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Publications in Science Advances by NOMIS researchers

Fluoxetine promotes IL-10–dependent metabolic defenses to protect from sepsis-induced lethality

NOMIS Researcher(s)

Published in

February 14, 2025

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial “off-target” effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

Partnership(s)
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Research field(s)
Biochemistry & Molecular Biology, Immunology, Pharmacology & Pharmacy, Microbiology

DOI
10.1126/sciadv.adu4034

Archaeal type six secretion system mediates contact-dependent antagonism

NOMIS Researcher(s)

Published in

November 15, 2024

Microbial communities are shaped by cell-cell interactions. Although archaea are often found in associations with other microorganisms, the mechanisms structuring these communities are poorly understood. Here, we report on the structure and function of haloarchaeal contractile injection systems (CISs). Using a combination of functional assays and time-lapse imaging, we show that Halogeometricum borinquense exhibits antagonism toward Haloferax volcanii by inducing cell lysis and inhibiting proliferation. This antagonism is contact-dependent and requires a functional CIS, which is encoded by a gene cluster that is associated with toxin-immunity pairs. Cryo–focused ion beam milling and imaging by cryo–electron tomography revealed that these CISs are bound to the cytoplasmic membrane, resembling the bacterial type six secretion systems (T6SSs). We show that related T6SS gene clusters are conserved and expressed in other haloarchaeal strains, which exhibit antagonistic behavior. Our data provide a mechanistic framework for understanding how archaea may shape microbial communities and affect the food webs they inhabit.

Research field(s)
Microbiology

DOI
10.1126/sciadv.adp7088

Addressing climate change with behavioral science: A global intervention tournament in 63 countries

NOMIS Researcher(s)

Published in

February 7, 2024

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions’ effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior—several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people’s initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors.

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

DOI
10.1126/sciadv.adj5778

Leaf metabolic traits reveal hidden dimensions of plant form and function

NOMIS Researcher(s)

Published in

August 30, 2023

The metabolome is the biochemical basis of plant form and function, but we know little about its macroecological variation across the plant kingdom. Here, we used the plant functional trait concept to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five metabolic functional traits reveals that plants vary on two major axes of leaf metabolic specialization—a leaf chemical defense spectrum and an expression of leaf longevity. Axes are similar for tropical and temperate species, with many trait combinations being viable. However, metabolic traits vary orthogonally to life-history strategies described by widely used functional traits. The metabolome thus expands the functional trait concept by providing additional axes of metabolic specialization for examining plant form and function. Copyright © 2023 The Authors,

Research field(s)
Natural Sciences, Physics & Astronomy, Fluids & Plasmas

DOI
10.1126/sciadv.adi4029

Female naïve human pluripotent stem cells carry X chromosomes with Xa-like and Xi-like folding conformations

NOMIS Researcher(s)

Published in

August 4, 2023

Three-dimensional (3D) genomics shows immense promise for studying X chromosome inactivation (XCI) by interrogating changes to the X chromosomes’ 3D states. Here, we sought to characterize the 3D state of the X chromosome in naïve and primed human pluripotent stem cells (hPSCs). Using chromatin tracing, we analyzed X chromosome folding conformations in these cells with megabase genomic resolution. X chromosomes in female naïve hPSCs exhibit folding conformations similar to the active X chromosome (Xa) and the inactive X chromosome (Xi) in somatic cells. However, naïve X chromosomes do not exhibit the chromatin compaction typically associated with these somatic X chromosome states. In H7 naïve human embryonic stem cells, XIST accumulation observed on damaged X chromosomes demonstrates the potential for naïve hPSCs to activate XCI-related mechanisms. Overall, our findings provide insight into the X chromosome status of naïve hPSCs with a single-chromosome resolution and are critical in understanding the unique epigenetic regulation in early embryonic cells. Copyright © 2023 The Authors, some rights reserved.

Research field(s)
Health Sciences

DOI
10.1126/sciadv.adf2245

RNA binding protein DDX5 restricts RORγt+Tregsuppressor function to promote intestine inflammation

NOMIS Researcher(s)

Published in

February 1, 2023

Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt+ Tregs) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt+ Tregs. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt+ Tregs. T cell-specific Ddx5 knockout (DDX5ΔT) mice have augmented RORγt+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5ΔT mice. The DDX5-HIF1α- IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases. Copyright © 2023 The Authors.

Research field(s)
Health Sciences

DOI
10.1126/sciadv.add6165

Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development

NOMIS Researcher(s)

Published in

July 29, 2022

Since the ancestors of modern humans separated from those of Neanderthals, around 100 amino acid substitutions spread to essentially all modern humans. The biological significance of these changes is largely unknown. Here, we examine all six such amino acid substitutions in three proteins known to have key roles in kinetochore function and chromosome segregation and to be highly expressed in the stem cells of the developing neocortex. When we introduce these modern human-specific substitutions in mice, three substitutions in two of these proteins, KIF18a and KNL1, cause metaphase prolongation and fewer chromosome segregation errors in apical progenitors of the developing neocortex. Conversely, the ancestral substitutions cause shorter metaphase length and more chromosome segregation errors in human brain organoids, similar to what we find in chimpanzee organoids. These results imply that the fidelity of chromosome segregation during neocortex development improved in modern humans after their divergence from Neanderthals.

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

DOI
10.1126/sciadv.abn7702

Microwave quantum illumination using a digital receiver

NOMIS Researcher(s)

Published in

May 1, 2020

Quantum illumination uses entangled signal-idler photon pairs to boost the detection efficiency of low-reflectivity objects in environments with bright thermal noise. Its advantage is particularly evident at low signal powers, a promising feature for applications such as noninvasive biomedical scanning or low-power short-range radar. Here, we experimentally investigate the concept of quantum illumination at microwave frequencies. We generate entangled fields to illuminate a room-temperature object at a distance of 1 m in a free-space detection setup. We implement a digital phase-conjugate receiver based on linear quadrature measurements that outperforms a symmetric classical noise radar in the same conditions, despite the entanglement-breaking signal path. Starting from experimental data, we also simulate the case of perfect idler photon number detection, which results in a quantum advantage compared with the relative classical benchmark. Our results highlight the opportunities and challenges in the way toward a first room-temperature application of microwave quantum circuits.

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

DOI
10.1126/sciadv.abb0451

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