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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.

Targeting nuclear receptor corepressors for reversible male contraception

NOMIS Researcher(s)

Published in

February 20, 2024

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)–dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Research field(s)
Clinical Medicine

DOI
10.1073/pnas.2320129121

Cosmic dust fertilization of glacial prebiotic chemistry on early Earth

NOMIS Researcher(s)

Published in

February 19, 2024

Earth’s surface is deficient in available forms of many elements considered limiting for prebiotic chemistry. In contrast, many extraterrestrial rocky objects are rich in these same elements. Limiting prebiotic ingredients may, therefore, have been delivered by exogenous material; however, the mechanisms by which exogeneous material may be reliably and non-destructively supplied to a planetary surface remains unclear. Today, the flux of extraterrestrial matter to Earth is dominated by fine-grained cosmic dust. Although this material is rarely discussed in a prebiotic context due to its delivery over a large surface area, concentrated cosmic dust deposits are known to form on Earth today due to the action of sedimentary processes. Here we combine empirical constraints on dust sedimentation with dynamical simulations of dust formation and planetary accretion to show that localized sedimentary deposits of cosmic dust could have accumulated in arid environments on early Earth, in particular glacial settings that today produce cryoconite sediments. Our results challenge the widely held assumption that cosmic dust is incapable of fertilizing prebiotic chemistry. Cosmic dust deposits may have plausibly formed on early Earth and acted to fertilize prebiotic chemistry.

Research field(s)
Earth & Environmental Sciences, Physics & Astronomy

DOI
10.1038/s41550-024-02212-z

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

Stepwise assembly and release of Tc toxins from Yersinia entomophaga

NOMIS Researcher(s)

Published in

February 5, 2024

Tc toxins are virulence factors of bacterial pathogens. Although their structure and intoxication mechanism are well understood, it remains elusive where this large macromolecular complex is assembled and how it is released. Here we show by an integrative multiscale imaging approach that Yersinia entomophaga Tc (YenTc) toxin components are expressed only in a subpopulation of cells that are ‘primed’ with several other potential virulence factors, including filaments of the protease M66/StcE. A phage-like lysis cassette is required for YenTc release; however, before resulting in complete cell lysis, the lysis cassette generates intermediate ‘ghost’ cells, which may serve as assembly compartments and become packed with assembled YenTc holotoxins. We hypothesize that this stepwise mechanism evolved to minimize the number of cells that need to be killed. The occurrence of similar lysis cassettes in diverse organisms indicates a conserved mechanism for Tc toxin release that may apply to other extracellular macromolecular machines.

Partnership(s)
,

Research field(s)
Biochemistry & Molecular Biology, Microbiology

DOI
10.1038/s41564-024-01611-2

Incoherent probability judgments in large language models

NOMIS Researcher(s)

Published in

January 30, 2024

Autoregressive Large Language Models (LLMs) trained for next-word prediction have demonstrated remarkable proficiency at producing coherent text. But are they equally adept at forming coherent probability judgments? We use probabilistic identities and repeated judgments to assess the coherence of probability judgments made by LLMs. Our results show that the judgments produced by these models are often incoherent, displaying human-like systematic deviations from the rules of probability theory. Moreover, when prompted to judge the same event, the mean-variance relationship of probability judgments produced by LLMs shows an inverted-U-shaped like that seen in humans. We propose that these deviations from rationality can be explained by linking autoregressive LLMs to implicit Bayesian inference and drawing parallels with the Bayesian Sampler model of human probability judgments.

Research field(s)
Artificial Intelligence & Image Processing, Psychology & Cognitive Sciences

DOI
10.48550/arXiv.2401.16646

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation

NOMIS Researcher(s)

Published in

January 29, 2024

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

Research field(s)
Biochemistry & Molecular Biology, Genetics & Heredity

DOI
10.1038/s42255-024-00978-0

EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth

NOMIS Researcher(s)

Published in

January 25, 2024
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF–PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF–PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
Significance:

Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell–based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.

