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Research is the vital expression of humankind’s most important qualities: curiosity and imagination.

Explorers, inventors, pioneers—dedicated researchers on the frontiers of science and the humanities.

Insight, when it comes, changes everything.

Publications

The NOMIS community of researchers and partners is instrumental in driving interdisciplinary collaboration, generating insights and ultimately advancing our understanding of the world. A key component of these efforts is knowledge sharing. Comprising a unique offering of engaging scientific lectures, insightful films about our awardees’ research, and a comprehensive publication database, NOMIS Insights are designed to facilitate the sharing of knowledge. They showcase the groundbreaking findings and innovative perspectives born from NOMIS-supported research endeavors, embodying our dedication to enabling scientific progress.

Our NOMIS Insight database provides a comprehensive source of all publications resulting from NOMIS-supported research projects.

Machine learning for modeling human decisions

NOMIS Researcher(s)

Published in

January 1, 2024

The rapid development of machine learning has led to new opportunities for applying these methods to the study of human decision making. We highlight some of these opportunities and discuss some of the issues that arise when using machine learning to model the decisions people make. We first elaborate on the relationship between predicting decisions and explaining them, leveraging findings from computational learning theory to argue that, in some cases, the conversion of predictive models to interpretable ones with comparable accuracy is an intractable problem. We then identify an important bottleneck in using machine learning to study human cognition—data scarcity—and highlight active learning and optimal experimental design as a way to move forward. Finally, we touch on additional topics such as machine learning methods for combining multiple predictors arising from known theories and specific machine learning architectures that could prove useful for the study of judgment and decision making. In doing so, we point out connections to behavioral economics, computer science, cognitive science, and psychology. (PsycInfo Database Record (c) 2024 APA, all rights reserved)

Research field(s)
Artificial Intelligence & Image Processing, Psychology & Cognitive Sciences

DOI
10.1037/dec0000242

Emergence and collapse of reciprocity in semiautomatic driving coordination experiments with humans

NOMIS Researcher(s)

Published in

December 11, 2023

Forms of both simple and complex machine intelligence are increasingly acting within human groups in order to affect collective outcomes. Considering the nature of collective action problems, however, such involvement could paradoxically and unintentionally suppress existing beneficial social norms in humans, such as those involving cooperation. Here, we test theoretical predictions about such an effect using a unique cyber-physical lab experiment where online participants (N = 300 in 150 dyads) drive robotic vehicles remotely in a coordination game. We show that autobraking assistance increases human altruism, such as giving way to others, and that communication helps people to make mutual concessions. On the other hand, autosteering assistance completely inhibits the emergence of reciprocity between people in favor of self-interest maximization. The negative social repercussions persist even after the assistance system is deactivated. Furthermore, adding communication capabilities does not relieve this inhibition of reciprocity because people rarely communicate in the presence of autosteering assistance. Our findings suggest that active safety assistance (a form of simple AI support) can alter the dynamics of social coordination between people, including by affecting the trade-off between individual safety and social reciprocity. The difference between autobraking and autosteering assistance appears to relate to whether the assistive technology supports or replaces human agency in social coordination dilemmas. Humans have developed norms of reciprocity to address collective challenges, but such tacit understandings could break down in situations where machine intelligence is involved in human decision-making without having any normative commitments.

Research field(s)
Experimental Psychology

DOI
10.1073/pnas.2307804120

Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

NOMIS Researcher(s)

Published in

December 6, 2023

Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

Research field(s)
Oncology & Carcinogenesis

DOI
10.1038/s41467-023-42178-6

Clinically relevant antibiotic resistance genes are linked to a limited set of taxa within gut microbiome worldwide

NOMIS Researcher(s)

Published in

November 24, 2023

The acquisition of antimicrobial resistance (AR) genes has rendered important pathogens nearly or fully unresponsive to antibiotics. It has been suggested that pathogens acquire AR traits from the gut microbiota, which collectively serve as a global reservoir for AR genes conferring resistance to all classes of antibiotics. However, only a subset of AR genes confers resistance to clinically relevant antibiotics, and, although these AR gene profiles are well-characterized for common pathogens, less is known about their taxonomic associations and transfer potential within diverse members of the gut microbiota. We examined a collection of 14,850 human metagenomes and 1666 environmental metagenomes from 33 countries, in addition to nearly 600,000 isolate genomes, to gain insight into the global prevalence and taxonomic range of clinically relevant AR genes. We find that several of the most concerning AR genes, such as those encoding the cephalosporinase CTX-M and carbapenemases KPC, IMP, NDM, and VIM, remain taxonomically restricted to Proteobacteria. Even cfiA, the most common carbapenemase gene within the human gut microbiome, remains tightly restricted to Bacteroides, despite being found on a mobilizable plasmid. We confirmed these findings in gut microbiome samples from India, Honduras, Pakistan, and Vietnam, using a high-sensitivity single-cell fusion PCR approach. Focusing on a set of genes encoding carbapenemases and cephalosporinases, thus far restricted to Bacteroides species, we find that few mutations are required for efficacy in a different phylum, raising the question of why these genes have not spread more widely. Overall, these data suggest that globally prevalent, clinically relevant AR genes have not yet established themselves across diverse commensal gut microbiota. © 2023, The Author(s).

