Insight
is our reward

Publications in Health Sciences by NOMIS researchers

NOMIS Researcher(s)

Published in

February 19, 2025

Recent advances in stem cell-derived embryo models have transformed developmental biology, offering insights into embryogenesis without the constraints of natural embryos. However, variability in their development challenges research standardization. To address this, we use deep learning to enhance the reproducibility of selecting stem cell-derived embryo models. Through live imaging and AI-based models, we classify 900 mouse post-implantation stem cell-derived embryo-like structures (ETiX-embryos) into normal and abnormal categories. Our best-performing model achieves 88% accuracy at 90 h post-cell seeding and 65% accuracy at the initial cell-seeding stage, forecasting developmental trajectories. Our analysis reveals that normally developed ETiX-embryos have higher cell counts and distinct morphological features such as larger size and more compact shape. Perturbation experiments increasing initial cell numbers further supported this finding by improving normal development outcomes. This study demonstrates deep learning’s utility in improving embryo model selection and reveals critical features of ETiX-embryo self-organization, advancing consistency in this evolving field.

Research field(s)
Bioinformatics, Artificial Intelligence & Image Processing, Biophysics, Developmental Biology

NOMIS Researcher(s)

Published in

February 14, 2025

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial “off-target” effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

Research field(s)
Biochemistry & Molecular Biology, Immunology, Pharmacology & Pharmacy, Microbiology

NOMIS Researcher(s)

Published in

January 30, 2025

Human accelerated regions (HARs) have been implicated in human brain evolution. However, insight into the genes and pathways they control is lacking, hindering the understanding of their function. Here, we identify 2,963 conserved gene targets for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs). Conserved gene targets are enriched for neurodevelopmental functions and are overrepresented among differentially expressed genes (DEGs) identified in human NSCs (hNSCs) and chimpanzee NSCs (cNSCs) as well as in human versus non-human primate brains. Species-specific gene targets do not converge on any function and are not enriched among DEGs. HAR targets also show cell-type-specific expression in the human fetal brain, including in outer radial glia, which are linked to cortical expansion. Our findings support that HARs influence brain evolution by altering the expression of ancestral gene targets shared between human and chimpanzee rather than by gaining new targets in human and facilitate hypothesis-directed studies of HAR biology.

Research field(s)
Bioinformatics, Developmental Biology, Evolutionary Biology

NOMIS Researcher(s)

Published in

January 27, 2025

The sense of agency is the subjective feeling of control over one’s own actions and the associated outcomes. Here, we asked whether and to what extent the reasons behind our choices (operationalized by value differences, expected utility, and counterfactual option sets) drive our sense of agency. We simultaneously tested these three dimensions during a novel value-based decision-making task while recording explicit (self-reported) and implicit (brain signals) measures of agency. Our results show that choices that are more reasonable also come with a stronger sense of agency: humans report higher levels of control over the outcomes of their actions if (1) they were able to choose between different option values compared to randomly picking between options of identical value, (2) their choices maximizes utility (compared to otherwise) and yields higher than expected utility, and (3) they realize that they have not missed out on hidden opportunities. EEG results showed supporting evidence for factors (1) and (3): We found a higher P300 amplitude for picking than choosing and a higher Late-Positive Component when participants realized they had missed out on possible but hidden opportunities. Together, these results suggest that human agency is not only driven by the goal-directedness of our actions but also by their perceived rationality.

Research field(s)
Psychology & Cognitive Sciences, Behavioral Science & Comparative Psychology

NOMIS Researcher(s)

Published in

January 20, 2025

Science is crucial for evidence-based decision-making. Public trust in scientists can help decision makers act on the basis of the best available evidence, especially during crises. However, in recent years the epistemic authority of science has been challenged, causing concerns about low public trust in scientists. We interrogated these concerns with a preregistered 68-country survey of 71,922 respondents and found that in most countries, most people trust scientists and agree that scientists should engage more in society and policymaking. We found variations between and within countries, which we explain with individual- and country-level variables, including political orientation. While there is no widespread lack of trust in scientists, we cannot discount the concern that lack of trust in scientists by even a small minority may affect considerations of scientific evidence in policymaking. These findings have implications for scientists and policymakers seeking to maintain and increase trust in scientists.

Research field(s)
Sociology, Psychology & Cognitive Sciences, Social Psychology

NOMIS Researcher(s)

Published in

January 20, 2025

Science is integral to society because it can inform individual, government, corporate, and civil society decision-making on issues such as public health, new technologies or climate change. Yet, public distrust and populist sentiment challenge the relationship between science and society. To help researchers analyse the science-society nexus across different geographical and cultural contexts, we undertook a cross-sectional population survey resulting in a dataset of 71,922 participants in 68 countries. The data were collected between November 2022 and August 2023 as part of the global Many Labs study “Trust in Science and Science-Related Populism” (TISP). The questionnaire contained comprehensive measures for individuals’ trust in scientists, science-related populist attitudes, perceptions of the role of science in society, science media use and communication behaviour, attitudes to climate change and support for environmental policies, personality traits, political and religious views and demographic characteristics. Here, we describe the dataset, survey materials and psychometric properties of key variables. We encourage researchers to use this unique dataset for global comparative analyses on public perceptions of science and its role in society and policy-making.

