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.

The microbiome of cryospheric ecosystems

NOMIS Researcher(s)

Published in

December 1, 2022

The melting of the cryosphere is among the most conspicuous consequences of climate change, with impacts on microbial life and related biogeochemistry. However, we are missing a systematic understanding of microbiome structure and function across cryospheric ecosystems. Here, we present a global inventory of the microbiome from snow, ice, permafrost soils, and both coastal and freshwater ecosystems under glacier influence. Combining phylogenetic and taxonomic approaches, we find that these cryospheric ecosystems, despite their particularities, share a microbiome with representatives across the bacterial tree of life and apparent signatures of early and constrained radiation. In addition, we use metagenomic analyses to define the genetic repertoire of cryospheric bacteria. Our work provides a reference resource for future studies on climate change microbiology.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41467-022-30816-4

Genomic and metabolic adaptations of biofilms to ecological windows of opportunity in glacier-fed streams

NOMIS Researcher(s)

Published in

December 1, 2022

In glacier-fed streams, ecological windows of opportunity allow complex microbial biofilms to develop and transiently form the basis of the food web, thereby controlling key ecosystem processes. Using metagenome-assembled genomes, we unravel strategies that allow biofilms to seize this opportunity in an ecosystem otherwise characterized by harsh environmental conditions. We observe a diverse microbiome spanning the entire tree of life including a rich virome. Various co-existing energy acquisition pathways point to diverse niches and the exploitation of available resources, likely fostering the establishment of complex biofilms during windows of opportunity. The wide occurrence of rhodopsins, besides chlorophyll, highlights the role of solar energy capture in these biofilms while internal carbon and nutrient cycling between photoautotrophs and heterotrophs may help overcome constraints imposed by oligotrophy in these habitats. Mechanisms potentially protecting bacteria against low temperatures and high UV-radiation are also revealed and the selective pressure of this environment is further highlighted by a phylogenomic analysis differentiating important components of the glacier-fed stream microbiome from other ecosystems. Our findings reveal key genomic underpinnings of adaptive traits contributing to the success of complex biofilms to exploit environmental opportunities in glacier-fed streams, which are now rapidly changing owing to global warming.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41467-022-29914-0

Ultrasound and nanomaterial: an efficient pair to fight cancer

NOMIS Researcher(s)

Published in

December 1, 2022

Ultrasounds are often used in cancer treatment protocols, e.g. to collect tumor tissues in the right location using ultrasound-guided biopsy, to image the region of the tumor using more affordable and easier to use apparatus than MRI and CT, or to ablate tumor tissues using HIFU. The efficacy of these methods can be further improved by combining them with various nano-systems, thus enabling: (i) a better resolution of ultrasound imaging, allowing for example the visualization of angiogenic blood vessels, (ii) the specific tumor targeting of anti-tumor chemotherapeutic drugs or gases attached to or encapsulated in nano-systems and released in a controlled manner in the tumor under ultrasound application, (iii) tumor treatment at tumor site using more moderate heating temperatures than with HIFU. Furthermore, some nano-systems display adjustable sizes, i.e. nanobubbles can grow into micro-bubbles. Such dual size is advantageous since it enables gathering within the same unit the targeting properties of nano bubbles via EPR effect and the enhanced ultrasound contrasting properties of micro bubbles. Interestingly, the way in which nano-systems act against a tumor could in principle also be adjusted by accurately selecting the nano-system among a large choice and by tuning the values of the ultrasound parameters, which can lead, due to their mechanical nature, to specific effects such as cavitation that are usually not observed with purely electromagnetic waves and can potentially help destroying the tumor. This review highlights the clinical potential of these combined treatments that can improve the benefit/risk ratio of current cancer treatments. Graphical Abstract: [Figure not available: see fulltext.]

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Nanoscience & Nanotechnology

DOI
10.1186/s12951-022-01243-w

Serological fingerprints link antiviral activity of therapeutic antibodies to affinity and concentration

NOMIS Researcher(s)

Published in

December 1, 2022

The effectiveness of therapeutic monoclonal antibodies (mAbs) against variants of the SARS-CoV-2 virus is highly variable. As target recognition of mAbs relies on tight binding affinity, we assessed the affinities of five therapeutic mAbs to the receptor binding domain (RBD) of wild type (A), Delta (B.1.617.2), and Omicron BA.1 SARS-CoV-2 (B.1.1.529.1) spike using microfluidic diffusional sizing (MDS). Four therapeutic mAbs showed strongly reduced affinity to Omicron BA.1 RBD, whereas one (sotrovimab) was less impacted. These affinity reductions correlate with reduced antiviral activities suggesting that affinity could serve as a rapid indicator for activity before time-consuming virus neutralization assays are performed. We also compared the same mAbs to serological fingerprints (affinity and concentration) obtained by MDS of antibodies in sera of 65 convalescent individuals. The affinities of the therapeutic mAbs to wild type and Delta RBD were similar to the serum antibody response, indicating high antiviral activities. For Omicron BA.1 RBD, only sotrovimab retained affinities within the range of the serum antibody response, in agreement with high antiviral activity. These results suggest that serological fingerprints provide a route to evaluating affinity and antiviral activity of mAb drugs and could guide the development of new therapeutics.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1038/s41598-022-22214-z

