Insight
is our reward
Search

NOMIS Insights

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.

Single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease

NOMIS Researcher(s)

Published in

July 10, 2024

The emergence of single nucleus RNA sequencing (snRNA-seq) offers to revolutionize the study of Alzheimer’s disease (AD). Integration with complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link cell subpopulations and molecular networks with a broader disease-relevant context. We report snRNA-seq profiles from superior frontal gyrus samples from 101 well characterized subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in hematological parameters. We observed an AD-associated CD83(+) microglial subtype with unique molecular networks and which is associated with immunoglobulin IgG4 production in the transverse colon. Our major observations were replicated in two additional, independent snRNA-seq data sets. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal disease biology.

Research field(s)
Genetics & Heredity, Biology

DOI
10.1038/s41467-024-49790-0

FilamentID reveals the composition and function of metabolic enzyme polymers during gametogenesis

NOMIS Researcher(s)

Published in

June 20, 2024

Gamete formation and subsequent offspring development often involve extended phases of suspended cellular development or even dormancy. How cells adapt to recover and resume growth remains poorly understood. Here, we visualized budding yeast cells undergoing meiosis by cryo-electron tomography (cryoET) and discovered elaborate filamentous assemblies decorating the nucleus, cytoplasm, and mitochondria. To determine filament composition, we developed a “filament identification” (FilamentID) workflow that combines multiscale cryoET/cryo-electron microscopy (cryoEM) analyses of partially lysed cells or organelles. FilamentID identified the mitochondrial filaments as being composed of the conserved aldehyde dehydrogenase Ald4ALDH2 and the nucleoplasmic/cytoplasmic filaments as consisting of acetyl-coenzyme A (CoA) synthetase Acs1ACSS2. Structural characterization further revealed the mechanism underlying polymerization and enabled us to genetically perturb filament formation. Acs1 polymerization facilitates the recovery of chronologically aged spores and, more generally, the cell cycle re-entry of starved cells. FilamentID is broadly applicable to characterize filaments of unknown identity in diverse cellular contexts.

Research field(s)
Microbiology, Biology

DOI
10.1016/j.cell.2024.04.026

Waves of regulated protein expression and phosphorylation rewire the proteome to drive gametogenesis in budding yeast

NOMIS Researcher(s)

Published in

June 20, 2024

Sexually reproducing eukaryotes employ a developmentally regulated cell division program—meiosis—to generate haploid gametes from diploid germ cells. To understand how gametes arise, we generated a proteomic census encompassing the entire meiotic program of budding yeast. We found that concerted waves of protein expression and phosphorylation modify nearly all cellular pathways to support meiotic entry, meiotic progression, and gamete morphogenesis. Leveraging this comprehensive resource, we pinpointed dynamic changes in mitochondrial components and showed that phosphorylation of the FoF1-ATP synthase complex is required for efficient gametogenesis. Furthermore, using cryoET as an orthogonal approach to visualize mitochondria, we uncovered highly ordered filament arrays of Ald4ALDH2, a conserved aldehyde dehydrogenase that is highly expressed and phosphorylated during meiosis. Notably, phosphorylation-resistant mutants failed to accumulate filaments, suggesting that phosphorylation regulates context-specific Ald4ALDH2 polymerization. Overall, this proteomic census constitutes a broad resource to guide the exploration of the unique sequence of events underpinning gametogenesis.

Research field(s)
Biology

DOI
10.1016/j.devcel.2024.05.025

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease

NOMIS Researcher(s)

Published in

June 19, 2024

Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer’s disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer’s disease caused by the PSEN1E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3Ch). Heterozygosity for the APOE3Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1E280A variant is prevalent.

Research field(s)
Health Sciences, Genetics & Heredity, Clinical Medicine

DOI
10.1056/NEJMoa2308583

Geometry-driven migration efficiency of autonomous epithelial cell clusters

NOMIS Researcher(s)

Published in

June 19, 2024

The directed migration of epithelial cell collectives through coordinated movements plays a crucial role in various physiological processes and is increasingly understood at the level of large confluent monolayers. However, numerous processes rely on the migration of small groups of polarized epithelial clusters in complex environments, and their responses to external geometries remain poorly understood. To address this, we cultivate primary epithelial keratocyte tissues on adhesive microstripes to create autonomous epithelial clusters with well-defined geometries. We show that their migration efficiency is strongly influenced by the contact geometry and the orientation of cell–cell contacts with respect to the direction of migration. A combination of velocity and polarity alignment with contact regulation of locomotion in an active matter model captures quantitatively the experimental data. Furthermore, we predict that this combination of rules enables efficient navigation in complex geometries, which we confirm experimentally. Altogether, our findings provide a conceptual framework for extracting the interaction rules of active systems from their interaction with physical boundaries, as well as design principles for collective navigation in complex microenvironments.

