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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.

Mechanistic insight into bacterial entrapment by septin cage reconstitution

NOMIS Researcher(s)

Published in

December 1, 2021

Septins are cytoskeletal proteins that assemble into hetero-oligomeric complexes and sense micron-scale membrane curvature. During infection with Shigella flexneri, an invasive enteropathogen, septins restrict actin tail formation by entrapping bacteria in cage-like structures. Here, we reconstitute septin cages in vitro using purified recombinant septin complexes (SEPT2-SEPT6-SEPT7), and study how these recognize bacterial cells and assemble on their surface. We show that septin complexes recognize the pole of growing Shigella cells. An amphipathic helix domain in human SEPT6 enables septins to sense positively curved membranes and entrap bacterial cells. Shigella strains lacking lipopolysaccharide components are more efficiently entrapped in septin cages. Finally, cryo-electron tomography of in vitro cages reveals how septins assemble as filaments on the bacterial cell surface.

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

DOI
10.1038/s41467-021-24721-5

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer’s disease: findings from the Colombia-Boston (COLBOS) biomarker study

NOMIS Researcher(s)

Published in

December 1, 2021

Background: Neuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. Methods: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2–3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2–4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. Results: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. Conclusions: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.

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

DOI
10.1186/s13195-020-00765-5

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease

NOMIS Researcher(s)

Published in

December 1, 2021

Alzheimer’s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer’s disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer’s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer’s disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer’s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer’s disease to two separate Epstein–Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer’s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

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

DOI
10.1038/s41586-019-1895-7

Taking the pulse of social cognition: Cardiac afferent activity and interoceptive accuracy modulate emotional egocentricity bias

NOMIS Researcher(s)

Published in

December 1, 2021

At the heart of social cognition is our ability to distinguish between self and other and correctly attribute mental and affective states to their origin. Emotional egocentricity bias (EEB) reflects the tendency to use one’s own emotional state when relating to others. Although interoception underpins our emotional experience, little is known about its role on how we affectively relate to others. Here, we assessed how cardiac interoceptive impact, manipulated by presenting affective stimuli across different phases of the cardiac cycle coupled with trait-like levels of interoceptive accuracy, modulate the EEB. Individuals with higher interoceptive accuracy displayed an increased EEB when the other’s emotional state was presented at the point of maximum interoceptive impact (i.e., at systole), whereas the reverse was observed for individuals with lower interoceptive accuracy. These findings show how interoceptive activity provides the physiological context within which we process other’s emotional states in parallel to ours.

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

DOI
10.1016/j.cortex.2021.10.004

Multipronged dental analyses reveal dietary differences in last foragers and first farmers at Grotta Continenza, central Italy (15,500–7000 BP)

NOMIS Researcher(s)

Published in

December 1, 2021

This paper provides results from a suite of analyses made on human dental material from the Late Palaeolithic to Neolithic strata of the cave site of Grotta Continenza situated in the Fucino Basin of the Abruzzo region of central Italy. The available human remains from this site provide a unique possibility to study ways in which forager versus farmer lifeways affected human odonto-skeletal remains. The main aim of our study is to understand palaeodietary patterns and their changes over time as reflected in teeth. These analyses involve a review of metrics and oral pathologies, micro-fossils preserved in the mineralized dental plaque, macrowear, and buccal microwear. Our results suggest that these complementary approaches support the assumption about a critical change in dental conditions and status with the introduction of Neolithic foodstuff and habits. However, we warn that different methodologies applied here provide data at different scales of resolution for detecting such changes and a multipronged approach to the study of dental collections is needed for a more comprehensive and nuanced understanding of diachronic changes.

Research field(s)
Arts & Humanities, Historical Studies, Anthropology

DOI
10.1038/s41598-021-82401-2

A human-specific modifier of cortical connectivity and circuit function

NOMIS Researcher(s)

Published in

November 25, 2021

The cognitive abilities that characterize humans are thought to emerge from unique features of the cortical circuit architecture of the human brain, which include increased cortico–cortical connectivity. However, the evolutionary origin of these changes in connectivity and how they affected cortical circuit function and behaviour are currently unknown. The human-specific gene duplication SRGAP2C emerged in the ancestral genome of the Homo lineage before the major phase of increase in brain size1,2. SRGAP2C expression in mice increases the density of excitatory and inhibitory synapses received by layer 2/3 pyramidal neurons (PNs)3–5. Here we show that the increased number of excitatory synapses received by layer 2/3 PNs induced by SRGAP2C expression originates from a specific increase in local and long-range cortico–cortical connections. Mice humanized for SRGAP2C expression in all cortical PNs displayed a shift in the fraction of layer 2/3 PNs activated by sensory stimulation and an enhanced ability to learn a cortex-dependent sensory-discrimination task. Computational modelling revealed that the increased layer 4 to layer 2/3 connectivity induced by SRGAP2C expression explains some of the key changes in sensory coding properties. These results suggest that the emergence of SRGAP2C at the birth of the Homo lineage contributed to the evolution of specific structural and functional features of cortical circuits in the human cortex.