An arrayed genome-wide perturbation screen identifies the ribonucleoprotein Hnrnpk as rate-limiting for prion propagation

NOMIS Researcher(s)

Published in

December 1, 2022

A defining characteristic of mammalian prions is their capacity for self-sustained propagation. Theoretical considerations and experimental evidence suggest that prion propagation is modulated by cell-autonomous and non-autonomous modifiers. Using a novel quantitative phospholipase protection assay (QUIPPER) for high-throughput prion measurements, we performed an arrayed genome-wide RNA interference (RNAi) screen aimed at detecting cellular host-factors that can modify prion propagation. We exposed prion-infected cells in high-density microplates to 35,364 ternary pools of 52,746 siRNAs targeting 17,582 genes representing the majority of the mouse protein-coding transcriptome. We identified 1,191 modulators of prion propagation. While 1,151 modified the expression of both the pathological prion protein, PrPSc, and its cellular counterpart, PrPC, 40 genes selectively affected PrPSc. Of the latter 40 genes, 20 augmented prion production when suppressed. A prominent limiter of prion propagation was the heterogeneous nuclear ribonucleoprotein Hnrnpk. Psammaplysene A (PSA), which binds Hnrnpk, reduced prion levels in cultured cells and protected them from cytotoxicity. PSA also reduced prion levels in infected cerebellar organotypic slices and alleviated locomotor deficits in prion-infected Drosophila melanogaster expressing ovine PrPC. Hence, genome-wide QUIPPER-based perturbations can discover actionable cellular pathways involved in prion propagation. Further, the unexpected identification of a prion-controlling ribonucleoprotein suggests a role for RNA in the generation of infectious prions.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/embj.2022112338

Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions

NOMIS Researcher(s)

Published in

December 1, 2022

Mammalian models are essential for brain aging research. However, the long lifespan and poor amenability to genetic and pharmacological perturbations have hindered the use of mammals for dissecting aging-regulatory molecular networks and discovering new anti-aging interventions. To circumvent these limitations, we developed an ex vivo model system that faithfully mimics the aging process of the mammalian brain using cultured mouse brain slices. Genome-wide gene expression analyses showed that cultured brain slices spontaneously upregulated senescence-associated genes over time and reproduced many of the transcriptional characteristics of aged brains. Treatment with rapamycin, a classical anti-aging compound, largely abolished the time-dependent transcriptional changes in naturally aged brain slice cultures. Using this model system, we discovered that prions drastically accelerated the development of age-related molecular signatures and the pace of brain aging. We confirmed this finding in mouse models and human victims of Creutzfeldt-Jakob disease. These data establish an innovative, eminently tractable mammalian model of brain aging, and uncover a surprising acceleration of brain aging in prion diseases.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s42003-022-03496-5

Social alignment matters: Following pandemic guidelines is associated with better wellbeing

NOMIS Researcher(s)

Published in

December 1, 2022

Background: In response to the Covid-19 pandemic, most countries implemented physical distancing measures. Many mental health experts warned that through increasing social isolation and anxiety, these measures could negatively affect psychosocial wellbeing. However, socially aligning with others by adhering to these measures may also be beneficial for wellbeing. Methods: We examined these two contrasting hypotheses using cross-national survey data (N = 6675) collected fortnightly from participants in 115 countries over 3 months at the beginning of the pandemic. Participants reported their wellbeing, perceptions of how vulnerable they were to Covid-19 (i.e., high risk of infection) and how much they, and others in their social circle and country, were adhering to the distancing measures. Results: Linear mixed-effects models showed that being a woman, having lower educational attainment, living alone and perceived high vulnerability to Covid-19 were risk factors for poorer wellbeing. Being young (18–25) was associated with lower wellbeing, but longitudinal analyses showed that young people’s wellbeing improved over 3 months. In contrast to widespread views that physical distancing measures negatively affect wellbeing, results showed that following the guidelines was positively associated with wellbeing even for people in high-risk groups. Conclusions: These findings provide an important counterpart to the idea that pandemic containment measures such as physical distancing negatively impacted wellbeing unequivocally. Despite the overall burden of the pandemic on psychosocial wellbeing, social alignment with others can still contribute to positive wellbeing. The pandemic has manifested our propensity to adapt to challenges, particularly highlighting how social alignment can forge resilience.

