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

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

Insight, when it comes, changes everything.

Publications

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

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

Light-Interacting iron-based nanomaterials for localized cancer detection and treatment

NOMIS Researcher(s)

Published in

April 1, 2021

To improve the prognosis of cancer patients, methods of local cancer detection and treatment could be implemented. For that, iron-based nanomaterials (IBN) are particularly well-suited due to their biocompatibility and the various ways in which they can specifically target a tumor, i.e. through passive, active or magnetic targeting. Furthermore, when it is needed, IBN can be associated with well-known fluorescent compounds, such as dyes, clinically approved ICG, fluorescent proteins, or quantum dots. They may also be excited and detected using well-established optical methods, relying on scattering or fluorescent mechanisms, depending on whether IBN are associated with a fluorescent compound or not. Systems combining IBN with optical methods are diverse, thus enabling tumor detection in various ways. In addition, these systems provide a wealth of information, which is inaccessible with more standard diagnostic tools, such as single tumor cell detection, in particular by combining IBN with near-field scanning optical microscopy, dark-field microscopy, confocal microscopy or super-resolution microscopy, or the highlighting of certain dynamic phenomena such as the diffusion of a fluorescent compound in an organism, e.g. using fluorescence lifetime imaging, fluorescence resonance energy transfer, fluorescence anisotropy, or fluorescence tomography. Furthermore, they can in some cases be complemented by a therapeutic approach to destroy tumors, e.g. when the fluorescent compound is a drug, or when a technique such as photo-thermal or photodynamic therapy is employed. This review brings forward the idea that iron-based nanomaterials may be associated with various optical techniques to form a commercially available toolbox, which can serve to locally detect or treat cancer with a better efficacy than more standard medical approaches. Statement of Significance: New tools should be developed to improve cancer treatment outcome. For that, two closely-related aspects deserve to be considered, i.e. early tumor detection and local tumor treatment. Here, I present various types of iron-based nanomaterials, which can achieve this double objective when they interact with a beam of light under specific and accurately chosen conditions. Indeed, these materials are biocompatible and can be used/combined with most standard microscopic/optical methods. Thus, these systems enable on the one hand tumor cell detection with a high sensitivity, i.e. down to single tumor cell level, and on the other hand tumor destruction through various mechanisms in a controlled and localized manner by deciding whether or not to apply a beam of light and by having these nanomaterials specifically target tumor cells.

Research field(s)
Applied Sciences, Engineering, Biomedical Engineering

DOI
10.1016/j.actbio.2021.01.028

In Vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies

NOMIS Researcher(s)

Published in

April 1, 2021

Background: Neuroinflammation has received growing interest as a therapeutic target in neurodegenerative disorders, including 4-repeat tauopathies. Objectives: The aim of this cross-sectional study was to investigate 18 kDa translocator protein positron emission tomography (PET) as a biomarker for microglial activation in the 4-repeat tauopathies corticobasal degeneration and progressive supranuclear palsy. Methods: Specific binding of the 18 kDa translocator protein tracer 18F-GE-180 was determined by serial PET during pharmacological depletion of microglia in a 4-repeat tau mouse model. The 18 kDa translocator protein PET was performed in 30 patients with corticobasal syndrome (68 ± 9 years, 16 women) and 14 patients with progressive supranuclear palsy (69 ± 9 years, 8 women), and 13 control subjects (70 ± 7 years, 7 women). Group comparisons and associations with parameters of disease progression were assessed by region-based and voxel-wise analyses. Results: Tracer binding was significantly reduced after pharmacological depletion of microglia in 4-repeat tau mice. Elevated 18 kDa translocator protein labeling was observed in the subcortical brain areas of patients with corticobasal syndrome and progressive supranuclear palsy when compared with controls and was most pronounced in the globus pallidus internus, whereas only patients with corticobasal syndrome showed additionally elevated tracer binding in motor and supplemental motor areas. The 18 kDa translocator protein labeling was not correlated with parameters of disease progression in corticobasal syndrome and progressive supranuclear palsy but allowed sensitive detection in patients with 4-repeat tauopathies by a multiregion classifier. Conclusions: Our data indicate that 18F-GE-180 PET detects microglial activation in the brain of patients with 4-repeat tauopathy, fitting to predilection sites of the phenotype. The 18 kDa translocator protein PET has a potential for monitoring neuroinflammation in 4-repeat tauopathies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