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

DOI
10.1038/s41586-021-04039-4

CD4+ T cells contribute to neurodegeneration in Lewy body dementia

NOMIS Researcher(s)

Published in

November 12, 2021

Recent studies indicate that the adaptive immune system plays a role in Lewy body dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic neurons in postmortem LBD brains. Single-cell RNA sequencing of cerebrospinal fluid (CSF) identified up-regulated expression of C-X-C motif chemokine receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C motif chemokine ligand 12 (CXCL12), were associated with neuroaxonal damage in LBD. Furthermore, we observed clonal expansion and up-regulated interleukin 17A expression by CD4+ T cells stimulated with a phosphorylated a-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17-producing T cell trafficking in LBD.

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

DOI
10.1126/science.abf7266

Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain

NOMIS Researcher(s)

Published in

November 8, 2021

In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.

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

DOI
10.1016/j.devcel.2021.10.008

Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome

NOMIS Researcher(s)

Published in

November 2, 2021

The evolution of uniquely human traits likely entailed changes in developmental gene regulation. Human Accelerated Regions (HARs), which include transcriptional enhancers harboring a significant excess of human-specific sequence changes, are leading candidates for driving gene regulatory modifications in human development. However, insight into whether HARs alter the level, distribution, and timing of endogenous gene expression remains limited. We examined the role of the HAR HACNS1 (HAR2) in human evolution by interrogating its molecular functions in a genetically humanized mouse model. We find that HACNS1 maintains its human-specific enhancer activity in the mouse embryo and modifies expression of Gbx2, which encodes a transcription factor, during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in the limb chondrogenic mesenchyme of HACNS1 homozygous embryos, supporting that HACNS1 alters gene expression in cell types involved in skeletal patterning. Our findings illustrate that humanized mouse models provide mechanistic insight into how HARs modified gene expression in human evolution.

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

DOI
10.1038/s41467-021-27899-w

Glycine-Rich Peptides from FUS Have an Intrinsic Ability to Self-Assemble into Fibers and Networked Fibrils

NOMIS Researcher(s)

Published in

November 2, 2021

Glycine-rich regions feature prominently in intrinsically disordered regions (IDRs) of proteins that drive phase separation and the regulated formation of membraneless biomolecular condensates. Interestingly, the Gly-rich IDRs seldom feature poly-Gly tracts. The protein fused in sarcoma (FUS) is an exception. This protein includes two 10-residue poly-Gly tracts within the prion-like domain (PLD) and at the interface between the PLD and the RNA binding domain. Poly-Gly tracts are known to be highly insoluble, being potent drivers of self-assembly into solid-like fibrils. Given that the internal concentrations of FUS and FUS-like molecules cross the high micromolar and even millimolar range within condensates, we reasoned that the intrinsic insolubility of poly-Gly tracts might be germane to emergent fluid-to-solid transitions within condensates. To assess this possibility, we characterized the concentration-dependent self-assembly for three non-overlapping 25-residue Gly-rich peptides derived from FUS. Two of the three peptides feature 10-residue poly-Gly tracts. These peptides form either long fibrils based on twisted ribbon-like structures or self-supporting gels based on physical cross-links of fibrils. Conversely, the peptide with similar Gly contents but lacking a poly-Gly tract does not form fibrils or gels. Instead, it remains soluble across a wide range of concentrations. Our findings highlight the ability of poly-Gly tracts within IDRs that drive phase separation to undergo self-assembly. We propose that these tracts are likely to contribute to nucleation of fibrillar solids within dense condensates formed by FUS.