Research field(s)
Biophysics

DOI
10.1038/s41567-024-02532-x

Information content and optimization of self-organized developmental systems

NOMIS Researcher(s)

Published in

May 31, 2024

A key feature of many developmental systems is their ability to self-organize spatial patterns of functionally distinct cell fates. To ensure proper biological function, such patterns must be established reproducibly, by controlling and even harnessing intrinsic and extrinsic fluctuations. While the relevant molecular processes are increasingly well understood, we lack a principled framework to quantify the performance of such stochastic self-organizing systems. To that end, we introduce an information-theoretic measure for self-organized fate specification during embryonic development. We show that the proposed measure assesses the total information content of fate patterns and decomposes it into interpretable contributions corresponding to the positional and correlational information. By optimizing the proposed measure, our framework provides a normative theory for developmental circuits, which we demonstrate on lateral inhibition, cell type proportioning, and reaction–diffusion models of self-organization. This paves a way toward a classification of developmental systems based on a common information-theoretic language, thereby organizing the zoo of implicated chemical and mechanical signaling processes.

Research field(s)
Biology

DOI
10.1073/pnas.232232612

Evolution of diapause in the African turquoise killifish by remodeling the ancient gene regulatory landscape

NOMIS Researcher(s)

Published in

May 28, 2024

Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.

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

DOI
10.1016/j.cell.2024.04.048

Solutes unmask differences in clustering versus phase separation of FET proteins

NOMIS Researcher(s)

Published in

May 23, 2024

Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions of percolation are evident through the viscoelasticity of condensates and through the formation of heterogeneous distributions of nano- and mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that clusters formed in sub-saturated solutions of FET (FUS-EWSR1-TAF15) proteins are affected differently by glutamate versus chloride. These differences on the nanoscale, gleaned using a suite of methods deployed across a wide range of protein concentrations, are prevalent and can be unmasked even though the driving forces for phase separation remain unchanged in glutamate versus chloride. Strikingly, differences in anion-mediated interactions that drive clustering saturate on the micron-scale. Beyond this length scale the system separates into coexisting phases. Overall, we find that sequence-encoded interactions, mediated by solution components, make synergistic and distinct contributions to the formation of pre-percolation clusters in sub-saturated solutions, and to the driving forces for phase separation.

Research field(s)
Molecular Biology, Biological Physics, Chemistry

DOI
10.1038/s41467-024-48775-3

The first two blastomeres contribute unequally to the human embryo

NOMIS Researcher(s)

Published in

May 13, 2024

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body.

Research field(s)
Biology

DOI
10.1016/j.cell.2024.04.029

Proximity-induced gapless superconductivity in two-dimensional Rashba semiconductor in magnetic field

NOMIS Researcher(s)

Published in

May 1, 2024

Two-dimensional semiconductor-superconductor heterostructures form the foundation of numerous nanoscale physical systems. However, measuring the properties of such heterostructures, and characterizing the semiconductor in-situ is challenging. A recent experimental study by [Phys. Rev. Lett. 128, 107701 (2022)] was able to probe the semiconductor within the heterostructure using microwave measurements of the superfluid density. This work revealed a rapid depletion of superfluid density in semiconductor, caused by the in-plane magnetic field which in presence of spin-orbit coupling creates so-called Bogoliubov Fermi surfaces. The experimental work used a simplified theoretical model that neglected the presence of non-magnetic disorder in the semiconductor, hence describing the data only qualitatively. Motivated by experiments, we introduce a theoretical model describing a disordered semiconductor with strong spin-orbit coupling that is proximitized by a superconductor. Our model provides specific predictions for the density of states and superfluid density. Presence of disorder leads to the emergence of a gapless superconducting phase, that may be viewed as a manifestation of Bogoliubov Fermi surface. When applied to real experimental data, our model showcases excellent quantitative agreement, enabling the extraction of material parameters such as mean free path and mobility, and estimating g-tensor after taking into account the orbital contribution of magnetic field. Our model can be used to probe in-situ parameters of other superconductor-semiconductor heterostructures and can be further extended to give access to transport properties.