DOI
10.1002/mds.28395

Regional specification and complementation with non-neuroectodermal cells in human brain organoids

NOMIS Researcher(s)

Published in

April 1, 2021

Along with emergence of the organoids, their application in biomedical research has been currently one of the most fascinating themes. For the past few years, scientists have made significant contributions to deriving organoids representing the whole brain and specific brain regions. Coupled with somatic cell reprogramming and CRISPR/Cas9 editing, the organoid technologies were applied for disease modeling and drug screening. The methods to develop organoids further improved for rapid and efficient generation of cerebral organoids. Additionally, refining the methods to develop the regionally specified brain organoids enabled the investigation of development and interaction of the specific brain regions. Recent studies started resolving the issue in the lack of non-neuroectodermal cells in brain organoids, including vascular endothelial cells and microglia, which play fundamental roles in neurodevelopment and are involved in the pathophysiology of acute and chronic neural disorders. In this review, we highlight recent advances of neuronal organoid technologies, focusing on the region-specific brain organoids and complementation with endothelial cells and microglia, and discuss their potential applications to neuronal diseases.

Research field(s)
Health Sciences, Clinical Medicine, Immunology

DOI
10.1007/s00109-021-02051-9

Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

NOMIS Researcher(s)

Published in

April 1, 2021

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-Associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient albeit to a smaller extent to induce premature distal axonal trafficking deficits and increased DSBs.

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

DOI
10.26508/LSA.202000764

The impact of cardiac afferent signaling and interoceptive abilities on passive information sampling

NOMIS Researcher(s)

Published in

April 1, 2021

A growing body of research suggests that perception and cognition are affected by fluctuating bodily states. For example, the rate of information sampling is coupled with cardiac phases. However, the benefits of such spontaneous coupling between bodily oscillations and decision-making remains unclear. Here, we studied the role of the cardiac cycle in information sampling by testing whether sequential information sampling phase-locked to systolic or diastolic parts of the cardiac cycle impacts the rate of information gathering and processing. To this aim, we employed a modified Information Sampling Task, a standard measure of the rate of information gathering before reaching a decision, in which the onset of new information delivery in each trial was coupled either to cardiac systole or diastole. Information presented within cardiac systole did not significantly modulate the information processing in a manner that would produce clear behavioral changes. However, we found evidence suggesting that higher interoceptive awareness increased accuracy, especially in the costly version of the task, when new information was sequentially presented at systole. Overall, our results add to a growing body of research on body-brain interactions and suggest that our internal bodily rhythms (i.e., heartbeats) and our awareness of them can interact with the way we process the noisy world around us.

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

DOI
10.1016/j.ijpsycho.2021.02.010

Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

NOMIS Researcher(s)

Published in

March 4, 2021

Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in α-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson’s disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in α-synuclein-overexpressing cells, 11 were down- and 12 upregulated (P < 0.01; non-adjusted). The in silico analysis of known target genes of these miRNAs was complemented by the inclusion of a transcriptome dataset (BeadChip) of the same cellular system, revealing the G0/G1 cell cycle transition to be markedly enriched. Out of 124 KEGG-annotated cell cycle genes, 15 were present in the miRNA target gene dataset and six G0/G1 cell cycle genes were found to be significantly altered upon α-synuclein overexpression, with five genes up- (CCND1, CCND2, and CDK4 at P < 0.01; E2F3, MYC at P < 0.05) and one gene downregulated (CDKN1C at P < 0.001). Additionally, several of these altered genes are targeted by miRNAs hsa-miR-34a-5p and hsa-miR-34c-5p, which also modulate α-synuclein expression levels. Functional intervention by siRNA-mediated knockdown of the cell cycle gene cyclin D1 (CCND1) confirmed that silencing of cell cycle initiation is able to substantially reduce α-synuclein-mediated cytotoxicity. The present findings suggest that α-synuclein accumulation induces microRNA-mediated aberrant cell cycle activation in post-mitotic dopaminergic neurons. Thus, the mitotic cell cycle pathway at the level of miRNAs might offer interesting novel therapeutic targets for PD.