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

DOI
10.1021/acs.biochem.1c00501

Colon cancer checks in when bile acids check out: The bile acid–nuclear receptor axis in colon cancer

NOMIS Researcher(s)

Published in

November 1, 2021

Bile acids (BAs) are a class of hepatically derived metabolite-hormones with prominent roles in nutrient absorption, metabolic and immune homeostasis in the intestine. BAs are ligands for multiple nuclear receptors (NRs), through which they confer transcriptional regulation on target genes that form an enterohepatic hormonal feedback loop to regulate BA synthesis and maintain lipid homeostasis. Endogenous BAs made by the host undergo significant biotransformation by the gut microbiota in the intestine, which diversifies the intestinal BA pool and facilitate host–microbiota cross-talk through BA-mediated signaling. BAs dysregulation contributes to development of metabolic diseases, pathological inflammation and colon cancer. This review provides a brief historic perspective of the study of NR-mediated BA signaling transduction, with a focus on recent advancements in understanding the active role the gut microbiome plays in reshaping intestinal BA landscape, and the implications of novel microbially derived BAs in modulating immune homeostasis and cancer development in the host. Targeting the BA–NR signaling axis for pharmacological intervention provides ample opportunities in the prevention and treatment of intestinal diseases.

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

DOI
10.1042/EBC20210038

The impact of joint attention on the sound-induced flash illusions

NOMIS Researcher(s)

Published in

November 1, 2021

Humans coordinate their focus of attention with others, either by gaze following or prior agreement. Though the effects of joint attention on perceptual and cognitive processing tend to be examined in purely visual environments, they should also show in multisensory settings. According to a prevalent hypothesis, joint attention enhances visual information encoding and processing, over and above individual attention. If two individuals jointly attend to the visual components of an audiovisual event, this should affect the weighing of visual information during multisensory integration. We tested this prediction in this preregistered study, using the well-documented sound-induced flash illusions, where the integration of an incongruent number of visual flashes and auditory beeps results in a single flash being seen as two (fission illusion) and two flashes as one (fusion illusion). Participants were asked to count flashes either alone or together, and expected to be less prone to both fission and fusion illusions when they jointly attended to the visual targets. However, illusions were as frequent when people attended to the flashes alone or with someone else, even though they responded faster during joint attention. Our results reveal the limitations of the theory that joint attention enhances visual processing as it does not affect temporal audiovisual integration.

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

DOI
10.3758/s13414-021-02347-5

Anti-intellectualist motor knowledge

NOMIS Researcher(s)

Published in

November 1, 2021

Intellectualists suggest that practical knowledge, or ‘knowing- how’, can be reduced to propositional knowledge, or ‘knowing-that’. Anti-intellectualists, on the contrary, suggest, following the original insights by Ryle, that such a reduction is not possible. Rejection of intellectualism can be proposed either by offering purely philosophical analytical arguments, or by recruiting empirical evidence from cognitive science about the nature of the mental representations involved in these two forms of knowledge. In this paper, I couple these two strategies in order to analyze some crucial reasons for which intellectualism seems not to be the best theory we have to correctly understand and describe practical knowledge. In particular, I will start from a specific philosophical account against intellectualism offered by Dickie (Philos Phenomenol Res LXXXV(3):737–745, 2012), and suggest that it can be supported by current experimental results coming from motor neuroscience. The claim of the paper is that there is at least one kind of practical knowledge, which I call motor knowledge, and which is at the basis of the performance of skilled action, which cannot be reduced to propositional knowledge.

Research field(s)
Arts & Humanities, Philosophy & Theology, Philosophy

DOI
10.1007/s11229-020-02750-9

Feasibility of short imaging protocols for [18F]PI-2620 tau-PET in progressive supranuclear palsy

NOMIS Researcher(s)

Published in

November 1, 2021

Purpose: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [18F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [18F]PI-2620 tau-PET imaging of PSP. Methods: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [18F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0–60, 0–50, 0–40, 0–30, and 0–20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20–40, 30–50, and 40–60 min p.i. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier). Results: 0–50 and 0–40 DVR showed equivalent effect sizes as 0–60 DVR (averaged Cohen’s d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0–30 or 0–20 DVR. The 20–40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0–60 DVR (AUC: 0.96), 0–40 DVR (AUC: 0.96), and 20–40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%. Conclusion: Truncated and static imaging windows can be used for [18F]PI-2620 PET imaging of PSP. 0–40 min dynamic scanning offers the best balance between accuracy and economic scanning.