Research field(s)
Quantum

DOI
10.21468/SciPostPhys.16.5.115

Lifelong persistence of nuclear RNAs in the mouse brain

NOMIS Researcher(s)

Published in

April 4, 2024

Genomic DNA that resides in the nuclei of mammalian neurons can be as old as the organism itself. The life span of nuclear RNAs, which are critical for proper chromatin architecture and transcription regulation, has not been determined in adult tissues. In this work, we identified and characterized nuclear RNAs that do not turn over for at least 2 years in a subset of postnatally born cells in the mouse brain. These long-lived RNAs were stably retained in nuclei in a neural cell type–specific manner and were required for the maintenance of heterochromatin. Thus, the life span of neural cells may depend on both the molecular longevity of DNA for the storage of genetic information and also the extreme stability of RNA for the functional organization of chromatin.

Research field(s)
Genetics & Heredity, Biology

DOI
10.1126/science.adf3481

The Economics of Child Mental Health: Introducing the Causes and Consequences of Child Mental Health Special Issue

NOMIS Researcher(s)

Published in

April 1, 2024

This special issue of the Journal of Human Resources showcases an emerging literature on the economics of child mental health. Until recently, the severe stigma associated with mental health issues meant that few people felt comfortable talking about them or realized how very prevalent they are (Bharadwaj, Pai, and Suziedelyte 2017). Arguably, this changed with the COVID-19 pandemic, which precipitated widespread discussions of a child and youth mental health crisis (United States Public Health Service, Office of the Surgeon General 2021).

Research field(s)
Economics, Psychology & Cognitive Sciences

DOI
10.3368/jhr.2023SI-intro-child-mental-health

G-quadruplexes control hepatitis B virus replication by promoting cccDNA transcription and phase separation in hepatocytes

NOMIS Researcher(s)

Published in

March 21, 2024

Phase separation regulates fundamental processes in gene expression and is mediated by the local concentration of proteins and nucleic acids, as well as nucleic acid secondary structures such as G-quadruplexes (G4s). These structures play fundamental roles in both host gene expression and in viral replication due to their peculiar localisation in regulatory sequences. Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is an episomal minichromosome whose persistence is at the basis of chronic infection. Identifying the mechanisms controlling its transcriptional activity is indispensable to develop new therapeutic strategies against chronic hepatitis B. The aim of this study was to determine whether G4s are formed in cccDNA and regulate viral replication. Combining biochemistry and functional studies, we demonstrate that cccDNA indeed contains ten G4s structures. Furthermore, mutations disrupting two G4s located in the enhancer I HBV regulatory region altered cccDNA transcription and viral replication. Finally, we showed for the first time that cccDNA undergoes phase separation in a G4-dependent manner to promote its transcription in infected hepatocytes. Altogether, our data give new insight in the transcriptional regulation of the HBV minichromosome that might pave the way for the identification of novel targets to destabilize or silence cccDNA.

Research field(s)
Biochemistry & Molecular Biology, Biophysics, Virology

DOI
10.1093/nar/gkad1200

New Frontiers: The Origins and Content of New Work, 1940–2018

NOMIS Researcher(s)

Published in

March 15, 2024

We answer three core questions about the hypothesized role of newly emerging job categories (“new work”) in counterbalancing the erosive effect of task-displacing automation on labor demand: what is the substantive content of new work, where does it come from, and what effect does it have on labor demand? We construct a novel database spanning eight decades of new job titles linked to U.S. Census microdata and to patent-based measures of occupations’ exposure to labor-augmenting and labor-automating innovations. The majority of current employment is in new job specialties introduced since 1940, but the locus of new-work creation has shifted from middle-paid production and clerical occupations over 1940–1980 to high-paid professional occupations and secondarily to low-paid services since 1980. New work emerges in response to technological innovations that complement the outputs of occupations and demand shocks that raise occupational demand. Innovations that automate tasks or reduce occupational demand slow new-work emergence. Although the flow of augmentation and automation innovations is positively correlated across occupations, the former boosts occupational labor demand while the latter depresses it. The demand-eroding effects of automation innovations have intensified in the past four decades while the demand-increasing effects of augmentation innovations have not.

Research field(s)
Information & Communication Technologies, Economics

DOI
10.1093/qje/qjae008

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis

NOMIS Researcher(s)

Published in

March 14, 2024

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC – a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

Research field(s)
Developmental Biology, Genetics & Heredity, Evolutionary Biology

DOI
10.7554/eLife.82564

Uncovering the potential of evaluative conditioning in shaping attitudes toward sustainable product packaging

NOMIS Researcher(s)

Published in

March 14, 2024

Introduction: The necessity to promote pro-environmental behavior change in individuals and society is increasingly evident. This study aimed to investigate the effect of evaluative conditioning on consumers’ perception of product packaging.

