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High-spin state dynamics and quintet-mediated emission in intramolecular singlet fission
Get PDFHigh-spin states in molecular systems hold significant interest for applications ranging from optoelectronics to quantum technologies. Spin states generated in intramolecular singlet fission are of particular relevance, yet the mechanisms controlling triplet-pair formation are not fully understood – especially the involvement of quintet states in luminescence at room temperature remains experimentally elusive. Here, we investigate high-spin state formation and emission in dimers and trimers comprising multiple diphenylhexatriene units. We demonstrate the formation of pure quintet states in all these oligomers, with quintet-mediated emission dominating delayed fluorescence up to room temperature. By distinguishing between the formation of weakly exchange-coupled triplet pairs and triplet excitons generated by intersystem crossing, we identify the methylated trimer as the only oligomer exhibiting exclusively the desired singlet fission route. These findings establish quintet-mediated delayed emission as a distinct spin-selective pathway and show how molecular structure directs high-spin formation, opening opportunities for room-temperature molecular quantum technologies
Generalised multilevel Picard approximations
No full textIt is one of the most challenging problems in applied mathematics to approximatively solve highdimensional partial differential equations (PDEs). In particular, most of the numerical approximation schemes studied in the scientific literature suffer under the curse of dimensionality in the sense that the number of computational operations needed to compute an approximation with an error of size at most ε > 0 grows at least exponentially in the PDE dimension d ∈ N or in the reciprocal of ε. Recently, so-called full-history recursive multilevel Picard (MLP) approximation methods have been introduced to tackle the problem of approximately solving high-dimensional PDEs. MLP approximation methods currently are, to the best of our knowledge, the only methods for parabolic semi-linear PDEs with general time horizons and general initial conditions for which there is a rigorous proof that they are indeed able to beat the curse of dimensionality. The main purpose of this work is to investigate MLP approximation methods in more depth, to reveal more clearly how these methods can overcome the curse of dimensionality, and to propose a generalised class of MLP approximation schemes, which covers previously analysed MLP approximation schemes as special cases. In particular, we develop an abstract framework in which this class of generalised MLP approximations can be formulated and analysed and, thereafter, apply this abstract framework to derive a computational complexity result for suitable MLP approximations for semi-linear heat equations with gradient-independent and globally Lipschitz continuous non-linearities. These resulting MLP approximations essentially are generalisations of previously introduced MLP approximations for semi-linear heat equations
Malaria vaccine protection against intradermal or venous parasites: a randomized phase 2b human challenge trial
Get PDFTwo licensed vaccines block Plasmodium falciparum malaria sporozoites through anticircumsporozoite protein antibodies. In animal models, intradermal (ID) sporozoites are more readily blocked than intravenous sporozoites. We hypothesized that this complicates human studies, where infectious mosquito bites deliver a mixture of ID and venous sporozoites. Here, to test whether vaccine efficacy varies by route of inoculation, we undertook a phase 2b open, randomized controlled trial, recruiting healthy volunteers in Kenya for randomization to the circumsporozoite protein-based R21/Matrix-M vaccine (n = 38), thrombospondin-related adhesive protein fused to a multi-epitope string (ME-TRAP)-based vaccines (n = 24) or to control (n = 18). We enrolled 37 of these volunteers to controlled human malaria infection (CHMI) using ID or direct venous injection (DVI) of sporozoites, with PCR monitoring of parasitemia. Systemic and local postvaccination adverse events and systemic CHMI-related events were detected in 4.8%, 12.9% and 72.9% of volunteers, respectively, most commonly fever, headache and fatigue. No serious or severe adverse events were seen. Seven of 8 (88%) control volunteers and 11 of 12 (92%) ME-TRAP vaccinated volunteers, but none of the 12 R21 vaccinated volunteers receiving ID challenge met the prespecified treatment criteria for the primary endpoint. However, five of five R21 vaccinated volunteers receiving DVI sporozoites met the primary endpoint (P 20, >500, >1,000 and >10,000, respectively). R21/Matrix-M was highly protective against CHMI using ID. inoculation of sporozoites, but not against DVI sporozoites. CHMI is used in clinical development to select efficacious vaccines and to define correlates of efficacy. Correlates of efficacy for antibodies to sporozoites should also be assessed by separate DVI and ID challenges. The study was registered with ClinicalTrials.gov (NCT03947190) and PACTR (PACTR202108505632810)
Editorial: Polluted ecosystems: how global climate change drives pollutant dynamics in aquatic and terrestrial ecosystems
Get PDFBromodomain and extra-terminal protein inhibitors modulate natural killer cell function and differentiation
Get PDFNatural killer (NK) cells are integral to the innate immune system, playing a crucial role in immune surveillance and the rapid response to virally infected and tumor cells. Epigenetic gene expression regulation significantly influences NK cell function and differentiation. Using a high-throughput small-molecule drug screening approach, we identified bromodomain and extra-terminal domain (BET) inhibitors (BETi) as potent modulators of NK cell function, reducing proinflammatory cytokine secretion while increasing markers of NK cell maturation and cytotoxicity. During NK lineage specification from hematopoietic stem cells, we demonstrated that BETi reduced NK cell fate and promoted increased myeloid cell differentiation. Moreover, differentiated NK cell types had more functionally differentiated gene expression programs. Thus, BET proteins are crucial for both mature NK cell functions and controlling NK cell lineage development from progenitors in the bone marrow. These findings suggest that BETi can fine-tune NK cell responses, offering promising therapeutic potential for cancer immunotherapy and the treatment of inflammatory and autoimmune diseases. Our study underscores the critical role of BET inhibitors in regulating NK cell function and opens new avenues for targeted immune modulation