Research field(s)
Social Sciences, Psychology & Cognitive Sciences, Social Psychology, Public Health

Published in

January 9, 2025

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

Research field(s)
Biomedical Research, Biochemistry & Molecular Biology, Microbiology, Immunology, Oncology & Carcinogenesis

NOMIS Researcher(s)

Adolescence is a developmental period of relative volatility, where the individual experiences significant changes to their physical and social environment. The ability to adapt to the volatility of one’s surroundings is an important cognitive ability, particularly while foraging, a near-ubiquitous behaviour across the animal kingdom. As adolescents experience more volatility in their surroundings, we predicted that this age group would be more adept than adults at using exploration to adjust to volatility. We employed a foraging task with a well-validated computational model to characterise the mechanisms of exploration in volatile environments, preregistering the hypothesis that adolescents (aged 16–17; N = 91) would exhibit more optimal adaptation of their learning rate to changes in environmental volatility compared with adults (aged 24+; N = 90). However, surprisingly, both adolescents and adults exhibited suboptimal adjustment of their learning rate to environmental volatility. In contrast to the learning rate, it was instead participants’ stochasticity (i.e., decision variability) that better resembled the adjustment to volatility made by the optimal RL agent. Although heightened stochasticity in the volatile environment led participants to more often trial different responses that facilitated discovery of changes to the environment, we also found that anxiety impaired this adaptive ability. The finding of heightened stochasticity in volatile environments contradicts expectations that the learning rate is responsible for successful adaptation and motivates future work on the deleterious role that anxiety plays when adolescents manage periods of transition.

Research field(s)
Psychology & Cognitive Sciences

NOMIS Researcher(s)

Published in

January 8, 2025

The mammalian nervous system is impacted by aging. Aging alters brain architecture, is associated with molecular damage, and can manifest with cognitive and motor deficits that diminish the quality of life. Astrocytes are glial cells of the CNS that regulate the development, function, and repair of neural circuits during development and adulthood; however, their functions in aging are less understood. Astrocytes change their transcriptome during aging, with astrocytes in areas such as the cerebellum, the hypothalamus, and white matter-rich regions being the most affected. While numerous studies describe astrocyte transcriptional changes in aging, many questions still remain. For example, how is astrocyte function altered by transcriptional changes that occur during aging? What are the mechanisms promoting astrocyte aged states? How do aged astrocytes impact brain function? This review discusses features of aged astrocytes and their potential triggers and proposes ways in which they may impact brain function and health span.

Research field(s)
Immunology, Neurology & Neurosurgery

NOMIS Researcher(s)

December 20, 2024

Paediatric critical care units are designed for children at a vulnerable stage of development, yet the evidence base for practice and policy in paediatric critical care remains scarce. In this Health Policy, we present a roadmap providing strategic guidance for international paediatric critical care trials. We convened a multidisciplinary group of 32 paediatric critical care experts from six continents representing paediatric critical care research networks and groups. The group identified key challenges to paediatric critical care research, including lower patient numbers than for adult critical care, heterogeneity related to cognitive development, comorbidities and illness or injury, consent challenges, disproportionately little research funding for paediatric critical care, and poor infrastructure in resource-limited settings. A seven-point roadmap was proposed: (1) formation of an international paediatric critical care research network; (2) development of a web-based toolkit library to support paediatric critical care trials; (3) establishment of a global paediatric critical care trial repository, including systematic prioritisation of topics and populations for interventional trials; (4) development of a harmonised trial minimum set of trial data elements and data dictionary; (5) building of infrastructure and capability to support platform trials; (6) funder advocacy; and (7) development of a collaborative implementation programme. Implementation of this roadmap will contribute to the successful design and conduct of trials that match the needs of globally diverse paediatric populations.

Research field(s)
Emergency & Critical Care Medicine, Pediatrics

INTRODUCTION: While there may be microbial contributions to Alzheimer’s disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+)microglia subtype associated with increased immunoglobulinG4(IgG4) in the transverse colon (TC).

METHODS: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.

RESULTS: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death.

DISCUSSION: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+)microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+)microglia.

Research field(s)
Genetics & Heredity, Neurology & Neurosurgery, Biology

NOMIS Researcher(s)

December 18, 2024

Considerable research has shown that people make biased decisions in “optimal stopping problems”, where options are encountered sequentially, and there is no opportunity to recall rejected options or to know upcoming options in advance (e.g. when flat hunting or choosing a spouse). Here, we used computational modelling to identify the mechanisms that best explain decision bias in the context of an especially realistic version of this problem: the full-information problem. We eliminated a number of factors as potential instigators of bias. Then, we examined sequence length and payoff scheme: two manipulations where an optimality model recommends adjusting the sampling rate. Here, participants were more reluctant to increase their sampling rates when it was optimal to do so, leading to increased undersampling bias. Our comparison of several computational models of bias demonstrates that many participants maintain these relatively low sampling rates because of suboptimally pessimistic expectations about the quality of future options (i.e. a mis-specified prior distribution). These results support a new theory about how humans solve full information problems. Understanding the causes of decision error could enhance how we conduct real world sequential searches for options, for example how online shopping or dating applications present options to users.