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

DOI
10.3389/fcell.2021.561086

Proton pump inhibitor use status does not modify the microbiome signature for cirrhosis

NOMIS Researcher(s)

Published in

March 2, 2021
We appreciate the interest and comments on our article reporting a novel gut microbiome signature for predicting liver cirrhosis (). Dr. Chen raises concerns about the impact of proton pump inhibitor (PPI) treatment on the gut microbial profiles of cirrhosis patients in our main cohort (; ). He cites evidence that 4 species in our 19-species signature for cirrhosis (Veillonella parvula, Veillonella atypica, Streptococcus parasanguinis, and Streptococcus salivarius) are known to be impacted by PPI treatment. According to his analysis, these species alone were sufficient to detect cirrhosis in the Qin and Iebba cohorts. The question at hand is whether PPI usage in our training cohort may have skewed and thus compromised our gut microbiome signature for cirrhosis.
To address whether our 19-species signature remains valid, independent of PPI treatment status (Table S1), we first reviewed all 81 subjects in our training cohort (54 non-NAFLD controls and 27 NAFLD-cirrhosis patients) and identified 13 individuals who were using PPIs (4 non-NAFLD controls and 9 NAFLD-cirrhosis patients). After excluding those 13 subjects on PPIs, we retrained our 19-species Random Forest (RF) model on the revised cohort comprising only the 68 remaining non-PPI subjects (50 non-NAFLD controls and 18 NAFLD-cirrhosis patients) for cirrhosis prediction. For detection of cirrhosis, the model achieved an accuracy of AUC (area under the curve) 0.891, which is comparable to our original AUC of 0.91 (Figure S1A). In our original study, we included age during machine training as a default. Therefore, we also examined the 19 species+age in the non-PPI training set and achieved an AUC of 0.896, which again is comparable to our original AUC of 0.91 (Figure S1B). Furthermore, we tested the models comprising 19 species or 19 species+age with the independent dataset from the Qin et al. study (merged discovery and validation set, 114 controls and 123 cirrhosis) (). Notably, we still obtained AUCs of 0.851 and 0.832 for validation and testing scores, respectively (Figures S1C and S1D). Thus, even after removing subjects on PPIs from the training cohort, the revised model with 19 species still detected cirrhosis with high accuracy. This suggests the impact of PPI usage on the signature was minimal.
We observed no significant difference in the diagnostic accuracy of our gut microbiome signature for cirrhosis, regardless of whether it was evaluating mixed or only non-PPI cohorts. Although we agree that PPI drugs may have an effect on gut microbiota as a whole, our 19-species signature is robust and retains its diagnostic potential for distinguishing liver cirrhosis, independent of PPI treatment. Future studies encompassing more clinical samples and longitudinal follow-up will allow us to understand the specific effects of different classes of perturbants and provide more accuracy and robustness to power the machine-learning-based prediction model (; ).

Research field(s)
Clinical Medicine

DOI
10.1016/j.cmet.2021.02.013

A genomic region associated with protection against severe COVID-19 is inherited from Neandertals

NOMIS Researcher(s)

Published in

March 2, 2021

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.

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

DOI
10.1073/pnas.2026309118

Deconstructing and reconstructing the human brain with regionally specified brain organoids

NOMIS Researcher(s)

Published in

March 1, 2021

Brain organoids, three-dimensional neural cultures recapitulating the spatiotemporal organization and function of the brain in a dish, offer unique opportunities for investigating the human brain development and diseases. To model distinct parts of the brain, various region-specific human brain organoids have been developed. In this article, we review current approaches to produce human region-specific brain organoids, developed through the endeavor of many researchers. We highlight the applications of human region-specific brain organoids, especially in reconstructing regional interactions in the brain through organoid fusion. We also outline the existing challenges to drive forward further the brain organoid technology and its applications for future studies.