PerturbAgent: an agentic AI system for analysis and prediction of genetic perturbations
Get PDFWe introduce PerturbAgent, a large language model (LLM)- based multi-agent system for single-cell genetic perturbation studies. In biomedical research, understanding cellular responses to perturbations is essential for interpreting gene function and regulatory pathways in single-cell data. Existing methods focus only on either single-cell analysis pipelines or perturbation prediction models, and often lack this necessary biological interpretation. PerturbAgent addresses these limitations, targeting both analysis and prediction tasks while also generating comprehensive biological interpretations with results grounded in mechanisms, pathways, and existing knowledge. We further propose MAST++, a general framework that evaluates agentic performance across profile, reasoning, perception, interaction, and memory, and complement it with biological validity assessments. On public single-cell Perturbseq and RNA-seq datasets, PerturbAgent reliably achieves high task completion and delivers citation-backed biological summaries, representing progress toward practical and interpretable agent workflows for scientific discovery
Quantum spin resonance in engineered proteins for multimodal sensing
Get PDFSensing technologies that exploit quantum phenomena for measurement are finding increasing applications across materials, physical and biological sciences1, 2, 3, 4, 5, 6–7. Until recently, biological candidates for quantum sensors were limited to in vitro systems, had poor sensitivity and were prone to light-induced degradation. These limitations impeded practical biotechnological applications, and high-throughput study that would facilitate their engineering and optimization. We recently developed a class of magneto-sensitive fluorescent proteins including MagLOV, which overcomes many of these challenges8. Here we show that through directed evolution, it is possible to engineer these proteins to alter the properties of their response to magnetic fields and radio frequencies. We find that MagLOV exhibits optically detected magnetic resonance in living bacterial cells at room temperature, at sufficiently high signal-to-noise for single-cell detection. These effects are explained through the radical-pair mechanism, which involves the protein backbone and a bound flavin cofactor. Using optically detected magnetic resonance and fluorescence magnetic-field effects, we explore a range of applications, including spatial localization of fluorescence signals using gradient fields (that is, magnetic resonance imaging using a genetically encoded probe), sensing of the molecular microenvironment, multiplexing of bio-imaging and lock-in detection, mitigating typical biological imaging challenges such as light scattering and autofluorescence. Taken together, our results represent a suite of sensing modalities for engineered biological systems, based on and designed around understanding the quantum-mechanical properties of magneto-sensitive fluorescent proteins
Development of human iPSC-derived 3D cortical constructs for repair of traumatic brain injury
Get PDFTraumatic brain injury (TBI) causes neuronal loss and disruption of cortical circuitry, and current therapeutic strategies remain limited. Cell-based approaches hold promise, yet repairing the cerebral cortex is particularly challenging due to its complex structural and functional organisation. I hypothesised that, following TBI, implantation of 3D neuronal constructs derived from temporally specified early and late neuronal progenitor cells (ENPCs and LNPCs) can enhance implant survival and enable identity-dependent integration with the host cortex. Furthermore, the implantation of two-layered neuronal tissue that mimics key aspects of cortical lamination would facilitate the reconstruction of cortical columnar circuits by promoting both local and long-range connectivity. Human-induced pluripotent stem cells (hiPSCs) were differentiated into cortical neurons with distinct laminar fates: ENPCs, enriched in CTIP2+ subcerebral neurons, and LNPCs, enriched in SATB2+ callosal projecting neurons. Both populations are composed of excitatory glutamatergic and inhibitory GABAergic phenotypes that established functional synaptic networks, as confirmed by calcium imaging. hiPSCs-derived ENPCs and LNPCs were used to generate 3D ENPC and LNPC constructs, respectively, using a droplet-based microfluidic system. 3D constructs retained fundamental laminar-specific molecular profiles and exhibited distinct network activity reflecting their temporal developmental identity. When 3D ENPC and LNPC constructs were assembled into two-layered neuronal tissues, mimicking basic aspects of cortical lamination, they exhibited inter-laminar structural and functional connections. Functional calcium imaging of the two-layered neuronal tissue and cross-correlation analysis revealed temporal coordination between the two layers, consistent with reciprocal interactions. In vivo, implantation of hiPSC-derived RFP+ NPC constructs into postnatal NOD-SCID mice with aspiration-induced cortical injury resulted in robust survival, vascularisation, and progressive neuronal differentiation of the implants. RFP+ NPC implants contributed to circuit reconstruction in vivo, evidenced by implant-derived projections that extend across major white matter tracts, reaching cortical, subcortical, and subcerebral