DOI
10.1038/s41467-023-42998-6

Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation

NOMIS Researcher(s)

Published in

November 23, 2023

The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Research field(s)
Health Sciences

DOI
10.1038/s41593-023-01496-0

The moral landscape of biological conservation: Understanding conceptual and normative foundations

NOMIS Researcher(s)

Published in

November 16, 2023

Biological conservation practices and approaches take many forms. Conservation projects do not only differ in their aims and methods, but also concerning their conceptual and normative background assumptions and their underlying motivations and objectives. We draw on philosophical distinctions from the ethics of conservation to explain variances of different positions on conservation projects along six dimensions: (1) conservation ideals, (2) intervention intuitions, (3) the moral considerability of nonhuman beings, (4) environmental values, (5) views on nature and (6) human roles in nature. The result is a map of the moral landscape of biological conservation, on which these six dimensions are layered. This map functions as a heuristic tool to understand conceptual and normative foundations of specific conservation projects, which we will illustrate with four paradigmatic examples: the Pisavaara Strict Nature Reserve, Predator Free New Zealand, the Oostvaardersplassen Nature Reserve and the Great Green Wall Project. With this map as a heuristic tool, we aim to conceptually illuminate disagreement and clarify misunderstandings between representatives of different environmental protection strategies and to show that the same project can be supported (or criticised) on different grounds.

Research field(s)
Biology, Environmental Sciences

DOI
10.1016/j.biocon.2023.110350

The enmity paradox

NOMIS Researcher(s)

Published in

November 16, 2023

The “friendship paradox” of social networks states that, on average, “your friends have more friends than you do”. Here, we theoretically and empirically explore a related and overlooked paradox we refer to as the “enmity paradox”. We use empirical data from 24,678 people living in 176 villages in rural Honduras. We empirically show that, for a real negative undirected network (created by symmetrizing antagonistic interactions), the paradox exists as it does in the positive world. Specifically, a person’s enemies have more enemies, on average, than a person does. Furthermore, in a mixed world of positive and negative ties, we study the conditions for the existence of the paradox, which we refer to as the “mixed-world paradox”, both theoretically and empirically, finding that, for instance, a person’s friends typically have more enemies than a person does. We also confirm the “generalized” enmity paradox for non-topological attributes in real data, analogous to the generalized friendship paradox (e.g., the claim that a person’s enemies are richer, on average, than a person is). As a consequence, the naturally occurring variance in the degree distribution of both friendship and antagonism in social networks can skew people’s perceptions of the social world. © 2023, The Author(s).

DOI
10.1038/s41598-023-47167-9

Approaching disease transmission with network science

NOMIS Researcher(s)

Published in

November 15, 2023

Social connections are an important means for people to cope with adversity and illness. Thus, technologies, such as social network analysis, that can leverage close, face-to-face social networks could help optimize healthcare interventions and reduce healthcare-related costs, particularly in low-resource settings.

Research field(s)
Social Sciences

DOI
10.1038/s44222-023-00139-0

Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity

NOMIS Researcher(s)

Published in

November 6, 2023

Chromatin conformation reorganization is emerging as an important layer of regulation for gene expression and lineage specification. Yet, how lineage-specific transcription factors contribute to the establishment of cell type-specific 3D chromatin architecture in the immune cells remains unclear, especially for the late stages of T cell subset differentiation and maturation. Regulatory T cells (Treg) are mainly generated in the thymus as a subpopulation of T cells specializing in suppressing excessive immune responses. Here, by comprehensively mapping 3D chromatin organization during Treg cell differentiation, we show that Treg-specific chromatin structures were progressively established during its lineage specification, and highly associated with Treg signature gene expression. Additionally, the binding sites of Foxp3, a Treg lineage specifying transcription factor, were highly enriched at Treg-specific chromatin loop anchors. Further comparison of the chromatin interactions between wide-type Tregs versus Treg cells from Foxp3 knock-in/knockout or newly-generated Foxp3 domain-swap mutant mouse revealed that Foxp3 was essential for the establishment of Treg-specific 3D chromatin architecture, although it was not dependent on the formation of the Foxp3 domain-swapped dimer. These results highlighted an underappreciated role of Foxp3 in modulating Treg-specific 3D chromatin structure formation.