Research field(s)
Oncology & Carcinogenesis

DOI
10.1158/2159-8290.CD-23-0434

The Misleading count: an identity-based intervention to counter partisan misinformation sharing

NOMIS Researcher(s)

Published in

January 22, 2024

Interventions to counter misinformation are often less effective for polarizing content on social media platforms. We sought to overcome this limitation by testing an identity-based intervention, which aims to promote accuracy by incorporating normative cues directly into the social media user interface. Across three pre-registered experiments in the US (N = 1709) and UK (N = 804), we found that crowdsourcing accuracy judgements by adding a Misleading count (next to the Like count) reduced participants’ reported likelihood to share inaccurate information about partisan issues by 25% (compared with a control condition). The Misleading count was also more effective when it reflected in-group norms (from fellow Democrats/Republicans) compared with the norms of general users, though this effect was absent in a less politically polarized context (UK). Moreover, the normative intervention was roughly five times as effective as another popular misinformation intervention (i.e. the accuracy nudge reduced sharing misinformation by 5%). Extreme partisanship did not undermine the effectiveness of the intervention. Our results suggest that identity-based interventions based on the science of social norms can be more effective than identity-neutral alternatives to counter partisan misinformation in politically polarized contexts (e.g. the US).

This article is part of the theme issue ‘Social norm change: drivers and consequences’.

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

DOI
10.1098/rstb.2023.0040

DNA-guided transcription factor cooperativity shapes face and limb mesenchyme

NOMIS Researcher(s)

Published in

January 22, 2024

Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest that it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how “Coordinator,” a long DNA motif composed of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines the regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, whereas HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in the shared regulation of genes involved in cell-type and positional identities and ultimately shapes facial morphology and evolution.

Research field(s)
Genetics & Heredity

DOI
10.1016/j.cell.2023.12.032

International Consensus Criteria for Pediatric Sepsis and Septic Shock

NOMIS Researcher(s)

Published in

January 21, 2024

Importance  Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children.

Objective  To update and evaluate criteria for sepsis and septic shock in children.

Evidence Review  The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria.

Findings  Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4—respiratory, cardiovascular, coagulation, and/or neurological—organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively.

Conclusions and Relevance  The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Research field(s)
Emergency & Critical Care Medicine, Pediatrics

DOI
10.1001/jama.2024.0179

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock

NOMIS Researcher(s)

Published in

January 21, 2024

Importance  The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach.

Objective  To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings.

Design, Setting, and Participants  Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set.

Exposure  Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock.

Main Outcomes and Measures  The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity.

Results  Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings.

Conclusions and Relevance  The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Research field(s)
Emergency & Critical Care Medicine, Pediatrics

Population genomics of post-glacial western Eurasia

NOMIS Researcher(s)

Published in

January 10, 2024

Western Eurasia witnessed several large-scale human migrations during the Holocene. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Research field(s)
Archaeology

DOI
10.1038/s41586-023-06865-0

L’Exil, toujours recommencé: Chronique de la frontière

NOMIS Researcher(s)

January 5, 2024

Anthropologue et médecin, Didier Fassin est professeur au Collège de France, titulaire de la chaire Questions morales et enjeux politiques dans les sociétés contemporaines, et directeur d’études à l’EHESS. Anne-Claire Defossez est sociologue, chercheure à l’Institute for Advanced Study de Princeton.