Research field(s)
Health Sciences, Public Health & Health Services, Public Health

DOI
10.1186/s12889-022-13130-y

Diffusion of punishment in collective norm violations

NOMIS Researcher(s)

Published in

December 1, 2022

People assign less punishment to individuals who inflict harm collectively, compared to those who do so alone. We show that this arises from judgments of diminished individual causal responsibility in the collective cases. In Experiment 1, participants (N = 1002) assigned less punishment to individuals involved in collective actions leading to intentional and accidental deaths, but not failed attempts, emphasizing that harmful outcomes, but not malicious intentions, were necessary and sufficient for the diffusion of punishment. Experiments 2.a compared the diffusion of punishment for harmful actions with ‘victimless’ purity violations (e.g., eating a dead human’s flesh as a group; N = 752). In victimless cases, where the question of causal responsibility for harm does not arise, diffusion of collective responsibility was greatly reduced—an outcome replicated in Experiment 2.b (N = 479). Together, the results are consistent with discounting in causal attribution as the underlying mechanism of reduction in proposed punishment for collective harmful actions.

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

DOI
10.1038/s41598-022-19156-x

Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids

NOMIS Researcher(s)

Published in

December 1, 2022

Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-β (Aβ). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aβ. Furthermore, in mhCOs, we observed reduced expression of Aβ-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer’s disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aβ using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.

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

DOI
10.1038/s41467-022-28043-y

Methods to investigate intrathecal adaptive immunity in neurodegeneration

NOMIS Researcher(s)

Published in

December 1, 2022

Background: Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alterations. Evidence now exists for involvement of intrathecal T cells in the pathobiology of neurodegenerative diseases. However, a standardized method for long-term preservation of CSF immune cells is lacking. Further, the functional role of CSF T cells and their cognate antigens in neurodegenerative diseases are largely unknown. Results: We present a method for long-term cryopreservation of CSF immune cells for downstream single cell RNA and T cell receptor sequencing (scRNA-TCRseq) analysis. We observe preservation of CSF immune cells, consisting primarily of memory CD4+ and CD8+ T cells. We then utilize unbiased bioinformatics approaches to quantify and visualize TCR sequence similarity within and between disease groups. By this method, we identify clusters of disease-associated, antigen-specific TCRs from clonally expanded CSF T cells of patients with neurodegenerative diseases. Conclusions: Here, we provide a standardized approach for long-term storage of CSF immune cells. Additionally, we present unbiased bioinformatic approaches that will facilitate the discovery of target antigens of clonally expanded T cells in neurodegenerative diseases. These novel methods will help improve our understanding of adaptive immunity in the central nervous system.

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

DOI
10.1186/s13024-021-00423-w

The Self in the Mind’s Eye: Revealing How We Truly See Ourselves Through Reverse Correlation

NOMIS Researcher(s)

Published in

December 1, 2022

Is there a way to visually depict the image people “see” of themselves in their minds’ eyes? And if so, what can these mental images tell us about ourselves? We used a computational reverse-correlation technique to explore individuals’ mental “self-portraits” of their faces and body shapes in an unbiased, data-driven way (total N = 116 adults). Self-portraits were similar to individuals’ real faces but, importantly, also contained clues to each person’s self-reported personality traits, which were reliably detected by external observers. Furthermore, people with higher social self-esteem produced more true-to-life self-portraits. Unlike face portraits, body portraits had negligible relationships with individuals’ actual body shape, but as with faces, they were influenced by people’s beliefs and emotions. We show how psychological beliefs and attitudes about oneself bias the perceptual representation of one’s appearance and provide a unique window into the internal mental self-representation—findings that have important implications for mental health and visual culture.

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

DOI
10.1177/09567976211018618

Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease

NOMIS Researcher(s)

Published in

December 1, 2022

Objective: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. Background: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. Updated Hypothesis: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. Major Challenges for the Hypothesis: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common “sporadic” late-onset AD. Linkage to Other Major Theories: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.

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

DOI
10.1002/alz.12624

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

NOMIS Researcher(s)

Published in

December 1, 2022

Background: To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity. Methods: This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers. Results: The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance. Conclusions: The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms.