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

DOI
10.1016/j.semcdb.2020.05.023

Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing

NOMIS Researcher(s)

Published in

March 1, 2021

Biomolecular condensates are membraneless intracellular assemblies that often form via liquid−liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.

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

DOI
10.1038/s41580-020-00326-6

Engaging with the science and politics of biodiversity futures: A literature review

NOMIS Researcher(s)

Published in

March 1, 2021

Future global environmental change will have a significant impact on biodiversity through the intersecting forces of climate change, urbanization, human population growth, overexploitation, and pollution. This presents a fundamental challenge to conservation approaches, which seek to conserve past or current assemblages of species or ecosystems in situ. This review canvases diverse approaches to biodiversity futures, including social science scholarship on the Anthropocene and futures thinking alongside models and scenarios from the biophysical science community. It argues that charting biodiversity futures requires processes that must include broad sections of academia and the conservation community to ask what desirable futures look like, and for whom. These efforts confront political and philosophical questions about levels of acceptable loss, and how trade-offs can be made in ways that address the injustices in the distribution of costs and benefits across and within human and non-human life forms. As such, this review proposes that charting biodiversity futures is inherently normative and political. Drawing on diverse scholarship united under a banner of ‘futures thinking’ this review presents an array of methods, approaches and concepts that provide a foundation from which to consider research and decision-making that enables action in the context of contested and uncertain biodiversity futures.

Research field(s)
Natural Sciences, Biology, Ecology

DOI
10.1017/S037689292000048X

The als-associated fus (P525l) variant does not directly interfere with microtubule-dependent kinesin-1 motility

NOMIS Researcher(s)

Published in

March 1, 2021

Deficient intracellular transport is a common pathological hallmark of many neuro-degenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the fused-in-sarcoma (FUS) gene are one of the most common genetic causes for familial ALS. Motor neurons carrying a mutation in the nuclear localization sequence of FUS (P525L) show impaired axonal transport of several organelles, suggesting that mislocalized cytoplasmic FUS might directly interfere with the transport machinery. To test this hypothesis, we studied the effect of FUS on kinesin-1 motility in vitro. Using a modified microtubule gliding motility assay on surfaces coated with kinesin-1 motor proteins, we showed that neither recombinant wildtype and P525L FUS variants nor lysates from isogenic ALS-patient-specific iPSC-derived spinal motor neurons expressing those FUS variants significantly affected gliding velocities. We hence conclude that during ALS pathogenesis the initial negative effect of FUS (P525L) on axonal transport is an indirect nature and requires additional factors or mechanisms.

Research field(s)
Natural Sciences, Physics & Astronomy, Chemical Physics

DOI
10.3390/ijms22052422

HP1 proteins compact dna into mechanically and positionally stable phase separated domains

NOMIS Researcher(s)

Published in

March 1, 2021

In mammals, HP1-mediated heterochromatin forms positionally and mechanically stable genomic domains even though the component HP1 paralogs, HP1a, HP1b, and HP1g, display rapid on-off dynamics. Here, we investigate whether phase-separation by HP1 proteins can explain these biological observations. Using bulk and single-molecule methods, we show that, within phase-separated HP1a-DNA condensates, HP1a acts as a dynamic liquid, while compacted DNA molecules are constrained in local territories. These condensates are resistant to large forces yet can be readily dissolved by HP1b. Finally, we find that differences in each HP1 paralog’s DNA compaction and phase-separation properties arise from their respective disordered regions. Our findings suggest a generalizable model for genome organization in which a pool of weakly bound proteins collectively capitalize on the polymer properties of DNA to produce self-organizing domains that are simultaneously resistant to large forces at the mesoscale and susceptible to competition at the molecular scale.