targets. Subsequently, 3D ENPC or 3D LNPC constructs were implanted separately into the same TBI model and evaluated after two months. They displayed distinct axonal projection patterns that matched their neuronal identities. The 3D ENPC implants preferentially targeted subcortical regions and white matter pathways, while 3D LNPC implants exhibited localised cortical projections. Finally, the implantation of two-layered neuronal tissues further advanced architectural reconstruction, with ENPC compartment extending long-range connections, and LNPC compartment supporting local integration, thereby recapitulating the complementary projection patterns of deep- and upper-layer cortical neurons. Together, these findings demonstrated that temporal identity could influence the projection patterns and integration of the implants into the host brain, and that spatially patterned cortical tissues can restore both local and long-range connectivity. Further research is required to determine whether the implantation of 3D neuronal constructs, along with their structural integration, can restore the functional aspects of cortical circuitry. My thesis highlights the importance of constructing 3D neuronal tissues comprising predefined neuronal subtypes as a foundation for anatomically guided and personalised neural repair strategies following cortical injury
Incremental structure prediction during language comprehension: behavioral and neurobiological evidence from Mandarin Chinese and English
Get PDFThis thesis investigates the capacity of predictive mechanisms in real-time language comprehension to use subtle linguistic cues. Language comprehension, inherently sequential, involves incremental interpretation of linguistic inputs. However, predictive processing allows comprehenders to anticipate upcoming linguistic structures beyond the linear order, offering potential cognitive efficiency gains, particularly in long-distance dependency constructions. This study aims to understand the extent to which predictive strategies are employed, the level of detail comprehenders can predict, and the condition under which prediction occurs, through both behavioral and neurobiological measurements in Mandarin Chinese and English. This thesis comprises three independent yet interrelated studies focusing on different linguistic cues that might trigger predictions. Study 1 examines whether Chinese classifiers, which constrain animacy without specifying particular lexical items, elicit semantic feature predictions. Using Representational Similarity Analysis on EEG recordings, Study 1 provides neurobiological evidence that comprehenders can predict abstract semantic features beyond specific lexical items. Study 2 extends these findings by exploring whether animacy-constraining classifiers can guide comprehenders to predict structural elements, i.e., gap sites in head-final relative clauses in Mandarin Chinese. Both eye-tracking and self-paced reading results demonstrate the comprehenders’ability to utilize classifiers to modulate active gap search in the absence of head noun fillers. Study 3 examines the effect of a less understood element, presuppositional constraints, on modulating active gap search. It compares negative island constraint, a presuppositional constraint on filler-gap dependency formation with strong complex NP island constraint, however, the results suggest that negative island constraint cannot be rapidly used by the real-time parser to inhibit active gap filling in the same way strong islands do. Results across the three studies suggest that predictive structure building in real-time language processing is dynamically modulated by subtle linguistic cues, and cues at different levels might take their effects with different timings: syntactic and semantic cues have more immediate effects while pragmatic cues take longer to compute. These findings contribute to a nuanced understanding of real-time language comprehension, teasing apart various factors affecting predictive structural building in dependency constructions
Outcomes and complications of sponges versus tires for scleral buckling in primary rhegmatogenous retinal detachment: The Manchester Buckle Study
Get PDFPurpose: To compare preoperative characteristics and postoperative anatomical and functional outcomes of scleral buckle surgery using sponges versus tires, as well as explant‐related complications and the frequency of explant removal. Methods: This retrospective study included patients with primary rhegmatogenous retinal detachment (RRD) who underwent primary scleral buckling at the Manchester Royal Eye Hospital between 2008 and 2023. Preoperative data included age, macula status, type of RRD, ocular comorbidities and best‐corrected visual acuity (BCVA). Postoperative outcomes included single‐surgery anatomical success (SSAS), BCVA and explant‐related complications (extrusion, infection, high intraocular pressure and persistent diplopia). Results: Among 562 patients (mean age 36 ± 12 years), 183 received sponges and 379 received tires. Sponges were more commonly used in dialysis‐related RRD (54% vs. 10%; p < 0.01) and macula‐off eyes (52% vs. 36%; p < 0.01), and associated with worse preoperative BCVA (logMAR 0.84 ± 0.81 vs. 0.57 ± 0.72; p < 0.01). SSAS rates were similar between groups (86.0% vs. 83.4%; p = 0.44) and mean BCVA improvement (ΔBCVA) did not differ significantly (0.39 ± 0.57 vs. 0.29 ± 0.58 logMAR; p = 0.29). In multivariable analysis adjusting for relevant clinical covariates, explant type was not independently associated with postoperative BCVA (B = –0.10; p = 0.28) or SSAS (aOR = 0.79; p = 0.71). Buckle extrusion occurred more frequently in the sponge group (12.6% vs. 3.4%; p < 0.01), leading to higher explant removal rates (14.8% vs. 6.1%; p < 0.01). Conclusions: Sponges were preferentially used in dialysis‐related RRD cases and were associated with worse preoperative BCVA and a higher proportion of macula‐off RRDs. SSAS rates and ΔBCVA improvement were similar between groups. Sponges had significantly higher extrusion rates, resulting in more frequent explant removal