Research is the vital expression of humankind’s most important qualities: curiosity and imagination.
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Insight, when it comes, changes everything.
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.
NOMIS Researcher(s)
Published in Neuron
TDP-43 aggregation is the major hallmark of multiple neurodegenerative diseases, including ALS and FTD. Gasset-Rosa et al. demonstrate that transient stress induces long-lasting cytoplasmic TDP-43 de-mixing independent of stress granules, driving nuclear import defects, nuclear TDP-43 clearance, and cell death.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Science
Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases such as Creutzfeldt-Jakob disease attack different parts of the central nervous system (CNS) and elicit distinct symptoms, yet they share many biochemical and neuropathological features. These include the formation of protein aggregates in the affected brain regions and progressive activation of non-neuronal cells in the brain that play crucial roles in immune responses. The activation of immune cells in the CNS (“neuroinflammation”) is prominent in these diseases. However, it remains unclear whether boosting or suppressing the immune system, in the brain or in the periphery, may attenuate neurodegeneration. In the case of extraneural prion infections, genetic or pharmacological ablation of components of the immune system, such as B cells and complement, can prevent disease (1). However, immunotherapies, which have been successful in treating certain types of cancer, have yet to reverse neurodegeneration in any patients. Therefore, the therapeutic promise of this approach remains debatable.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Nature
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Journal of Experimental Medicine
SARM1 (sterile α and HEAT/armadillo motif-containing protein) is a member of the MyD88 (myeloid differentiation primary response gene 88) family, which mediates innate immune responses. Because inactivation of SARM1 prevents various forms of axonal degeneration, we tested whether it might protect against prion-induced neurotoxicity. Instead, we found that SARM1 deficiency exacerbates the progression of prion pathogenesis. This deleterious effect was not due to SARM1-dependent modulation of prion-induced neuroinflammation, since microglial activation, astrogliosis, and brain cytokine profiles were not altered by SARM1 deficiency. Whole-transcriptome analyses indicated that SARM1 deficiency led to strong, selective overexpression of the pro-apoptotic gene XAF1 (X-linked inhibitor of apoptosis-associated factor 1). Consequently, the activity of pro-apoptotic caspases and neuronal death were enhanced in prion-infected SARM1−/− mice. These results point to an unexpected function of SARM1 as a regulator of prion-induced neurodegeneration and suggest that XAF1 might constitute a therapeutic target in prion disease.
Research field(s)
Health Sciences, Clinical Medicine, Immunology
NOMIS Researcher(s)
Published in Journal of Biological Chemistry
Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor–ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling–based drugs and their potential to function as endocrine disruptors.
Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology
NOMIS Researcher(s)
Published in Environmental Science and Policy
For nexus approaches to be successful in their analysis and influence, integration dynamics must be understood in the context of larger power dynamics. Current analysis barely take this dimension into account. In this article, we aim to delimit and understand the power-related enabling conditions for integration processes in a situation of water, food and energy conflicts in Cambodia. To do so, we reflect on our experiences and outcomes in a knowledge co-production approach for identifying nexus indicators in a WWF Conservation Mekong Flooded Forest Landscape. We conduct an analysis of stakeholder and partner qualitative interview data collected within the LIVES (Linked Indicators for Vital Ecosystem Services) project to explore three examples how we engaged with power dynamics in the course of the research. By doing so, this article provides first (1) learning on existing challenges regarding integration in the nexus, then (2) it analyses effects of coproduction processes when considering power dynamics in the nexus both in terms of stalemate and enabling conditions for reinforced integration. Finally (3), this article analyses the role that plays structure and agency in such integration processes.
Research field(s)
Natural Sciences, Earth & Environmental Sciences, Environmental Sciences
NOMIS Researcher(s)
Published in Alzheimer's and Dementia
Introduction: Recruitment for Alzheimer’s disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies. Methods: Individuals aged 55-75 years who live in the United States and self-report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies. Results: As of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P <.001). Discussion: GeneMatch, the first trial-independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Molecular Cell
FUS is an RNA binding protein associated with several neurodegenerative diseases, for which mode of nucleic acid binding has been elusive. Loughlin et al. solved the solution structure of FUS bound to RNA, revealing a sequence-specific recognition for a GGU motif and an unusual shape recognition of a stem loop by two separate domains.