Research field(s)
Genetics & Heredity, Immunology, Oncology & Carcinogenesis

DOI
10.1038/s41467-023-42647-y

From the Viscera to First Impressions: Phase-Dependent Cardio-Visual Signals Bias the Perceived Trustworthiness of Faces

NOMIS Researcher(s)

Published in

November 2, 2023

When we see new people, we rapidly form first impressions. Whereas past research has focused on the role of morphological or emotional cues, we asked whether transient visceral states bias the impressions we form. Across three studies (N = 94 university students), we investigated how fluctuations of bodily states, driven by the interoceptive impact of cardiac signals, influence the perceived trustworthiness of faces. Participants less often chose faces presented in synchrony with their own cardiac systole as more trustworthy than faces presented out of synchrony. Participants also explicitly judged faces presented in synchrony with their cardiac systole as less trustworthy. Finally, the presentation of faces in synchrony with participants’ cardiac diastole did not modulate participants’ perceptions of the faces’ trustworthiness, suggesting that the systolic phase is necessary for such interoceptive effects. These findings highlight the role of phasic interoceptive information in the processing of social information and provide a mechanistic account of the role of visceroception for social perception. © The Author(s) 2022.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.1177/09567976221131519

Compact vacuum-gap transmon qubits: Selective and sensitive probes for superconductor surface losses

NOMIS Researcher(s)

Published in

October 20, 2023

State-of-the-art transmon qubits rely on large capacitors, which systematically improve their coherence due to reduced surface-loss participation. However, this approach increases both the footprint and the parasitic cross-coupling and is ultimately limited by radiation losses – a potential roadblock for scaling up quantum processors to millions of qubits. In this work we present transmon qubits with sizes as low as 36×39μm2 with ≳100-nm-wide vacuum-gap capacitors that are micromachined from commercial silicon-on-insulator wafers and shadow evaporated with aluminum. We achieve a vacuum participation ratio up to 99.6% in an in-plane design that is compatible with standard coplanar circuits. Qubit relaxation-time measurements for small gaps with high zero-point electric field variance of up to 22 V/m reveal a double exponential decay indicating comparably strong qubit interaction with long-lived two-level systems. The exceptionally high selectivity of up to 20 dB to the superconductor-vacuum interface allows us to precisely back out the sub-single-photon dielectric loss tangent of aluminum oxide previously exposed to ambient conditions. In terms of future scaling potential, we achieve a ratio of qubit quality factor to a footprint area equal to 20μm-2, which is comparable with the highest T1 devices relying on larger geometries, a value that could improve substantially for lower surface-loss superconductors. © 2023 American Physical Society.

Research field(s)
Natural Sciences, Quantum, Josephson Junctions, Microwave, Qubits

DOI
10.1103/PhysRevApplied.20.044054

Fronto-striatal alterations correlate with apathy severity in behavioral variant frontotemporal dementia

NOMIS Researcher(s)

Published in

October 19, 2023

Structural and functional changes in cortical and subcortical regions have been reported in behavioral variant frontotemporal dementia (bvFTD), however, a multimodal approach may provide deeper insights into the neural correlates of neuropsychiatric symptoms. In this multicenter study, we measured cortical thickness (CTh) and subcortical volumes to identify structural abnormalities in 37 bvFTD patients, and 37 age- and sex-matched healthy controls. For seed regions with significant structural changes, whole-brain functional connectivity (FC) was examined in a sub-cohort of N = 22 bvFTD and N = 22 matched control subjects to detect complementary alterations in brain network organization. To explore the functional significance of the observed structural and functional deviations, correlations with clinical and neuropsychological outcomes were tested where available. Significantly decreased CTh was observed in the bvFTD group in caudal middle frontal gyrus, left pars opercularis, bilateral superior frontal and bilateral middle temporal gyrus along with subcortical volume reductions in bilateral basal ganglia, thalamus, hippocampus, and amygdala. Resting-state functional magnetic resonance imaging showed decreased FC in bvFTD between: dorsal striatum and left caudal middle frontal gyrus; putamen and fronto-parietal regions; pallidum and cerebellum. Conversely, bvFTD showed increased FC between: left middle temporal gyrus and paracingulate gyrus; caudate nucleus and insula; amygdala and parahippocampal gyrus. Additionally, cortical thickness in caudal, lateral and superior frontal regions as well as caudate nucleus volume correlated negatively with apathy severity scores of the Neuropsychiatry Inventory Questionnaire. In conclusion, multimodal structural and functional imaging indicates that fronto-striatal regions have a considerable influence on the severity of apathy in bvFTD. © 2023, The Author(s).