Fuyant les violences politiques, les persécutions religieuses ou la pauvreté, des hommes, des femmes, des enfants d’Afghanistan, d’Iran, du Maghreb et d’Afrique subsaharienne, se mettent en route pour des voyages de plusieurs années au cours desquels ils affrontent les rackets des bandes armées, les brutalités des polices, les camps d’enfermement, les murs de barbelés, les rigueurs du désert, les périls de la mer. Beaucoup y perdent la vie.
Cinq années durant, été comme hiver, Didier Fassin et Anne-Claire Defossez ont mené une recherche à la frontière entre l’Italie et la France, dans les Alpes, auprès de nombre de ces exilés, pour reconstituer leur périple en l’inscrivant dans le contexte géopolitique des bouleversements du monde. Ils ont pris part aux activités menées pour leur porter assistance. Ils ont rencontré les multiples acteurs de ce territoire de migrations millénaires.
Leur enquête donne ainsi à comprendre l’expérience des exilés, l’engagement des volontaires et même le désarroi des forces de l’ordre, conscientes de la vanité de leur mission. Elle dévoile l’inefficacité d’une militarisation de la frontière qui rend plus dangereuse la traversée de la montagne et d’une politique qui nie les droits de personnes en quête de protection.

Research field(s)
Social Sciences

Machine learning for modeling human decisions

NOMIS Researcher(s)

Published in

January 1, 2024

The rapid development of machine learning has led to new opportunities for applying these methods to the study of human decision making. We highlight some of these opportunities and discuss some of the issues that arise when using machine learning to model the decisions people make. We first elaborate on the relationship between predicting decisions and explaining them, leveraging findings from computational learning theory to argue that, in some cases, the conversion of predictive models to interpretable ones with comparable accuracy is an intractable problem. We then identify an important bottleneck in using machine learning to study human cognition—data scarcity—and highlight active learning and optimal experimental design as a way to move forward. Finally, we touch on additional topics such as machine learning methods for combining multiple predictors arising from known theories and specific machine learning architectures that could prove useful for the study of judgment and decision making. In doing so, we point out connections to behavioral economics, computer science, cognitive science, and psychology. (PsycInfo Database Record (c) 2024 APA, all rights reserved)

Research field(s)
Artificial Intelligence & Image Processing, Psychology & Cognitive Sciences

DOI
10.1037/dec0000242

Emergence and collapse of reciprocity in semiautomatic driving coordination experiments with humans

NOMIS Researcher(s)

Published in

December 11, 2023

Forms of both simple and complex machine intelligence are increasingly acting within human groups in order to affect collective outcomes. Considering the nature of collective action problems, however, such involvement could paradoxically and unintentionally suppress existing beneficial social norms in humans, such as those involving cooperation. Here, we test theoretical predictions about such an effect using a unique cyber-physical lab experiment where online participants (N = 300 in 150 dyads) drive robotic vehicles remotely in a coordination game. We show that autobraking assistance increases human altruism, such as giving way to others, and that communication helps people to make mutual concessions. On the other hand, autosteering assistance completely inhibits the emergence of reciprocity between people in favor of self-interest maximization. The negative social repercussions persist even after the assistance system is deactivated. Furthermore, adding communication capabilities does not relieve this inhibition of reciprocity because people rarely communicate in the presence of autosteering assistance. Our findings suggest that active safety assistance (a form of simple AI support) can alter the dynamics of social coordination between people, including by affecting the trade-off between individual safety and social reciprocity. The difference between autobraking and autosteering assistance appears to relate to whether the assistive technology supports or replaces human agency in social coordination dilemmas. Humans have developed norms of reciprocity to address collective challenges, but such tacit understandings could break down in situations where machine intelligence is involved in human decision-making without having any normative commitments.

Research field(s)
Experimental Psychology

DOI
10.1073/pnas.2307804120

Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

NOMIS Researcher(s)

Published in

December 6, 2023

Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

Research field(s)
Oncology & Carcinogenesis

DOI
10.1038/s41467-023-42178-6

Clinically relevant antibiotic resistance genes are linked to a limited set of taxa within gut microbiome worldwide

NOMIS Researcher(s)