Research field(s)
Behavioral Science & Comparative Psychology

Published in

December 18, 2024

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Immunology, Neurology & Neurosurgery

NOMIS Researcher(s)

Published in

December 11, 2024

SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.

Research field(s)
Molecular Biology, Virology, Immunology

NOMIS Researcher(s)

December 4, 2024

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. The quadruple-sgRNA libraries yielded high perturbation efficacies in deletion (75–99%) and silencing (76–92%) experiments and substantial fold changes in activation experiments. Moreover, an arrayed activation screen of 1,634 human transcription factors uncovered 11 novel regulators of the cellular prion protein PrPC, screening with a pooled version of the ablation library led to the identification of 5 novel modifiers of autophagy that otherwise went undetected, and ‘post-pooling’ individually produced lentiviruses eliminated template-switching artefacts and enhanced the performance of pooled screens for epigenetic silencing. Quadruple-sgRNA arrayed libraries are a powerful and versatile resource for targeted genome-wide perturbations.

Research field(s)
Bioinformatics, Biotechnology, Biochemistry & Molecular Biology, Genetics & Heredity

NOMIS Researcher(s)

Published in

November 27, 2024

The DNA-PKcs inhibitor AZD7648 enhances CRISPR–Cas9-directed homology-directed repair efficiencies, with potential for clinical utility, but its possible on-target consequences are unknown. We found that genome editing with AZD7648 causes frequent kilobase-scale and megabase-scale deletions, chromosome arm loss and translocations. These large-scale chromosomal alterations evade detection through typical genome editing assays, prompting caution in deploying AZD7648 and reinforcing the need to investigate multiple types of potential editing outcomes.

Research field(s)
Biochemistry & Molecular Biology, Genetics & Heredity

NOMIS Researcher(s)

Published in

November 15, 2024

Microbial communities are shaped by cell-cell interactions. Although archaea are often found in associations with other microorganisms, the mechanisms structuring these communities are poorly understood. Here, we report on the structure and function of haloarchaeal contractile injection systems (CISs). Using a combination of functional assays and time-lapse imaging, we show that Halogeometricum borinquense exhibits antagonism toward Haloferax volcanii by inducing cell lysis and inhibiting proliferation. This antagonism is contact-dependent and requires a functional CIS, which is encoded by a gene cluster that is associated with toxin-immunity pairs. Cryo–focused ion beam milling and imaging by cryo–electron tomography revealed that these CISs are bound to the cytoplasmic membrane, resembling the bacterial type six secretion systems (T6SSs). We show that related T6SS gene clusters are conserved and expressed in other haloarchaeal strains, which exhibit antagonistic behavior. Our data provide a mechanistic framework for understanding how archaea may shape microbial communities and affect the food webs they inhabit.

Research field(s)
Microbiology

NOMIS Researcher(s)

October 31, 2024

There is growing concern about the impact of declining political trust on democracies. Psychological research has introduced the concept of epistemic (mis)trust as a stable disposition acquired through development, which may influence our sociopolitical engagement. Given trust’s prominence in current politics, we examined the relationship between epistemic trust and people’s choices of (un)trustworthy political leaders. In two representative samples in the UK and US (N = 1096), we tested whether epistemic trust predicts political leader choices through three political dimensions: dogmatism, political trust, and ideology. Although epistemic trust did not directly predict choices of political leaders, it predicted dogmatism and political ideology, which in turn predicted choices of political leaders. A network analysis revealed that epistemic trust and political dimensions only interact through their common connection with dogmatism. These findings suggest that cognitive and affective development may underlie an individual’s political ideology and associated beliefs.

Research field(s)
Political Science & Public Administration, Psychology & Cognitive Sciences

NOMIS Researcher(s)

Published in

October 18, 2024

Ixotrophy is a contact-dependent predatory strategy of filamentous bacteria in aquatic environments for which the molecular mechanism remains unknown. We show that predator-prey contact can be established by gliding motility or extracellular assemblages we call “grappling hooks.” Cryo–electron microscopy identified the grappling hooks as heptamers of a type IX secretion system substrate. After close predator-prey contact is established, cryo–electron tomography and functional assays showed that puncturing by a type VI secretion system mediated killing. Single-cell analyses with stable isotope–labeled prey revealed that prey components are taken up by the attacker. Depending on nutrient availability, insertion sequence elements toggle the activity of ixotrophy. A marine metagenomic time series shows coupled dynamics of ixotrophic bacteria and prey. We found that the mechanism of ixotrophy involves multiple cellular machineries, is conserved, and may shape microbial populations in the environment.

Research field(s)
Microbiology