Research field(s)
Health Sciences

DOI
10.1007/s11682-023-00812-3

Evaluating potential of leaf reflectance spectra to monitor plant genetic variation

NOMIS Researcher(s)

Published in

October 14, 2023

Remote sensing of vegetation by spectroscopy is increasingly used to characterize trait distributions in plant communities. How leaves interact with electromagnetic radiation is determined by their structure and contents of pigments, water, and abundant dry matter constituents like lignins, phenolics, and proteins. High-resolution (“hyperspectral”) spectroscopy can characterize trait variation at finer scales, and may help to reveal underlying genetic variation—information important for assessing the potential of populations to adapt to global change. Here, we use a set of 360 inbred genotypes of the wild coyote tobacco Nicotiana attenuata: wild accessions, recombinant inbred lines (RILs), and transgenic lines (TLs) with targeted changes to gene expression, to dissect genetic versus non-genetic influences on variation in leaf spectra across three experiments. We calculated leaf reflectance from hand-held field spectroradiometer measurements covering visible to short-wave infrared wavelengths of electromagnetic radiation (400–2500 nm) using a standard radiation source and backgrounds, resulting in a small and quantifiable measurement uncertainty. Plants were grown in more controlled (glasshouse) or more natural (field) environments, and leaves were measured both on- and off-plant with the measurement set-up thus also in more to less controlled environmental conditions. Entire spectra varied across genotypes and environments. We found that the greatest variance in leaf reflectance was explained by between-experiment and non-genetic between-sample differences, with subtler and more specific variation distinguishing groups of genotypes. The visible spectral region was most variable, distinguishing experimental settings as well as groups of genotypes within experiments, whereas parts of the short-wave infrared may vary more specifically with genotype. Overall, more genetically variable plant populations also showed more varied leaf spectra. We highlight key considerations for the application of field spectroscopy to assess genetic variation in plant populations. © 2023, BioMed Central Ltd., part of Springer Nature.

Research field(s)
Natural Sciences, Biology, Plant Biology & Botany

DOI
10.1186/s13007-023-01089-9

Bradyphrenia and Tachyphrenia in Idiopathic Parkinsonism Appear, in Part, Iatrogenic: An Observational Study with Systematic Review Background

NOMIS Researcher(s)

Published in

October 12, 2023

We question whether bradyphrenia, slowing of cognitive processing not explained by depression or a global cognitive assessment, is a nosological entity in idiopathic parkinsonism (IP). The time taken to break contact of an index finger with a touch-sensitive plate was measured, with and without a warning in the alerting signal as to which side the imperative would indicate, in 77 people diagnosed with IP and in 124 people without an IP diagnosis. The ability to utilise a warning, measured by the difference between loge-transformed reaction times (unwarned minus warned), was termed ‘cognitive efficiency’. It was approximately normally distributed. A questionnaire on self- and partner perception of proband’s bradyphrenia was applied. A multivariable model showed that those prescribed levodopa were less cognitively efficient (mean −5.2 (CI −9.5, −1.0)% per 300 mg/day, p = 0.02), but those prescribed the anti-muscarinic trihexyphenidyl were more efficient (14.7 (0.2, 31.3)% per 4 mg/day, p < 0.05) and those prescribed monoamine oxidase-B inhibitor (MAOBI) tended to be more efficient (8.3 (0.0, 17.4)%, p = 0.07). The variance in efficiency was greater within IP (F-test, p = 0.01 adjusted for any demographic covariates: coefficient of variation, with and without IP, 0.68 and 0.46, respectively), but not so after adjustment for anti-parkinsonian medication (p = 0.13: coefficient of variation 0.62). The within-participant follow-up time, a median of 4.8 (interquartile range 3.1, 5.5) years (101 participants), did not influence efficiency, irrespective of IP status. Perception of bradyphrenia did not usefully predict efficiency. We conclude that both bradyphrenia and ‘tachyphrenia’ in IP appear to have iatrogenic components, of clinically important size, related to the dose of antiparkinsonian medication. Levodopa is the most commonly prescribed first-line medication: co-prescribing a MAOBI may circumvent its associated bradyphrenia. The previously reported greater efficiency associated with (low-dose) anti-muscarinic was confirmed. © 2023 by the authors.