Published in

November 24, 2023

The acquisition of antimicrobial resistance (AR) genes has rendered important pathogens nearly or fully unresponsive to antibiotics. It has been suggested that pathogens acquire AR traits from the gut microbiota, which collectively serve as a global reservoir for AR genes conferring resistance to all classes of antibiotics. However, only a subset of AR genes confers resistance to clinically relevant antibiotics, and, although these AR gene profiles are well-characterized for common pathogens, less is known about their taxonomic associations and transfer potential within diverse members of the gut microbiota. We examined a collection of 14,850 human metagenomes and 1666 environmental metagenomes from 33 countries, in addition to nearly 600,000 isolate genomes, to gain insight into the global prevalence and taxonomic range of clinically relevant AR genes. We find that several of the most concerning AR genes, such as those encoding the cephalosporinase CTX-M and carbapenemases KPC, IMP, NDM, and VIM, remain taxonomically restricted to Proteobacteria. Even cfiA, the most common carbapenemase gene within the human gut microbiome, remains tightly restricted to Bacteroides, despite being found on a mobilizable plasmid. We confirmed these findings in gut microbiome samples from India, Honduras, Pakistan, and Vietnam, using a high-sensitivity single-cell fusion PCR approach. Focusing on a set of genes encoding carbapenemases and cephalosporinases, thus far restricted to Bacteroides species, we find that few mutations are required for efficacy in a different phylum, raising the question of why these genes have not spread more widely. Overall, these data suggest that globally prevalent, clinically relevant AR genes have not yet established themselves across diverse commensal gut microbiota. © 2023, The Author(s).

DOI
10.1038/s41467-023-42998-6

Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation

NOMIS Researcher(s)

Published in

November 23, 2023

The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Research field(s)
Health Sciences

DOI
10.1038/s41593-023-01496-0

The moral landscape of biological conservation: Understanding conceptual and normative foundations

NOMIS Researcher(s)

Published in

November 16, 2023

Biological conservation practices and approaches take many forms. Conservation projects do not only differ in their aims and methods, but also concerning their conceptual and normative background assumptions and their underlying motivations and objectives. We draw on philosophical distinctions from the ethics of conservation to explain variances of different positions on conservation projects along six dimensions: (1) conservation ideals, (2) intervention intuitions, (3) the moral considerability of nonhuman beings, (4) environmental values, (5) views on nature and (6) human roles in nature. The result is a map of the moral landscape of biological conservation, on which these six dimensions are layered. This map functions as a heuristic tool to understand conceptual and normative foundations of specific conservation projects, which we will illustrate with four paradigmatic examples: the Pisavaara Strict Nature Reserve, Predator Free New Zealand, the Oostvaardersplassen Nature Reserve and the Great Green Wall Project. With this map as a heuristic tool, we aim to conceptually illuminate disagreement and clarify misunderstandings between representatives of different environmental protection strategies and to show that the same project can be supported (or criticised) on different grounds.

Research field(s)
Biology, Environmental Sciences

DOI
10.1016/j.biocon.2023.110350

The enmity paradox

NOMIS Researcher(s)

Published in

November 16, 2023

The “friendship paradox” of social networks states that, on average, “your friends have more friends than you do”. Here, we theoretically and empirically explore a related and overlooked paradox we refer to as the “enmity paradox”. We use empirical data from 24,678 people living in 176 villages in rural Honduras. We empirically show that, for a real negative undirected network (created by symmetrizing antagonistic interactions), the paradox exists as it does in the positive world. Specifically, a person’s enemies have more enemies, on average, than a person does. Furthermore, in a mixed world of positive and negative ties, we study the conditions for the existence of the paradox, which we refer to as the “mixed-world paradox”, both theoretically and empirically, finding that, for instance, a person’s friends typically have more enemies than a person does. We also confirm the “generalized” enmity paradox for non-topological attributes in real data, analogous to the generalized friendship paradox (e.g., the claim that a person’s enemies are richer, on average, than a person is). As a consequence, the naturally occurring variance in the degree distribution of both friendship and antagonism in social networks can skew people’s perceptions of the social world. © 2023, The Author(s).

DOI
10.1038/s41598-023-47167-9

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