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Each year, the Nuffield Department of Medicine awards prizes to its graduate research students for various achievements, including success in terms of discoveries and published work, significant achievements in establishing infrastructure, success in strongly collaborative projects, and involvement in public engagement and other departmental activities.
Pneumococcal serotype epidemiology
This chapter summarizes the relative prevalences of the most common serotypes prior to and following the introduction of the heptavalent pneumococcal capsular polysaccharide vaccine (PCV-7). It provides thoughts about the selection of serotypes for future-generation conjugate vaccines. A remarkable feature of the global epidemiology of pneumococcal carriage is the consistency of the dominant carriage serotypes in very different environments and at different times. Invasive disease potential, or invasiveness, is a measure of the ability of pneumococci to progress from nasopharyngeal carriage to invasive disease in humans. It differs from virulence in that the latter is often used to describe the ability of a pathogen to cause disease in laboratory animals. The 11-valent formulation prevented vaccine-related otitis media and was also shown to elicit antibodies with functional immunogenicity (opsonophagocytic activity) against 6A comparable to that seen with PCV-7. The incidence of invasive pneumococcal disease (IPD) due to vaccine serotypes has decreased substantially since the introduction of PCV-7 in the United States, in vaccinated children as well as all other age groups, indicating that pneumococcal transmission was interrupted as a result of the reduction in carriage in the vaccinated pediatric population. For mucosal disease, otitis media and nonbacteremic pneumonia, it is less clear which serotypes it would be most valuable to add since there appear to be less clearcut differences in invasiveness among serotypes. The only certain way of preventing mucosal disease is to sterilize the nasopharynx with respect to pneumococci.
SARS-CoV-2 infection enhancement by amphotericin B: implications for disease management.
Severe coronavirus disease 2019 (COVID-19) patients who require hospitalization are at high risk of invasive pulmonary mucormycosis. Amphotericin B (AmB), which is the first-line therapy for invasive pulmonary mucormycosis, has been shown to promote or inhibit replication of a spectrum of viruses. In this study, we first predicted that AmB and nystatin had strong interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins using in silico screening, indicative of drugs with potential therapeutic activity against this virus. Subsequently, we investigated the impact of AmB, nystatin, natamycin, fluconazole, and caspofungin on SARS-CoV-2 infection and replication in vitro. Results showed that AmB and nystatin actually increased SARS-CoV-2 replication in Vero E6, Calu-3, and Huh7 cells. At optimal concentrations, AmB and nystatin increase SARS-CoV-2 replication by up to 100- and 10-fold in Vero E6 and Calu-3 cells, respectively. The other antifungals tested had no impact on SARS-CoV-2 infection in vitro. Drug kinetic studies indicate that AmB enhances SARS-CoV-2 infection by promoting viral entry into cells. Additionally, knockdown of genes encoding for interferon-induced transmembrane (IFITM) proteins 1, 2, and 3 suggests AmB enhances SARS-CoV-2 cell entry by overcoming the antiviral effect of the IFITM3 protein. This study further elucidates the role of IFITM3 in viral entry and highlights the potential dangers of treating COVID-19 patients, with invasive pulmonary mucormycosis, using AmB.IMPORTANCEAmB and nystatin are common treatments for fungal infections but were predicted to strongly interact with SARS-CoV-2 proteins, indicating their potential modulation or inhibition against the virus. However, our tests revealed that these antifungals, in fact, enhance SARS-CoV-2 infection by facilitating viral entry into cells. The magnitude of enhancement could be up to 10- or 100-fold, depending on cell lines used. These findings indicate that AmB and nystatin have the potential to enhance disease when given to patients infected with SARS-CoV-2 and therefore should not be used for treatment of fungal infections in active COVID-19 cases.
Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling
Abstract In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we use a disease-positioned mouse and human tissue to explore the consequences of pathological BMP signalling dysregulation on epithelial-mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist Grem1 results in ectopic crypt formation, with lineage tracing demonstrating the presence of Lgr5(−) stem/progenitor cells. Isolated epithelial cell Grem1 expression has no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with an anti-Grem1 antibody abrogates the polyposis phenotype, and triangulation of specific pathway inhibitors defines a pathological sequence of events, with Wnt-ligand-dependent ectopic stem cell niches forming through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function.
The limitations of mobile phone data for measuring movement patterns of populations at risk of malaria.