Methods: We first produced two stimulus sets: one including images of supermarket products with different packaging and the other containing affective images of healthy nature (positive) and climate change impact (negative). These images were then paired in an evaluative conditioning experiment where respondents were informed about the impact of product packaging.

Results: We found an effect of conditioning depending on the initial sustainability perception that participants had toward product packaging. Pairing products for which participants were uncertain about their sustainability with negative or positive affective images had a significant effect on the sustainable associations of the consumers in a negative or positive direction, respectively. However, the impact of conditioning on products that clearly had (un)sustainable packaging was not that strong.

Discussion: These results provide new tools and evidence to further investigate the power of evaluative conditioning in pro-environmental attitude and behavior change.

Research field(s)
Psychology & Cognitive Sciences

DOI
10.3389/fpsyg.2024.1284422

Global emergent responses of stream microbial metabolism to glacier shrinkage

NOMIS Researcher(s)

Published in

March 1, 2024

Most cryospheric ecosystems are energy limited. How their energetics will respond to climate change remains largely unknown. This is particularly true for glacier-fed streams, which interface with the cryosphere and initiate some of Earth’s largest river systems. Here, by studying resource stoichiometry and microbial energetics in 154 glacier-fed streams sampled by the Vanishing Glaciers project across Earth’s major mountain ranges, we show that these ecosystems and their benthic microbiome are overall carbon and phosphorus limited. Threshold elemental ratios and low carbon use efficiencies (median: 0.15) modelled from extracellular enzymatic activities corroborate resource limitation in agreement with maintenance metabolism of benthic microorganisms. Space-for-time substitution analyses suggest that glacier shrinkage will stimulate benthic primary production in glacier-fed streams, thereby relieving microbial metabolism from carbon limitation. Concomitantly, we find that increasing streamwater temperature will probably stimulate microbial growth (temperature sensitivity: 0.62 eV). Consequently, elevated microbial demands for phosphorus, but diminishing inputs from subglacial sources, may intensify phosphorus limitation as glaciers shrink. Our study thus unveils a ‘green transition’ towards autotrophy in the world’s glacier-fed streams, entailing shifts in the energetics of their microorganisms.

Research field(s)
Ecology, Environmental Sciences

DOI
10.1038/s41561-024-01393-6

Massively parallel disruption of enhancers active in human neural stem cells

NOMIS Researcher(s)

Published in

February 27, 2024

Changes in gene regulation have been linked to the expansion of the human cerebral cortex and to neurodevelopmental disorders, potentially by altering neural progenitor proliferation. However, the effects of genetic variation within regulatory elements on neural progenitors remain obscure. We use sgRNA-Cas9 screens in human neural stem cells (hNSCs) to disrupt 10,674 genes and 26,385 conserved regions in 2,227 enhancers active in the developing human cortex and determine effects on proliferation. Genes with proliferation phenotypes are associated with neurodevelopmental disorders and show biased expression in specific fetal human brain neural progenitor populations. Although enhancer disruptions overall have weaker effects than gene disruptions, we identify enhancer disruptions that severely alter hNSC self-renewal. Disruptions in human accelerated regions, implicated in human brain evolution, also alter proliferation. Integrating proliferation phenotypes with chromatin interactions reveals regulatory relationships between enhancers and their target genes contributing to neurogenesis and potentially to human cortical evolution.

Research field(s)
Developmental Biology, Genetics & Heredity

DOI
10.1016/j.celrep.2024.113693

Publish or perish: Simulating the impact of publication policies on science

NOMIS Researcher(s)

Published in

February 26, 2024

Science can be viewed as a collective, epistemic endeavor. However, a variety of factors- such as the publish-or-perish culture, institutional incentives, and publishers who favor novel and positive findings- may challenge the ability of science to accurately aggregate information about the world. Evidence of the shortcomings in the current structure of science can be seen in the replication crisis that faces psychology and other disciplines. We analyze scientific publishing through the lens of cultural evolution, framing the scientific process as a multi-generational interplay between scientists and publishers in a multi-armed bandit setting. We examine the dynamics of this model through simulations, exploring the effect that different publication policies have on the accuracy of the published scientific record. Our findings highlight the need for replications and caution against behaviors that prioritize factors uncorrelated with result accuracy.

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

Load More