143174 research outputs found
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HIV diagnosis during acute infection: implications of long-acting preexposure prophylaxis and other evolving challenges
No full textPurpose of review
Tests for HIV may perform differently in some circumstances such as with preexposure prophylaxis (PrEP) or other HIV prevention agents. Testing algorithms may not account for this, with a risk of false negative or positive HIV results. In this review we have explored the challenges of HIV testing in these special circumstances.
Recent findings
Long-acting injectable PrEP using cabotegravir or lenacapavir has been studied in large randomized controlled trials (HPTN083/084 and PURPOSE1/2 respectively). Injectable PrEP was significantly more efficacious than oral PrEP, but infections still occurred risking the emergence of HIV drug-resistance. HIV diagnostic test results were atypical in those receiving injectable PrEP, with low or undetectable HIV viral loads, delayed or diminished antibody, and HIV detection assays reverting from reactive to unreactive; so-called long acting early viral inhibition (LEVI) syndrome. In these cases, missed or delayed HIV diagnoses could be reduced with the use of HIV nucleic acid amplification tests in addition to routine testing, but this remains unfeasible in many settings.
Summary
Finding HIV testing strategies that are affordable and practical in low- and middle-income countries that can accurately diagnose HIV in the context of HIV prevention is of high importance, but more research is needed in this area
Third exposure to COVID-19 infection or vaccination differentially impacts T cell responses
No full textBackground
In 2021, the rapid rollout of two doses of SARS-CoV-2 vaccines reduced COVID-19 severity and mortality. However, further vaccine doses as a prime-boost schedule were limited, and lifting of public health restrictions by late 2021 frequently led to infection, rather than vaccine, as a third exposure.
Objective
To compare how the third exposure through mRNA booster or SARS-CoV-2 infection shapes humoral and cellular immunity following two vaccine doses.
Methods
We compared immune responses after the third exposure in healthy adults enrolled in the UCLH-Crick Legacy cohort study (NCT04750356) between those receiving ancestral spike-encoded mRNA booster (vaccine immunity, n = 38) or COVID-19 infection (hybrid immunity, n = 13) following two vaccine doses. Immune profiles were evaluated using live virus neutralization assays, IFN-γ ELISpot, Luminex assay, flow cytometry and mass cytometry.
Results
Both total anti-Spike IgG and variant-specific neutralising antibodies were comparable following infection or vaccine as a third exposure. Overall, T cell populations were similar but functionally different. CD8⁺ Effector Memory (TEM) cells in the vaccine group showed higher expression of CD69 and Granzyme B following stimulation with SARS-CoV-2 Spike peptides. In contrast, the hybrid group produced higher levels of innate immune associated cytokines IL-10 and IL-34, as well as the T cell homing chemokine CCL25, after stimulation.
Conclusions
While both exposures generated comparable breadth of protection against SARS-CoV-2 variants, our findings suggest that the route of third exposure influences different aspects of the immune response, warranting further investigation into long-term immunity at both systemic and mucosal sites
Competing societal objectives in epidemic mitigation: a modelling study of COVID-19 in the Philippines
No full textSchool closures and suspension of non-essential economic activities are highly effective respiratory-pandemic mitigation strategies because they effectively interrupt disease transmission. However, they come with high societal costs. Most of these costs are borne by workers who lose their income, especially those who are not supported by welfare benefits, and students whose future income depends on their education. In countries where many households live close to the poverty line, closures should be designed to minimise impacts on the most vulnerable. The objective of this study is to learn and compare policy responses that minimise the number of householdspeople that fall below the poverty line, maximise GDP, or maximise societal welfare in a model of the COVID-19 outbreak in the Philippines. Towards this objective, we construct social welfare functions that take into account lives, education, poverty, and GDPquantify societal welfare in terms of lives, education, GDP, and we introduce poverty as a novel fourth dimension. We then use a population microsimulation model together with an economy-structured, an epidemiological model, and GDP and education projections to determine intervention strategies involving the partial closure of schools and economic sectors with the objective of mitigating the epidemic while minimising societal losses. We find the cost of reducing poverty is substantial in terms of the other outcomes, making a case for poverty reduction as an important tool for increasing societal resilience and preparedness for crises such as pandemics. From a modelling perspective, we identify the need for timely data collection in order to create tools to assist in future epidemics
Phase space dynamics of non-Hermitian quantum systems
No full textIn this thesis, we shall study phase space dynamics of non-Hermitian quantum systems in the semiclassical limit. I derive the (semi)classical dynamics generated by non-Hermitian Hamiltonians from quantum dynamical equations for two quasiprobability distributions, the Husimi and Wigner distributions. The methodology presented applies to generic Hamiltonians expressed as power series of n-dimensional position and momentum operators and the quasi-probability distributions are allowed to have arbitrary initial conditions. In the Husimi and Wigner representations, we uncover an important function, the norm landscape, contained within the classical dynamics, which evolves over time and phase space. The norm landscape
describes the classical analogue of loss and gain, a fundamental characteristic of non-Hermitian system.
This thesis analyses the quantum and classical phase space dynamics of several examples of non-Hermitian systems. The examples include linear systems, which in some cases have exact analytic solutions in either the Husimi or Wigner representation; non-linear systems, including a dissipative and a PT-symmetric Hamiltonian, and a two-dimensional billiard model. The conclusion of the thesis summarises preliminary results for further research projects.Open Acces
Structural integrity of hybrid joints for transport applications
No full textThis thesis examines the structural integrity of automotive joints in lightweight vehicle design, focusing on aluminium alloys AA6082 (6xxx series) and AA7075 (7xxx series). With the automotive industry increasingly adopting lightweight materials such as advanced high-strength steels, aluminium alloys, and carbon-fibre-reinforced polymer composites to improve fuel efficiency and reduce emissions, reliable joining methods are essential. Three joining techniques were investigated: self-piercing riveting (SPR), adhesive bonding (SikaPower® 497 epoxy), and hybrid SPR–adhesive bonding. Single lap shear specimens were prepared for similar (AA6082–AA6082) and dissimilar (AA6082–AA7075) configurations. Quasi-static tests were performed under a constant displacement rate, and fatigue tests under tension–tension loading (load ratio R = 0.1, and frequency 10Hz) in both ambient and wet conditions.
Quasi-static results showed SPR joints had the lowest failure loads and displacements, while adhesive joints achieved the highest failure loads and greater displacements. Hybrid joints exhibited slightly lower failure loads than adhesive joints but the greatest displacements and energy absorption, with a distinct two-stage failure process. Dissimilar joints showed higher strengths but lower energy absorption than similar joints. Fatigue results indicated SPR joints had the shortest fatigue lives, failing at rivet-induced stress concentrations. Adhesive joints performed best, failing in a mixed cohesive–interfacial fracture in the adhesive layer. Hybrid joints matched adhesive joints at low loads but had improved lives at high loads; however, their fatigue curves were steeper, indicating greater load sensitivity. Dissimilar substrates generally improved fatigue lives but increased load sensitivity. The wet testing conditions had no significant effect on fatigue performance in this research due to the relatively short duration of exposure to water.