Research field(s)
Health Sciences, Clinical Medicine, Nuclear Medicine & Medical Imaging

DOI
10.1007/s00259-021-05391-3

Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET

NOMIS Researcher(s)

Published in

November 1, 2021

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer’s disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

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

DOI
10.1177/0271678X211018904

Establishing the Foundation for the Global Observing System for Marine Life

NOMIS Researcher(s)

Published in

October 25, 2021

Maintaining healthy, productive ecosystems in the face of pervasive and accelerating human impacts including climate change requires globally coordinated and sustained observations of marine biodiversity. Global coordination is predicated on an understanding of the scope and capacity of existing monitoring programs, and the extent to which they use standardized, interoperable practices for data management. Global coordination also requires identification of gaps in spatial and ecosystem coverage, and how these gaps correspond to management priorities and information needs. We undertook such an assessment by conducting an audit and gap analysis from global databases and structured surveys of experts. Of 371 survey respondents, 203 active, long-term (>5 years) observing programs systematically sampled marine life. These programs spanned about 7% of the ocean surface area, mostly concentrated in coastal regions of the United States, Canada, Europe, and Australia. Seagrasses, mangroves, hard corals, and macroalgae were sampled in 6% of the entire global coastal zone. Two-thirds of all observing programs offered accessible data, but methods and conditions for access were highly variable. Our assessment indicates that the global observing system is largely uncoordinated which results in a failure to deliver critical information required for informed decision-making such as, status and trends, for the conservation and sustainability of marine ecosystems and provision of ecosystem services. Based on our study, we suggest four key steps that can increase the sustainability, connectivity and spatial coverage of biological Essential Ocean Variables in the global ocean: (1) sustaining existing observing programs and encouraging coordination among these; (2) continuing to strive for data strategies that follow FAIR principles (findable, accessible, interoperable, and reusable); (3) utilizing existing ocean observing platforms and enhancing support to expand observing along coasts of developing countries, in deep ocean basins, and near the poles; and (4) targeting capacity building efforts. Following these suggestions could help create a coordinated marine biodiversity observing system enabling ecological forecasting and better planning for a sustainable use of ocean resources.

Research field(s)
Natural Sciences, Biology, Marine Biology & Hydrobiology

DOI
10.3389/fmars.2021.737416

Shared Responsibility Decreases the Sense of Agency in the Human Brain

NOMIS Researcher(s)

Published in

October 19, 2021

Sharing responsibility in social decision-making helps individuals use the flexibility of the collective context to benefit them-selves by claiming credit for good outcomes or avoiding the blame for bad outcomes. Using magnetoencephalography, we examined the neuronal basis of the impact that social context has on this flexible sense of responsibility. Participants performed a gambling task in various social contexts and reported feeling less responsibility when playing as a member of a team. A reduced magnetoencephalography outcome processing effect was observed as a function of decreasing responsibility at 200 msec post outcome onset and was centered over parietal, central, and frontal brain regions. Before outcome revelation in socially made decisions, an attenuated motor preparation signature at 500 msec after stimulus onset was found. A boost in reported responsibility for positive outcomes in social contexts was associated with increased activity in regions related to social and reward processing. Together, these results show that sharing responsibility with others reduces agency, influencing pre-outcome motor preparation and post-outcome processing, and provides opportunities to flexibly claim credit for positive outcomes.

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

DOI
10.1162/jocn_a_01896

How do we relate to our heart? Neurobehavioral differences across three types of engagement with cardiac interoception

NOMIS Researcher(s)

Published in

October 1, 2021

Standard measures of interoception are typically limited to the conscious perception of heartbeats. However, the fundamental purpose of interoceptive signaling, is to regulate the body. We present a novel biofeedback paradigm to explore the neurobehavioral consequences of three different types of engagement with cardiac interoception (Attend, Feel, Regulate) while participants perform a ‘cardiac recognition’ task. For both the Feel and Regulate conditions, participants displayed enhanced recognition of their own heartbeat, accompanied by larger heartbeat-evoked potentials (HEPs), suggesting that these approaches could be used interchangeably. Importantly, meta-cognitive interoceptive insight was highest in the Regulate condition, indicative of stronger engagement with interoceptive signals in addition to greater ecological validity. Only in the passive interoception condition (Feel) was a significant association found between accuracy in recognising one’s own heartbeat and the amplitude of HEPs. Overall, our results imply that active conditions have an important role to play in future investigation of interoception.