Research field(s)
Health Sciences, Biomedical Research, Developmental Biology
NOMIS Researcher(s)
Published in Alzheimer's Research and Therapy
Background: Autosomal dominant Alzheimer’s disease (ADAD) is distinguished from late-onset AD by early striatal amyloid-β deposition. To determine whether striatal Pittsburgh compound B (PiB)-PET measurements of amyloid-β can help predict disease severity in ADAD, we compared relationships of striatal and neocortical PiB-PET to age, tau-PET, and memory performance in the Colombian Presenilin 1 E280A kindred. Methods: Fourteen carriers (age = 28-42, Mini-Mental State Examination = 26-30) and 20 age-matched non-carriers were evaluated using PiB, flortaucipir (FTP; tau), and memory testing (CERAD Word List Learning). PiB-PET signal was measured in neocortical and striatal aggregates. FTP-PET signal was measured in entorhinal cortex. Results: Compared to non-carriers, mutation carriers had age-related elevations in both neocortical and striatal PiB binding. The PiB elevation in carriers was significantly greater in the striatum than in the neocortex. In mutation carriers, PiB binding in both the neocortex and the striatum is related to entorhinal FTP; however, the association was stronger with the striatum. Only striatal PiB was associated with worse memory. Remarkably, PiB binding in the striatum, but not in the neocortex, predicted entorhinal FTP and lower memory scores after adjusting for age, indicating that striatal PiB identified the carriers with the most severe disease. Conclusions: Based on these preliminary cross-sectional findings, striatal PiB-PET measurements may offer particular value in the detection and tracking of preclinical ADAD, informing a mutation carrier’s prognosis and evaluating amyloid-β-modifying ADAD treatments.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Neuropathology and Applied Neurobiology
Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome associated with frontotemporal lobar degeneration (FTLD) as a relatively consistent neuropathological hallmark feature. However, the discoveries in the past decade of many of the relevant pathological proteins aggregating in human FTD brains in addition to several new FTD causing gene mutations underlined that FTD is a diverse condition on the neuropathological and genetic basis. This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA-binding protein 43 or FET protein accumulation (FTLD-tau, FTLD-TDP and FTLD-FET respectively). This review will provide an overview of the molecular neuropathology of non-tau FTLD, insights into disease mechanisms gained from the study of human post mortem tissue as well as discussion of current controversies in the field.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Journal of Cell Biology
Many adult tissues contain postmitotic cells as old as the host organism. Te only organelle that does not turn over in these cells is the nucleus, and its maintenance represents a formidable challenge, as it harbors regulatory proteins that persist throughout adulthood. Here we developed strategies to visualize two classes of such long-lived proteins, histones and nucleoporins, to understand the function of protein longevity in nuclear maintenance. Genome-wide mapping of histones revealed specifc enrichment of long-lived variants at silent gene loci. Interestingly, nuclear pores are maintained by piecemeal replacement of subunits, resulting in mosaic complexes composed of polypeptides with vastly different ages. In contrast, nondividing quiescent cells remove old nuclear pores in an ESCRT-dependent manner. Our fndings reveal distinct molecular strategies of nuclear maintenance, linking lifelong protein persistence to gene regulation and nuclear integrity.
Research field(s)
Health Sciences, Biomedical Research, Developmental Biology
NOMIS Researcher(s)
Published in Frontiers in Neural Circuits
Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, dysfunction of these neurons is involved in both degenerative and psychiatric disorders. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channelrhodopsin to readily enable cell-type specific activation. However, corresponding lines to silence these monoaminergic neurons have been lacking. We have generated two BAC transgenic mouse lines expressing the outward proton pump, enhanced ArchT3.0 (eArchT3.0), and GFP under control of the regulatory elements of either the dopamine transporter (DAT; Jax# 031663) or the tryptophan hydroxylase 2 (TPH2; Jax# 031662) gene locus. We demonstrate highly faithful and specific expression of these lines in dopaminergic and serotonergic neurons respectively. Additionally we validate effective and sensitive eArchT3.0-mediated silencing of these neurons using slice electrophysiology as well as with a well-established behavioral assay. These new transgenic tools will help expedite the study of dopaminergic and serotonergic system function in normal behavior and disease.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Neuron
Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Current Biology
One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1–4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4, 5]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [6, 7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.
Research field(s)
Health Sciences, Biomedical Research, Developmental Biology
NOMIS Researcher(s)
Published in Frontiers in Environmental Science
As the water-energy-food (WEF) nexus becomes an increasingly common framework for bridging science and policy, there is a growing need to unpack and make explicit many of the methods and assumptions being used to operationalize the nexus. In this paper, we focus on two common approaches to nexus research, quantitative modeling and futures thinking, and the ways that each set of methodological tools address uncertainty. We first review the underlying assumptions of each approach with a focus on sources of and ability to measure uncertainty, and potential complementarities. Quantitative modeling takes a probabilistic approach to predicting the likelihood of a specific outcome or future state based on estimates of current system dynamics. In contrast, futures thinking approaches, such as scenario processes, explore novel changes that cannot be fully predicted or even anticipated based on current understandings of the nexus. We then examine a set of applied nexus projects that bridge science and policy-making contexts to better understand practitioner experiences with different methodological tools and how they are utilized to navigate uncertainty. We explore one nexus case study, LIVES Cambodia, in-depth, to better understand the opportunities and challenges associated with participatory modeling and stakeholder engagement with uncertainty in a policy-making context. Across the cases, practitioners identify the complementarity between modeling and futures thinking approaches, and those projects that integrated both into the planning process experienced benefits from having multiple angles on uncertainty within the nexus. In particular, stakeholder engagement provided critical opportunities to address some types of uncertainties (e.g., data gaps) through the use of local knowledge. Explicit discussions of model uncertainty and use of scenario processes also enabled stakeholders to deepen their understandings of uncertainties and envision policy pathways that would be robust to uncertainty. In many senses, models became boundary objects that encouraged critical thinking and questioning of assumptions across diverse stakeholders. And, for some nexus projects, confronting uncertainty in explicit and transparent ways build capacity for policy flexibility and adaptiveness. We conclude with a discussion of when and how these benefits can be fully realized through the strategic use of appropriate approaches to characterizing and navigating nexus uncertainty.