Research field(s)
Health Sciences

DOI
10.3390/jcm12206499

CD8+ T cells in the cancer-immunity cycle

NOMIS Researcher(s)

Published in

October 10, 2023

CD8+ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8+ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8+ T cell subtypes and states. We discuss factors that influence CD8+ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal—metabolism—and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as “pro-drugs” that act to augment or modulate T cells, which ultimately serve as the drug in vivo, and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients. © 2023 Elsevier Inc.

Research field(s)
Health Sciences

DOI
10.1016/j.immuni.2023.09.005

Displaced people’s perilous journeys: border violence as a public health issue

NOMIS Researcher(s)

Published in

October 7, 2023

The 21st century has seen displacement of migrants and refugees unprecedented since World War 2. As of the end of 2022, of the 108 million people who had to leave their homes because of persecution, conflict, violence, or human rights violations, 62·5 million were internally displaced, 35·3 million were refugees, and 5·4 million were officially asylum seekers.

However, the number of people still in transit in search of protection or a better life is unknown. Whether they are Venezuelans trying to reach the USA, Senegalese trying to reach the Canary Islands, or Ethiopians trying to reach Saudi Arabia, or whether they are Guineans crossing the Sahara, Afghans crossing the Evros River, or Rohingyas crossing the Andaman Sea, the only figures that we have about these people are the conservative statistics produced by the International Organization for Migration of the number of deaths worldwide: 58 280 in 10 years.

But what about those who survived? In Europe, an indirect source is the number of asylum seekers, since most people arriving after forcible displacement apply for refugee status. In 2022, not counting Ukrainians who were granted temporary protection, there were 881 000 people seeking asylum, mostly from Syria, Afghanistan, Venezuela, and Türkiye.

This means at least an equivalent number of people travelled from their home country to their host country in the previous months or years. Yet, we know little of the journey of this approximately 1 million displaced people.

Research field(s)
Social Sciences

DOI
10.1016/S0140-6736(23)02030-5

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes—an international multicentre retrospective study

NOMIS Researcher(s)

Published in

October 5, 2023

Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. Methods: We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. Findings: LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04–3.34) in the European cohort and 1.6 (1.2–2.2) in the U.S. cohort. Interpretation: We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Funding: Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. © 2023 The Authors

Research field(s)
Health Sciences

DOI
10.1016/j.eclinm.2023.102252

The interplay of nuclear pores and lipids

NOMIS Researcher(s)

Published in

October 5, 2023

Nuclear pore complexes (NPCs) mediate the bidirectional transport of cargo across the nuclear envelope (NE). NPCs are also membrane remodeling machines with a capacity to curve and fuse the membranes of the NE. However, little is known about the interplay of NPCs and lipids at a mechanistic level. A full understanding of NPC structure and function needs to encompass how the NPC shapes membranes and is itself shaped by lipids. Here we attempt to connect recent findings in NPC research with the broader field of membrane biochemistry to illustrate how an interplay between NPCs and lipids may facilitate the conformational plasticity of NPCs and the generation of a unique pore membrane topology. We highlight the need to better understand the NPC’s lipid environment and outline experimental avenues towards that goal. © 2023 The Authors

Research field(s)
Health Sciences

DOI
10.1016/j.ceb.2023.102251

Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy

NOMIS Researcher(s)

Published in

September 29, 2023

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody–drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).

DOI
10.1084/jem.20231235

Psychological Status of the Participants in Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Colombia

NOMIS Researcher(s)

Published in

September 26, 2023

The SARS-CoV2 global pandemic impacted participants in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. Objective: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. Methods: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. Results: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. Conclusions: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19. © 2023 – IOS Press. All rights reserved.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.3233/JAD-220941

Fueling next-generation genome editing with DNA repair

NOMIS Researcher(s)

Published in

September 22, 2023

Genome editing technologies generate targeted DNA lesions and rely on cellular DNA repair pathways for resolution. Understanding the DNA repair mechanisms responsible for resolving the specific damage caused by gene editing tools can significantly advance their optimization and facilitate their broader application in research and therapeutic contexts. Here we explore the cellular processes involved in repairing base and prime editor-generated DNA lesions and strategies to leverage and manipulate DNA repair pathways for desired genomic changes. © 2023 The Author(s)

Research field(s)
Health Sciences

DOI
10.1016/j.cobme.2023.100506

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