This study demonstrates the relative advantages and limitations of SPR, adhesive, and hybrid joints for lightweight automotive structures, highlighting how joint type, material pairing, and loading conditions influence strength, energy absorption, and fatigue life.Open Acces
Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses
No full textThe SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A virus with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness
Sanna Passino and Heard's contribution to the Discussion of 'Statistical exploration of the Manifold Hypothesis' by Whiteley et al
No full textCAR-iNKT cells: redefining the frontiers of cellular immunotherapy
No full textDespite significant advances in cancer therapies, many malignancies remain resistant to current treatments due to complex immunosuppressive mechanisms, limited neoantigen expression, and dynamic tumor adaptations, underscoring the need for innovative therapeutic strategies. Adoptive cell therapy (ACT), particularly with chimeric antigen receptors (CARs and recombinant TCRs) targeting cancer-associated antigens, has emerged as a transformative strategy. However, conventional CAR-T cell therapies face substantial limitations such as manufacturing challenges, severe toxicities, and limited efficacy against solid tumors. Invariant natural killer T (iNKT) cells, a unique lymphocyte subset bridging innate and adaptive immunity, have emerged as a compelling alternative platform for CAR-based therapies, due to their distinctive ability to persist, penetrate in and remodel the tumor microenvironment (TME). Unlike conventional T cells, iNKT cells exhibit rapid activation without priming, potent cytotoxicity, and extensive immunomodulatory functions. Furthermore, the inherent immunomodulatory properties of iNKT cells through interactions with the monomorphic antigen-presenting molecule CD1d or stress ligands augment endogenous anti-tumor immunity by activating NK cells and cytotoxic T lymphocytes, promoting dendritic cell maturation, and reducing immunosuppressive myeloid cells, unlike other Innate T cells. CAR-engineered iNKT (CAR-iNKT) cells therefore leverage multiple targeting mechanisms through their native semi-invariant T-cell receptor (TCR), NK receptors (NKRs) and engineered CARs, enabling broader and more effective tumor recognition while actively reshaping immunosuppressive TME. Notably, iNKT cells lack alloreactivity, circumventing the risk of graft-versus-host disease (GvHD), positioning CAR-iNKT cells as ideal candidates for “off-the-shelf” allogeneic therapies that can overcome the limitations of existing immunotherapies
The importance of past rifting in large igneous province development
No full textLithospheric thin zones, such as recently-failed rifts, are generally assumed weak spots where magmatism and deformation can concentrate during rifting and large igneous province development¹¯³. Yet, the Turkana Depression in East Africa, site of the failed 66 Ma Anza Rift, did not experience the widespread flood magmatism seen on the adjacent Ethiopian Plateau, despite being a lithospheric thin-spot when the region encountered hot plume material ca. 45 Ma⁴. Here, we jointly invert surface-wave and receiver function data to constrain crustal and upper-mantle seismic structure below the Depression to evaluate lithospheric thermo-mechanical modification. Evidence for thick lower-crustal intrusions, ubiquitous below the uplifted Ethiopian Plateau⁵;⁶, is comparatively lacking below the Depression’s failed Anza Rift system, which ongoing East African rifting is circumnavigating, not exploiting. The mantle lithosphere below the Depression has also retained its cool, fast wavespeed ‘lid’ character, contrasting the Ethiopian Plateau. Volatile depletion during failed Anza rifting likely rendered the thinned lithosphere refractory without later rejuvenation. Subsequent rifting and magmatism thus initiated away from the still-thin Anza Rift, in regions where fertile lithosphere enabled melting and the sufficient lowering of plate yield strength. Areas of thinned lithosphere are thus not necessarily persistent weak zones where significant extension and magmatic provinces will develop
T follicular helper cells drive functionally distinct lymphoid and lung resident germinal centres and limit allergic airway disease
No full textT follicular helper cells (TFH) play a central role in orchestrating antibody mediated immunity. Despite the importance of antibody responses, especially allergen-specific IgE, in allergic airway diseases (AAD) such as asthma, the precise role TFH play in AADs has remained elusive. Using a mouse model of chronic allergen induced AAD we now show that germinal centres (GCs) containing TFH and GC B cells accumulate in both the lung draining lymph nodes (dLNs) and the lungs themselves after allergen exposure. The formation of these GCs is dependent on TFH, as is generation of allergen specific IgA, IgG and IgE, with IgG1 and IgE-switched B cells being predominantly found in the dLNs while IgA switched B cells were only found in the lungs. Fitting with this, allergen-induced lung resident TFH and B cells are functionally and transcriptionally distinct from their lymphoid counterparts, with lung GCs providing a unique site of IgA-switch, a process that is partially IL-17A dependent. Finally while TFH deficiency did not worsen allergic airways disease after 3 weeks of aero-allergen exposure, worsened lung function and enhanced TH2-based inflammation in the respiratory tract were seen following 5 weeks of exposure. Overall these data suggest that TFH play a pivotal role in shaping immune responses both in the dLNs and the respiratory tract, and while they can promote key type-2 inflammatory pathways such as IgE production, they can also act to limit prolonged type-2 inflammation