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

DOI
10.7554/eLife.64563

A nation-wide, multi-center study on the quality of life of ALS patients in Germany

NOMIS Researcher(s)

Published in

March 1, 2021

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and Eu-roQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb onset” ALS (lALS) was associated with a better QoL than “bulbar onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = –5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antide-pressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.

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

DOI
10.3390/brainsci11030372

How well do brain organoids capture your brain?

NOMIS Researcher(s)

Published in

February 19, 2021

Neuroscience; tissue engineering

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

DOI
10.1016/j.isci.2021.102063

Geroprotective effects of Alzheimer’s disease drug candidates

NOMIS Researcher(s)

Published in

February 15, 2021

Geroprotectors are compounds that slow the biological aging process in model organisms and may therefore extend healthy lifespan in humans. It is hypothesized that they do so by preserving the more youthful function of multiple organ systems. However, this hypothesis has rarely been tested in any organisms besides C. elegans and D. melanogaster. To determine if two life-extending compounds for Drosophila maintain a more youthful phenotype in old mice, we asked if they had anti-aging effects in both the brain and kidney. We utilized rapidly aging senescence-accelerated SAMP8 mice to investigate age-associated protein level alterations in these organs. The test compounds were two cognition-enhancing Alzheimer’s disease drug candidates, J147 and CMS121. Mice were fed the compounds in the last quadrant of their lifespan, when they have cognitive deficits and are beginning to develop CKD. Both compounds improved physiological markers for brain and kidney function. However, these two organs had distinct, tissue-specific protein level alterations that occurred with age, but in both cases, drug treatments restored a more youthful level. These data show that geroprotective AD drug candidates J147 and CMS121 prevent age-associated disease in both brain and kidney, and that their apparent mode of action in each tissue is distinct.

Research field(s)
Health Sciences, Clinical Medicine, Geriatrics

DOI
10.18632/aging.202631

Osseous tools and personal ornaments from the Epigravettian sequence at Badanj

NOMIS Researcher(s)

Published in

February 12, 2021

The Late Upper Palaeolithic (Epigravettian) sequence at Badanj has yielded an important dataset about the occupation of the hinterland of the Eastern Adriatic catchment zone in the late Pleniglacial. The site also harbors one of the rare occurrences of Upper Palaeolithic parietal “art” in southeastern Europe in the form of a large rock engraving. Another notable aspect of the site is the presence of engravings on portable objects made from bone. The first excavations at Badanj, conducted in 1976–1979 in the zone around the engraved rock, yielded a surprisingly large number of personal ornaments (over 1000 specimens) from a variety of primarily marine gastropods, scaphopods, and bivalves, and red deer canines. Here we review what is currently known about the site and report our preliminary findings from the study of the collection of personal ornaments as well as osseous tools, some of which were marked by regular incisions forming decorative motifs. We also report two new direct accelerator mass spectrometry (AMS) dates on antler barbed points.

Research field(s)
Archaeology

DOI
10.21203/rs.3.rs-209080/v1

HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells

NOMIS Researcher(s)

Published in

February 5, 2021

The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding-deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which we named “anisosomes”, have shells that exhibit birefringence, thus indicating liquid crystal formation. Guided by mathematical modeling, we identified the primary components of the liquid core to be HSP70 family chaperones, whose adenosine triphosphate (ATP)-dependent activity maintained the liquidity of shells and cores. In vivo proteasome inhibition within neurons, to mimic aging-related reduction of proteasome activity, induced TDP-43-containing anisosomes. These structures converted to aggregates when ATP levels were reduced. Thus, acetylation, HSP70, and proteasome activities regulate TDP-43 phase separation and conversion into a gel or solid phase.

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

DOI
10.1126/science.abb4309

A neuronal blood marker is associated with mortality in old age

NOMIS Researcher(s)

Published in

February 1, 2021

Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21–107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2–30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

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

DOI
10.1038/s43587-021-00028-4

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