BACKGROUND: As global mobile phone adoption increases, mobile phone data has been increasingly used to measure movement patterns of populations at risk of malaria. However, the representativeness of mobile phone data for populations at risk of malaria has not been assessed. This study aimed to assess this representativeness using prospectively collected data on mobile phone ownership and use from malaria patients in Lao PDR. METHODS: A prospective observational study was conducted from 2017 to 2021. 6320 patients with confirmed malaria in 107 health facilities in the five southernmost provinces of Lao PDR were surveyed regarding their demographics, mobile phone ownership and use. Data on the demographics of mobile phone owners and users in the general population of Lao PDR were obtained from the 2017 Lao Social Indicator Survey II, which was a nationally representative survey sample. Descriptive analysis was performed, and logistic regression with weights on aggregate data was used to compare the demographic distribution of mobile phone ownership and use in malaria patients with that in the general population. RESULTS: Most patients with malaria (76%) did not own or use a mobile phone. From 2017 to 2021, mobile phone usage in the general population consistently ranged between 53 and 67%, whereas among malaria patients, usage remained significantly lower, fluctuating between 20 and 28%. At the district level, log malaria incidence rate (API) was weakly negatively correlated with the proportion of mobile owners (R2 = 0.3, p = 0.005). Mobile phone ownership and usage among malaria patients were significantly lower than in the general population (p-value
Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity
AbstractCancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
Paediatric anaemia in rural Kenya and the role of travel time to emergency care services.
BACKGROUND: Access to emergency care (EC) services is crucial for severe anaemia outcome. Limited information exists on the association between travel times to EC services and the presentation and severity of anaemia upon hospital admission. Here, we investigate the association between travel time and presentation of severe anaemia (compared to mild/moderate anaemia) at admission in western Kenya. METHODS: Data from January 2020 to July 2023 from Busia County Referral Hospital were assembled for paediatric admissions aged 1-59 months residing in Busia County. Travel time from a patient's village to the hospital was calculated using a least cost path algorithm. Anaemia severity was categorised as mild (Hb ≥ 7-<10 g dl-1), moderate (Hb ≥ 5-<7 g dl-1) and severe (Hb
Impact of GLP-1 receptor agonist-induced weight loss on 22 cancers in the next ten years using a Markov state-transition model - A UK weight and wellness cancer landscape analysis.
BACKGROUND: Obesity is a major risk factor for many cancers. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have emerged as highly effective agents for weight loss. There is a lack of published modelling studies describing the broader implications of GLP-1RA-induced weight loss on cancer incidence. METHODS: A Markov state-transition model was devised to evaluate the impact of GLP-1RA-induced weight loss on future cancer incidence in adults. Contemporary data on weight distribution, cancer incidence, and body mass index (BMI)-associated cancer risk were integrated into the model. Two scenarios were assessed, GLP-1RAs were made available to all people with obesity (BMI>30) or only those with severe obesity (BMI>35). New cancer cases were simulated over a decade. RESULTS: Our simulation within a closed cohort indicated that GLP-1RA-induced weight loss would lead to a marked decrease in cancer cases over 10 years in adults. If GLP-1RAs were made available for all people with obesity and 50 % of people with obesity moved into a lower BMI category, there was a simulated reduction in cumulative cancer cases of 21,443. If access to GLP-1RAs was restricted to people with severe obesity and 50 % of people with severe obesity moved into a lower BMI category, there was a simulated reduction in cumulative cancer cases of 7476. This effect was greatest for uterine, kidney, liver and colon cancer. CONCLUSION: Targeted weight control measures using GLP-1RAs could reduce new cancer cases. Based on our models, the potential risk of thyroid cancer is balanced by a reduction in other cancer types. This modelling study shows for the first time that implementing effective weight loss programmes could enhance the health of the population over the next decade through a reduction in cancer cases.
Unveiling the structural spectrum of SARS-CoV-2 fusion by in situ cryo-ET.
SARS-CoV-2 entry into host cells is mediated by the spike protein, which drives membrane fusion. While cryo-EM reveals stable prefusion and postfusion conformations of the spike, the transient fusion intermediate states during the fusion process remain poorly understood. Here, we design a near-native viral fusion system that recapitulates SARS-CoV-2 entry and use cryo-electron tomography (cryo-ET) to capture fusion intermediates leading to complete fusion. The spike protein undergoes extensive structural rearrangements, progressing through extended, partially folded, and fully folded intermediates prior to fusion-pore formation, a process that depends on protease cleavage and is inhibited by the WS6 S2 antibody. Upon interaction with ACE2 receptor dimer, spikes cluster at membrane interfaces and following S2' cleavage concurrently transition to postfusion conformations encircling the hemifusion and initial fusion pores in a distinct conical arrangement. S2' cleavage is indispensable for advancing fusion intermediates to the fully folded postfusion state, culminating in membrane integration. Subtomogram averaging reveals that the WS6 S2 antibody binds to the spike's stem-helix, crosslinks and clusters prefusion spikes, as well as inhibits refolding of fusion intermediates. These findings elucidate the entire process of spike-mediated fusion and SARS-CoV-2 entry, highlighting the neutralizing mechanism of S2-targeting antibodies.
Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity.
Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHATL8F/p53R175H) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.
Quantifying biomolecular organisation in membranes with brightness-transit statistics.
Cells crucially rely on the interactions of biomolecules at their plasma membrane to maintain homeostasis. Yet, a methodology to systematically quantify biomolecular organisation, measuring diffusion dynamics and oligomerisation, represents an unmet need. Here, we introduce the brightness-transit statistics (BTS) method based on fluorescence fluctuation spectroscopy and combine information from brightness and transit times to elucidate biomolecular diffusion and oligomerisation in both cell-free in vitro and in vitro systems incorporating living cells. We validate our approach in silico with computer simulations and experimentally using oligomerisation of EGFP tethered to supported lipid bilayers. We apply our pipeline to study the oligomerisation of CD40 ectodomain in vitro and endogenous CD40 on primary B cells. While we find a potential for CD40 to oligomerize in a concentration or ligand depended manner, we do not observe mobile oligomers on B cells. The BTS method combines sensitive analysis, quantification, and intuitive visualisation of dynamic biomolecular organisation.
Comparison of different methods for isolating CD8+ T lymphocyte‐derived extracellular vesicles and supramolecular attack particles
AbstractCD8+ T lymphocytes play vital roles in killing infected or deranged host cells, recruiting innate immune cells, and regulating other aspects of immune responses. Like any other cell, CD8+ T cells also produce extracellular particles. These include extracellular vesicles (EVs) and non‐vesicular extracellular particles (NVEPs). T cell‐derived EVs are proposed to mediate cell‐to‐cell signalling, especially in the context of inflammatory responses, autoimmunity, and infectious diseases. CD8+ T cells also produce supramolecular attack particles (SMAPs), which are in the same size range as EVs and mediate a component of T cell mediated killing. The isolation technique selected will have a profound effect on yield, purity, biochemical properties and function of T cell‐derived particles; making it important to directly compare different approaches. In this study, we compared commonly used techniques (membrane spin filtration, ultracentrifugation, or size exclusion liquid chromatography) to isolate particles from activated human CD8+ T cells and validated our results by single‐particle methods, including nanoparticle tracking analysis, flow cytometry, electron microscopy and super‐resolution microscopy of the purified sample as well as bulk proteomics and lipidomics analyses to evaluate the quality and nature of enriched T cell‐derived particles. Our results show that there is a trade‐off between the yield and the quality of T cell‐derived particles. Furthermore, the protein and lipid composition of the particles is dramatically impacted by the isolation technique applied. We conclude that from the techniques evaluated, size exclusion liquid chromatography offers the highest quality of T cell derived EVs and SMAPs with acceptable yields for compositional and functional studies.
Clathrin mediates both internalization and vesicular release of triggered T cell receptor at the immunological synapse.
Ligation of T cell receptor (TCR) to peptide-MHC (pMHC) complexes initiates signaling leading to T cell activation and TCR ubiquitination. Ubiquitinated TCR is then either internalized by the T cell or released toward the antigen-presenting cell (APC) in extracellular vesicles. How these distinct fates are orchestrated is unknown. Here, we show that clathrin is first recruited to TCR microclusters by HRS and STAM2 to initiate release of TCR in extracellular vesicles through clathrin- and ESCRT-mediated ectocytosis directly from the plasma membrane. Subsequently, EPN1 recruits clathrin to remaining TCR microclusters to enable trans-endocytosis of pMHC-TCR conjugates from the APC. With these results, we demonstrate how clathrin governs bidirectional membrane exchange at the immunological synapse through two topologically opposite processes coordinated by the sequential recruitment of ecto- and endocytic adaptors. This provides a scaffold for direct two-way communication between T cells and APCs.
Androgens Profile in Blood Serum and Follicular Fluid of Women With Poor Ovarian Response During Controlled Ovarian Stimulation Reveals Differences Amongst POSEIDON Stratification Groups: A Pilot Study.
Patients with poor ovarian response (POR) to exogenous gonadotropins stimulation for assisted reproductive technology (ART) have decreased circulating androgens during spontaneous cycles. The Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) is a 4-tier stratification of women with POR to controlled ovarian stimulation (COH) based on age and biomarkers of ovarian reserve has been proposed to maximize the clinical management of this group for ART. The aim of the present study was to characterize the levels of androgens during COH in follicular fluid (FF) and serum in POSEIDON subgroups and compared them with women of normal ovarian response. Sixty nine consecutive patients undergoing ART were included and testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), estradiol, sex hormone-binding globulin (SHBG), and insulin-like growth factor 1 (IGF-1) were measured in serum and FF collected at the time of oocyte pick-up. The number of retrieved oocytes was registered for each patient for their allocation to the respective POSEIDON subgroup. The control group comprised 19 women and the POSEIDON group 1 (age < 35, normal ovarian reserve biomarkers) n = 14, group 2 (age ≥ 35, normal ovarian reserve biomarkers) n = 8, group 3 (age < 35, poor ovarian reserve biomarkers) n = 6 and group 4 (age ≥ 35, poor ovarian reserve biomarkers) n = 22. Serum levels of total testosterone, androstenedione and DHEA-S were not different in group 1 vs. control but significantly decreased in group 3 vs. control. DHEA-S in FF was also significantly decreased in group 3 vs. control. In addition, serum testosterone was decreased in groups 2 and 4 vs. control; and serum androstenedione and estradiol were reduced in group 4 vs. control. No differences were observed for estradiol, SHBG and IGF-1 in FF. Finally, a high correlation between serum and FF DHEA-S was observed when data from samples of all groups were pooled. Group 1 did not show hypoandrogenemia however group 3 had low levels of all measured androgens in serum and DHEA-S in FF. Such differences might help to better characterize and/or improve the clinical management of women with POR according to their respective POSEIDON stratification.
Percepciones y creencias sobre criopreservación embrionaria en mujeres y hombres que se realizan técnicas de reproducción asistida en Santiago, Chile.
Background and objetiveAlthough embryo cryopreservation is frequently used as part of assisted reproductive technology, quantitave information addressing how infertile couples live the experience of having cryopreserved embryos is lacking in Chile. The aim of this study is to examine men and women's perception and beliefs regarding their cryopreserved embryos, as well as their perspective on embryo donation and disposition. Methods: 153 women and men with frozen embryos from a public hospital, Instituto de Investigactiones Materno Infantil, and a private clinic, Clínica Las Condes, in Santiago, Chile, responded between May 2015 and May 2016 to an anonymous online survey addressing their perceptions and beliefs concerning their cryopreserved embryos.ResultsRespondents considered their frozen embryos to be equivalent to a child (53.2%) or a potential child (40.7%). Only 8% regard them as an organized group of cells. Over 60% of respondents disagree with destroying surplus embryos or using them for research. Participants from the public hospital are more willing to donate their embryos to another couple than those from the private center (61% vs 40%; P=0.016); 34% of respondents agreed to donate surplus embryos to same sex couples.ConclusionThis study reveals that Chilean couples are emotionally bound to their frozen embryos, and that discarding them is not an option. The results from this survey will help strengthen counseling for couples to enable them to make informed decisions regarding their surplus embryos.
[Prevalence of endometriosis in 287 women undergoing surgical sterilization in Santiago Chile].
BackgroundThe clinical manifestations of endometriosis are infertility, dysmenorrhea, sexuality disturbances, and chronic pelvic pain. It is the cause of 30 to 50% of infertility cases. In developed countries, the prevalence of endometriosis among women undergoing surgical sterilization is approximately 6%.AimTo determine the prevalence of endometriosis among women with proven fertility in Santiago de Chile.Material and methodsReview of surgical protocols of 287 women aged 25 to 49 years, subjected to a surgical sterilization between 2007 and 2011.ResultsEndometriosis was found in 14 of the 287 women (4.9%). In spite of being asymptomatic, five of the 14 women with endometriosis were classified as severe, due to the presence of at least one endometrioma. In order of frequency, the most commonly affected anatomical sites were the ovary, the peritoneum, the posterior cul-de-sac and uterosacral ligaments.ConclusionsOur findings are very similar to those found elsewhere and suggest that fertile women could better tolerate endometriosis than their infertile counterparts.
[Effects of smoking on plasma antimüllerian hormone concentrations among infertile women].
BackgroundSmoking may hamper female fertility, probably modifying ovarian reserve. Antimüllerian hormone (AMH) is an accurate marker for ovarian reserve.AimTo look for an association between smoking status and plasma AMH concentration.Patients and methodsA cohort of 141 infertile women in a university setting in Santiago, Chile was studied. Demographic and smoking data, including the number of cigarettes smoked during the last week, were collected. A blood sample was obtained and kept frozen until determination of AMH by ELISA and follicle stimulating hormone (FSH) and estradiol at day three of the menstrual cycle, by radioimmunoanalysis.ResultsThirty two participants smoked (23%). There were no significant differences in age, parity, body mass index, causes of infertility and day three FSH and estradiol between smokers and nonsmokers. According to a regression analysis, there was a significant decrease in AMH concentration with age and active cigarette smoking. A drop in AMH of -0.189 ng/mL with a unitary change in age and a decrease of -2.29 ng/mL when everything else remains constant, except the smoking status, were established (p < 0.001 and r2 = 0.134). However, no dose response was observed when the number of cigarettes smoked during the last week were introduced in the model. Furthermore, no significant association of plasma AMH with day three plasma FSH and estradiol concentrations was observed.ConclusionsCigarette smoking is associated with decreased AMH plasma concentrations among infertile women. However there was no dose response relationship. The mechanisms underlying this association are unknown and further investigation is required.