Research field(s)
Natural Sciences, Earth & Environmental Sciences, Environmental Sciences
NOMIS Researcher(s)
Published in Nature Reviews Genetics
The genome is packaged and organized nonrandomly within the 3D space of the nucleus to promote efficient gene expression and to faithfully maintain silencing of heterochromatin. The genome is enclosed within the nucleus by the nuclear envelope membrane, which contains a set of proteins that actively participate in chromatin organization and gene regulation. Technological advances are providing views of genome organization at unprecedented resolution and are beginning to reveal the ways that cells co-opt the structures of the nuclear periphery for nuclear organization and gene regulation. These genome regulatory roles of proteins of the nuclear periphery have important influences on development, disease and ageing.
Research field(s)
Health Sciences, Biomedical Research, Developmental Biology
NOMIS Researcher(s)
Published in Current Neurology and Neuroscience Reports
Purpose of Review: We provide an overview about unbiased screens to identify modifiers of alpha-synuclein (αSyn)-induced toxicity, present the models and the libraries that have been used for screening, and describe how hits from primary screens were selected and validated. Recent Findings: Screens can be classified as either genetic or chemical compound modifier screens, but a few screens do not fit this classification. Most screens addressing αSyn-induced toxicity, including genome-wide overexpressing and deletion, were performed in yeast. More recently, newer methods such as CRISPR-Cas9 became available and were used for screening purposes. Paradoxically, given that αSyn-induced toxicity plays a role in neurological diseases, there is a shortage of human cell-based models for screening. Moreover, most screens used mutant or fluorescently tagged forms of αSyn and only very few screens investigated wild-type αSyn. Particularly, no genome-wide αSyn toxicity screen in human dopaminergic neurons has been published so far. Summary: Most unbiased screens for modifiers of αSyn toxicity were performed in yeast, and there is a lack of screens performed in human and particularly dopaminergic cells.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Life Science Alliance
FUS (fused in sarcoma) plays a key role in several steps of RNA metabolism, and dominant mutations in this protein are associated with neurodegenerative diseases. Here, we show that FUS is a component of the cellular response to topoisomerase I (TOP1)–induced DNA breakage; relocalising to the nucleolus in response to RNA polymerase II (Pol II) stalling at sites of TOP1-induced DNA breaks. This relocalisation is rapid and dynamic, reversing following the removal of TOP1-induced breaks and coinciding with the recovery of global transcription. Importantly, FUS relocalisation following TOP1-induced DNA breakage is associated with increased FUS binding at sites of RNA polymerase I transcription in ribosomal DNA and reduced FUS binding at sites of RNA Pol II transcription, suggesting that FUS relocates from sites of stalled RNA Pol II either to regulate pre-mRNA processing during transcriptional stress or to modulate ribosomal RNA biogenesis. Importantly, FUS-mutant patient fibroblasts are hypersensitive to TOP1-induced DNA breakage, highlighting the possible relevance of these findings to neurodegeneration.
Research field(s)
Health Sciences, Biomedical Research, Developmental Biology
NOMIS Researcher(s)
Introduction: Alzheimer’s disease (AD) pathology, including the accumulation of amyloid beta (Aβ) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer’s Prevention Initiative Generation Program, therapies targeting Aβ, including CNP520 (umibecestat), a β-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aβ immunotherapy, are in clinical development in preclinical AD. Methods: The Alzheimer’s Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60–75 years), APOE4 genotype, and, for heterozygotes (APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer’s Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. Discussion: The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.
Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery
NOMIS Researcher(s)
Published in Perception
The Warburg Dance Movement Library is a validated set of 234 video clips of dance movements for empirical research in the fields of cognitive science and neuroscience of action perception, affect perception and neuroaesthetics. The library contains two categories of video clips of dance movement sequences. Of each pair, one version of the movement sequence is emotionally expressive (Clip a), while the other version of the same sequence (Clip b) is not expressive but as technically correct as the expressive version (Clip a). We sought to complement previous dance video stimuli libraries. Facial information, colour and music have been removed, and each clip has been faded in and out. We equalised stimulus length (6 seconds, 8 counts in dance theory), the dancers’ clothing and video background and included both male and female dancers, and we controlled for technical correctness of movement execution. The Warburg Dance Movement Library contains both contemporary and ballet movements. Two online surveys (N = 160) confirmed the classification into the two categories of expressivity. Four additional online surveys (N = 80) provided beauty and liking ratings for each clip. A correlation matrix illustrates all variables of this norming study (technical correctness, expressivity, beauty, liking, luminance, motion energy).
Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology
NOMIS Researcher(s)
Published in Bioinformatics
Motivation Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. Results We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. Availability and implementation Datasets and scripts for reproduction of results are available through: Https://nalab.stanford.edu/multiomics-pregnancy/.
Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics