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

DOI
10.1016/j.biopsycho.2021.108198

The Polar Legionella Icm/Dot T4SS Establishes Distinct Contact Sites with the Pathogen Vacuole Membrane

NOMIS Researcher(s)

Published in

October 1, 2021

Legionella pneumophila, the causative agent of Legionnaires’ disease, is a facultative intracellular pathogen that survives inside phagocytic host cells by establishing a protected replication niche, termed the “Legionella-containing vacuole” (LCV). To form an LCV and subvert pivotal host pathways, L. pneumophila employs a type IV secretion system (T4SS), which translocates more than 300 different effector proteins into the host cell. The L. pneumophila T4SS complex has been shown to span the bacterial cell envelope at the bacterial poles. However, the interactions between the T4SS and the LCV membrane are not understood. Using cryo-focused ion beam milling, cryo-electron tomography, and confocal laser scanning fluorescence microscopy, we show that up to half of the intravacuolar L. pneumophila bacteria tether their cell pole to the LCV membrane. Tethering coincides with the presence and function of T4SSs and likely promotes the establishment of distinct contact sites between T4SSs and the LCV membrane. Contact sites are characterized by indentations in the limiting LCV membrane and localize juxtaposed to T4SS machineries. The data are in agreement with the notion that effector translocation occurs by close membrane contact rather than by an extended pilus. Our findings provide novel insights into the interactions of the L. pneumophila T4SS with the LCV membrane in situ. IMPORTANCE Legionnaires’ disease is a life-threatening pneumonia, which is characterized by high fever, coughing, shortness of breath, muscle pain, and headache. The disease is caused by the amoeba-resistant bacterium L. pneumophila found in various soil and aquatic environments and is transmitted to humans via the inhalation of small bacteria-containing droplets. An essential virulence factor of L. pneumophila is a so-called “type IV secretion system” (T4SS), which, by injecting a plethora of “effector proteins” into the host cell, determines pathogen-host interactions and the formation of a distinct intracellular compartment, the “Legionella-containing vacuole” (LCV). It is unknown how the T4SS makes contact to the LCV membrane to deliver the effectors. In this study, we identify indentations in the host cell membrane in close proximity to functional T4SSs localizing at the bacterial poles. Our work reveals first insights into the architecture of Legionella-LCV contact sites.

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

DOI
10.1128/mBio.02180-21

Helping the waiter to hold his tray: Rigid haptic linkage promotes inter-personal motor coordination

NOMIS Researcher(s)

Published in

October 1, 2021

When a glass is lifted from a tray, there is a challenge for the waiter. He must quickly compensate for the reduction in the weight of the tray to keep it balanced. This compensation is easily achieved if the waiter lifts the glass himself. Because he has, himself, initiated the action, he can predict the timing and the magnitude of the perturbation of the tray and respond (via the holding hand) accordingly. In this study, we examined coordination when either one or two people hold the tray while either one of them or a third person removes the glass. Our results show that there is exquisite coordination between the two people holding the tray. We suggest that this coordination depends upon the haptic link provided by the rigid platform that both people are holding. We conclude that the guest at a reception should not lift his drink from the waiter’s tray until they have the waiter’s attention but, if too thirsty to wait, should lend a hand holding the tray.

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

DOI
10.1177/17470218211009082

The porphyrin TMPyP4 inhibits elongation during the noncanonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene

NOMIS Researcher(s)

Published in

October 1, 2021

GGGGCC (G4C2) repeat expansion in the C9orf72 gene has been shown to cause frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Dipeptide repeat proteins produced through repeat-associated non-AUG (RAN) translation are recognized as potential drivers for neurodegeneration. Therefore, selective inhibition of RAN translation could be a therapeutic avenue to treat these neurodegenerative diseases. It was previously known that the porphyrin TMPyP4 binds to G4C2 repeat RNA. However, the consequences of this interaction have not been well characterized. Here, we confirmed that TMPyP4 inhibits C9orf72 G4C2 repeat translation in cellular and in in vitro translation systems. An artificial insertion of an AUG codon failed to cancel the translation inhibition, suggesting that TMPyP4 acts downstream of non-AUG translation initiation. Polysome profiling assays also revealed polysome retention on G4C2 repeat RNA, along with inhibition of translation, indicating that elongating ribosomes stall on G4C2 repeat RNA. Urea-resistant interaction between G4C2 repeat RNA and TMPyP4 likely contributes to this ribosome stalling and thus to selective inhibition of RAN translation. Taken together, our data reveal a novel mode of action of TMPyP4 as an inhibitor of G4C2 repeat translation elongation.

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

DOI
10.1016/j.jbc.2021.101120

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