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

DOI
10.1186/s13195-022-01030-7

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

NOMIS Researcher(s)

Published in

December 1, 2022

Background: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1186/s13073-022-01035-9

Deep residual inception encoder-decoder network for amyloid PET harmonization

NOMIS Researcher(s)

Published in

December 1, 2022

Introduction: Multiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy. Method: A Residual Inception Encoder-Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound-B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10-fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects. Results: Significantly stronger between-tracer correlations (P <.001) were observed after harmonization for both global amyloid burden indices and voxel-wise measurements in the training cohort and the external testing cohort. Discussion: We proposed and validated a novel encoder-decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers.

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

DOI
10.1002/alz.12564

SepN is a septal junction component required for gated cell–cell communication in the filamentous cyanobacterium Nostoc

NOMIS Researcher(s)

Published in

December 1, 2022

Multicellular organisms require controlled intercellular communication for their survival. Strains of the filamentous cyanobacterium Nostoc regulate cell–cell communication between sister cells via a conformational change in septal junctions. These multi-protein cell junctions consist of a septum spanning tube with a membrane-embedded plug at both ends, and a cap covering the plug on the cytoplasmic side. The identities of septal junction components are unknown, with exception of the protein FraD. Here, we identify and characterize a FraD-interacting protein, SepN, as the second component of septal junctions in Nostoc. We use cryo-electron tomography of cryo-focused ion beam-thinned cyanobacterial filaments to show that septal junctions in a sepN mutant lack a plug module and display an aberrant cap. The sepN mutant exhibits highly reduced cell–cell communication rates, as shown by fluorescence recovery after photobleaching experiments. Furthermore, the mutant is unable to gate molecule exchange through septal junctions and displays reduced filament survival after stress. Our data demonstrate the importance of controlling molecular diffusion between cells to ensure the survival of a multicellular organism.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41467-022-34946-7

Improved gRNA secondary structures allow editing of target sites resistant to CRISPR-Cas9 cleavage

NOMIS Researcher(s)

Published in

December 1, 2022

The first step in CRISPR-Cas9-mediated genome editing is the cleavage of target DNA sequences that are complementary to so-called spacer sequences in CRISPR guide RNAs (gRNAs). However, some DNA sequences are refractory to CRISPR-Cas9 cleavage, which is at least in part due to gRNA misfolding. To overcome this problem, we have engineered gRNAs with highly stable hairpins in their constant parts and further enhanced their stability by chemical modifications. The ‘Genome-editing Optimized Locked Design’ (GOLD)-gRNA increases genome editing efficiency up to around 1000-fold (from 0.08 to 80.5%) with a mean increase across different other targets of 7.4-fold. We anticipate that this improved gRNA will allow efficient editing regardless of spacer sequence composition and will be especially useful if a desired genomic site is difficult to edit.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-022-28137-7

Respecting the Nonhuman Other: Individual Natural Otherness and the Case for Incommensurability of Moral Standing

NOMIS Researcher(s)

Published in

December 1, 2022

The concept of natural otherness can be found throughout the environmental ethics literature. Drawing on this concept, this article pursues two aims. For one, it argues for an account of individual natural otherness as stable difference as opposed to accounts of natural otherness that put more emphasis on inde-pendence for the purpose of differentiating individual natural otherness from the concept of wildness. Secondly, this account of natural otherness is engaged to argue for a particular way of theorising the moral standing of individual nonhuman entities. While individual natural otherness in itself does not pro-vide an account of whether an entity matters morally in itself (that is, whether it is morally considerable); it points to an account of incommensurable moral significance for all entities which are attributed moral considerability. That is an often-overlooked alternative to egalitarian or hierarchical accounts of moral significance. Individual natural otherness understood in this way in turn pro-vides another explanatory story for why relational accounts of environmental ethics that strongly emphasise the importance of concepts such as wildness are particularly salient.

Research field(s)
Natural Sciences, Earth & Environmental Sciences, Environmental Sciences

DOI
10.3197/096327121X16328186623913

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

NOMIS Researcher(s)

Published in

December 1, 2022

Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer’s disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.

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

DOI
10.1186/s40478-022-01387-8

Comparative analysis of machine learning algorithms for multi-syndrome classification of neurodegenerative syndromes

NOMIS Researcher(s)

Published in

December 1, 2022

Importance: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. Objective: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. Design, setting, and participants: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. Interventions: N.A. Main outcomes and measures: Cohen’s kappa, accuracy, and F1-score to assess model performance. Results: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. Conclusions and relevance: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

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

DOI
10.1186/s13195-022-00983-z

National identity predicts public health support during a global pandemic

NOMIS Researcher(s)

Published in

December 1, 2022

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = −0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.

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

DOI
10.1038/s41467-021-27668-9

Load More