIAL REGISTRATION NUMBER: ISRCTN96296121.
PMID:38631839 | DOI:10.1136/bmjopen-2023-073639
Lipoarabinomannan modification as a source of phenotypic heterogeneity in host-adapted <em>Mycobacterium abscessus</em> isolates
Proc Natl Acad Sci U S A. 2024 Apr 23;121(17):e2403206121. doi: 10.1073/pnas.2403206121. Epub 2024 Apr 17.
ABSTRACT
Mycobacterium abscessus is increasingly recognized as the causative agent of chronic pulmonary infections in humans. One of the genes found to be under strong evolutionary pressure during adaptation of M. abscessus to the human lung is embC which encodes an arabinosyltransferase required for the biosynthesis of the cell envelope lipoglycan, lipoarabinomannan (LAM). To assess the impact of patient-derived embC mutations on the physiology and virulence of M. abscessus, mutations were introduced in the isogenic background of M. abscessus ATCC 19977 and the resulting strains probed for phenotypic changes in a variety of in vitro and host cell-based assays relevant to infection. We show that patient-derived mutational variations in EmbC result in an unexpectedly large number of changes in the physiology of M. abscessus, and its interactions with innate immune cells. Not only did the mutants produce previously unknown forms of LAM with a truncated arabinan domain and 3-linked oligomannoside chains, they also displayed significantly altered cording, sliding motility, and biofilm-forming capacities. The mutants further differed from wild-type M. abscessus in their ability to replicate and induce inflammatory responses in human monocyte-derived macrophages and epithelial cells. The fact that different embC mutations were associated with distinct physiologic and pathogenic outcomes indicates that structural alterations in LAM caused by nonsynonymous nucleotide polymorphisms in embC may be a rapid, one-step, way for M. abscessus to generate broad-spectrum diversity beneficial to survival within the heterogeneous and constantly evolving environment of the infected human airway.
PMID:38630725 | DOI:10.1073/pnas.2403206121
Human Genetics and Genomics for Drug Target Identification and Prioritization: Open Targets' Perspective
Annu Rev Biomed Data Sci. 2024 Apr 12. doi: 10.1146/annurev-biodatasci-102523-103838. Online ahead of print.
ABSTRACT
Open Targets, a consortium among academic and industry partners, focuses on using human genetics and genomics to provide insights to key questions that build therapeutic hypotheses. Large-scale experiments generate foundational data, and open-source informatic platforms systematically integrate evidence for target-disease relationships and provide dynamic tooling for target prioritization. A locus-to-gene machine learning model uses evidence from genome-wide association studies (GWAS Catalog, UK BioBank, and FinnGen), functional genomic studies, epigenetic studies, and variant effect prediction to predict potential drug targets for complex diseases. These predictions are combined with genetic evidence from gene burden analyses, rare disease genetics, somatic mutations, perturbation assays, pathway analyses, scientific literature, differential expression, and mouse models to systematically build target-disease associations (https://platform.opentargets.org). Scored target attributes such as clinical precedence, tractability, and safety guide target prioritization. Here we provide our perspective on the value and impact of human genetics and genomics for generating therapeutic hypotheses.
PMID:38608311 | DOI:10.1146/annurev-biodatasci-102523-103838
Limited oxygen in standard cell culture alters metabolism and function of differentiated cells
EMBO J. 2024 Apr 5. doi: 10.1038/s44318-024-00084-7. Online ahead of print.
ABSTRACT
The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1α activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, recapitulating a healthier adipocyte model. The functional benefits of increasing pericellular oxygen were also observed in macrophages, hPSC-derived hepatocytes and cardiac organoids. Our findings demonstrate that oxygen is limiting in many terminally-differentiated cell types, and that considering pericellular oxygen improves the quality, reproducibility and translatability of culture models.
PMID:38580776 | DOI:10.1038/s44318-024-00084-7
Bayesian profile regression for clustering analysis involving a longitudinal response and explanatory variables
Methodology (Gott). 2024 Mar 11;73(2):314-339. doi: 10.1093/jrsssc/qlad097. Epub 2023 Nov 8.
ABSTRACT
The identification of sets of co-regulated genes that share a common function is a key question of modern genomics. Bayesian profile regression is a semi-supervised mixture modelling approach that makes use of a response to guide inference toward relevant clusterings. Previous applications of profile regression have considered univariate continuous, categorical, and count outcomes. In this work, we extend Bayesian profile regression to cases where the outcome is longitudinal (or multivariate continuous) and provide PReMiuMlongi, an updated version of PReMiuM, the R package for profile regression. We consider multivariate normal and Gaussian process regression response models and provide proof of principle applications to four simulation studies. The model is applied on budding yeast data to identify groups of genes co-regulated during the Saccharomyces cerevisiae cell cycle. We identify 4 distinct groups of genes associated with specific patterns of gene expression trajectories, along with the bound transcriptional factors, likely involved in their co-regulation process.
PMID:38577633 | PMC:PMC7615733 | DOI:10.1093/jrsssc/qlad097
Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells
iScience. 2024 Mar 20;27(4):109546. doi: 10.1016/j.isci.2024.109546. eCollection 2024 Apr 19.
ABSTRACT
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity.
PMID:38577107 | PMC:PMC10993187 | DOI:10.1016/j.isci.2024.109546
Author Correction: Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
Nat Commun. 2024 Apr 4;15(1):2918. doi: 10.1038/s41467-024-47320-6.
NO ABSTRACT
PMID:38575615 | DOI:10.1038/s41467-024-47320-6
Immune microniches shape intestinal T<sub>reg</sub> function
Nature. 2024 Apr;628(8009):854-862. doi: 10.1038/s41586-024-07251-0. Epub 2024 Apr 3.
ABSTRACT
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
PMID:38570678 | PMC:PMC11041794 | DOI:10.1038/s41586-024-07251-0
Author Correction: A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Nat Commun. 2024 Mar 26;15(1):2658. doi: 10.1038/s41467-024-47041-w.
NO ABSTRACT
PMID:38531897 | DOI:10.1038/s41467-024-47041-w
Neuropsychiatric symptoms in Systemic Lupus Erythematosus: mixed methods analysis of patient-derived attributional evidence in the international INSPIRE project
Rheumatology (Oxford). 2024 Mar 22:keae194. doi: 10.1093/rheumatology/keae194. Online ahead of print.
ABSTRACT
OBJECTIVE: Attribution of neuropsychiatric symptoms in systemic lupus erythematosus (SLE) relies heavily on clinician assessment. Limited clinic time, variable knowledge, and symptom under-reporting contributes to discordance between clinician assessments and patient symptoms. We obtained attributional data directly from patients and clinicians in order to estimate and compare potential levels of direct attribution to SLE of multiple neuropsychiatric symptoms using different patient-derived measures.
METHODS: Quantitative and qualitative data analysed included: prevalence and frequency of neuropsychiatric symptoms, response to corticosteroids, and concurrence of neuropsychiatric symptoms with non-neuropsychiatric SLE disease activity. SLE patients were also compared with controls and inflammatory arthritis (IA) patients to explore attributability of neuropsychiatric symptoms to the direct disease effects on the brain/nervous system.
RESULTS: We recruited 2,817 participants, including 400 clinicians. SLE patients (n = 609) reported significantly higher prevalences of neuropsychiatric symptoms than controls (n = 463) and IA patients (n = 489). SLE and IA patients' quantitative data demonstrated multiple neuropsychiatric symptoms relapsing/remitting with other disease symptoms such as joint pain. Over 45% of SLE patients reported resolution/improvement of fatigue, positive sensory symptoms, severe headache, and cognitive dysfunction with corticosteroids. Evidence of direct attributability in SLE was highest for hallucinations and severe headache. SLE patients had greater reported improvement from corticosteroids (p= 0.008), and greater relapsing-remitting with disease activity (p< 0.001) in the comparisons with IA patients for severe headache. Clinician and patients reported insufficient time to discuss patient-reported attributional evidence. Symptoms viewed as indirectly related/non-attributable were often less prioritised for discussion and treatment.
CONCLUSION: We found evidence indicating varying levels of direct attributability of both common and previously unexplored neuropsychiatric symptoms in SLE patients, with hallucinations and severe headache assessed as the most directly attributable. There may also be-currently under-estimated-direct effects on the nervous system in IA and other systemic rheumatological diseases.
PMID:38518094 | DOI:10.1093/rheumatology/keae194
Venous-plexus-associated lymphoid hubs support meningeal humoral immunity
Nature. 2024 Mar 20. doi: 10.1038/s41586-024-07202-9. Online ahead of print.
ABSTRACT
There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system1,2. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development3-6. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.
PMID:38509366 | DOI:10.1038/s41586-024-07202-9
Trends in Systemic Glucocorticoid Utilization in the United Kingdom from 1990 to 2019: A Population-Based, Serial Cross-Sectional Analysis
Pragmat Obs Res. 2024 Mar 15;15:53-64. doi: 10.2147/POR.S442959. eCollection 2024.
ABSTRACT
PURPOSE: Associations between systemic glucocorticoid (SGC) exposure and risk for adverse outcomes have spurred a move toward steroid-sparing treatment strategies. Real-world changes in SGC exposure over time, after the introduction of steroid-sparing treatment strategies, reveal areas of successful risk mitigation as well as unmet needs.
PATIENTS AND METHODS: A population-based ecological study was performed from the Optimum Patient Care Research Database to describe SGC prescribing trends of steroid-sparing treatment strategies in primary care practices before and after licensure of biologics in the United Kingdom from 1990 to 2019. Each analysis year included patients aged ≥5 years who were registered for ≥1 year with a participating primary care practice. The primary analysis was SGC exposure, defined as total cumulative SGC dose per patient per year, for asthma, severe asthma, chronic obstructive pulmonary disease (COPD), nasal polyps, Crohn's disease, rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus. Secondary outcomes were percentages of patients prescribed SGCs and number of SGC prescriptions per patient per year.
RESULTS: The number of patients who met study inclusion criteria ranged from 219,862 (1990) to 1,261,550 (2019). At the population level, patients with asthma or COPD accounted for 67.7% to 73.2% of patients per year with an SGC prescription. Over three decades, decreases in SGC total yearly dose ≥1000 mg have been achieved in multiple conditions. Patients with COPD prescribed SGCs increased from 5.8% (1990) to 34.8% (2017). SGC prescribing trends for severe asthma, Crohn's disease, and ulcerative colitis show decreased prescribing trends after the introduction of biologics.
CONCLUSION: Decreases in total yearly SGC doses have been shown in multiple conditions; however, for conditions such as severe asthma and COPD, an unmet need remains for increased awareness of SGC burden and the adoption or development of SGC-sparing alternatives to reduce overuse.
PMID:38505738 | PMC:PMC10949995 | DOI:10.2147/POR.S442959
resPAINT: Accelerating Volumetric Super-Resolution Localisation Microscopy by Active Control of Probe Emission
Angew Chem Weinheim Bergstr Ger. 2022 Oct 17;134(42):e202206919. doi: 10.1002/ange.202206919. Epub 2022 Aug 23.
ABSTRACT
Points for accumulation in nanoscale topography (PAINT) allows practically unlimited measurements in localisation microscopy but is limited by background fluorescence at high probe concentrations, especially in volumetric imaging. We present reservoir-PAINT (resPAINT), which combines PAINT and active control of probe photophysics. In resPAINT, an activatable probe "reservoir" accumulates on target, enabling a 50-fold increase in localisation rate versus conventional PAINT, without compromising contrast. By combining resPAINT with large depth-of-field microscopy, we demonstrate super-resolution imaging of entire cell surfaces. We generalise the approach by implementing various switching strategies and 3D imaging techniques. Finally, we use resPAINT with a Fab to image membrane proteins, extending the operating regime of PAINT to include a wider range of biological interactions.
PMID:38505515 | PMC:PMC10946633 | DOI:10.1002/ange.202206919
