bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–04–13
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Effect of hypoxia on extracellular vesicles in malignant and non-malignant conditions.
  2. The PERK-ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.
  3. FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes.
  4. NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
  5. Acidosis-induced p38-kinase activation triggers an IL-6-mediated crosstalk of renal proximal tubule cells with fibroblasts leading to their inflammatory response.
  6. A neuroimmune circuit mediates cancer cachexia-associated apathy.
  7. Lipocalin-2 promotes NSCLC progression by activating the JAK2/STAT3 signaling pathway.
  8. Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
  9. Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
  10. MiR-204-5p mediates PERK inhibition to suppress growth and induce apoptosis in ovarian cancer through the eIF2α/ATF-4/CHOP pathway.
  11. Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
  12. HIF-1 regulates mitochondrial function in bone marrow-derived macrophages but not in tissue-resident alveolar macrophages.
  13. A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth.
  1. Cancer Treat Res Commun. 2025 Apr 07. pii: S2468-2942(25)00061-9. [Epub ahead of print]43 100924
    Effect of hypoxia on extracellular vesicles in malignant and non-malignant conditions.
    Vahid Niazi, Soudeh Ghafouri-Fard.
      Extracellular vesicles (EVs) are produced by virtually all types of cells and can be detected in nearly all extracellular places. These particles mediate intercellular communication and transfer their cargo to the recipient cells, inducing a variety of processes in these cells through transmission of several biomolecules such as miRNAs, lncRNAs, other transcripts and a variety of proteins. It has been documented that size, quantity, and expression of biomolecules in the EVs are influenced by the level of oxygen. In fact, hypoxia can affect several cellular processes through modulation of the cargo of these vesicles. Hypoxic exosomes derived from tumor cells have several protumoral effects on the recipient cells, including enhancement of proliferation, migration, and invasion in other tumoral cells, induction of metastasis in distant organs, stimulation of angiogenesis in the endothelial cells, and modulation of macrophage polarization. Hypoxic EVs also contribute to several non-malignant diseases. This review summarizes the effect of hypoxia on EVs cargo in malignant and nonmalignant diseases of different organs.
    Keywords:  Cancer; Exosome; Extracellular vesicle; Hypoxia
    DOI:  https://doi.org/10.1016/j.ctarc.2025.100924
  2. JCI Insight. 2025 Apr 10. pii: e189330. [Epub ahead of print]
    The PERK-ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.
    Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter.
      Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in PERK activation in human subjects with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis subjects had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/-Lyz2-cre mice was reduced to control levels. PERK increased Atf4 expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a unique therapeutic target to reverse established fibrosis.
    Keywords:  Fatty acid oxidation; Fibrosis; Immunology; Macrophages; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.189330
  3. Nat Commun. 2025 Apr 10. 16(1): 3422
    FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes.
    Xinyi Chen, Jingchen Shao, Isabell Brandenburger, Weikun Qian, Lisa Hahnefeld, Rémy Bonnavion, Haaglim Cho, ShengPeng Wang, Juan Hidalgo, Nina Wettschureck, Gerd Geisslinger, Robert Gurke, Zheng Wang, Stefan Offermanns.
      The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-58706-5
  4. Nat Metab. 2025 Apr 11.
    NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
    Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M Wensveen.
      The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.
    DOI:  https://doi.org/10.1038/s42255-025-01273-2
  5. Cell Commun Signal. 2025 Apr 11. 23(1): 180
    Acidosis-induced p38-kinase activation triggers an IL-6-mediated crosstalk of renal proximal tubule cells with fibroblasts leading to their inflammatory response.
    Marie-Christin Schulz, Nathalie Wolff, Michael Kopf, Micheal Gekle.
       BACKGROUND: Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling.
    METHODS: HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention.
    RESULTS: In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects.
    CONCLUSION: This study identifies IL-6 as a key mediator of tubule-fibroblast crosstalk in an acidic milieu, promoting inflammatory processes. Acidosis induces IL-6 expression, secretion, and biological effects, with p38 kinase as a crucial mediator. If validated in vivo, these findings could enhance understanding of CKD and support early interventions.
    DOI:  https://doi.org/10.1186/s12964-025-02180-5
  6. Science. 2025 Apr 11. 388(6743): eadm8857
    A neuroimmune circuit mediates cancer cachexia-associated apathy.
    Xiaoyue Aelita Zhu, Sarah Starosta, Miriam Ferrer, Junxiao Hou, Quentin Chevy, Federica Lucantonio, Rodrigo Muñoz-Castañeda, Fengrui Zhang, Kaikai Zang, Xiang Zhao, Francesca R Fiocchi, Mason Bergstrom, Aubrey A Siebels, Thomas Upin, Michael Wulf, Sarah Evans, Alexxai V Kravitz, Pavel Osten, Tobias Janowitz, Marco Pignatelli, Adam Kepecs.
      Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. We alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti-IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. Our findings uncovered a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.
    DOI:  https://doi.org/10.1126/science.adm8857
  7. J Transl Med. 2025 Apr 10. 23(1): 419
    Lipocalin-2 promotes NSCLC progression by activating the JAK2/STAT3 signaling pathway.
    Jinjin Zhang, Qin Xu, Gengyun Sun.
       BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Lipocalin-2 (LCN2), a pleiotropic protein implicated in tumorigenesis and cancer progression, has been associated with multiple malignancies. However, its precise role in NSCLC and the underlying molecular mechanisms remain incompletely understood. This study aimed to elucidate the function of LCN2 in NSCLC, with a particular focus on its involvement in the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway.
    METHODS: LCN2 expression in NSCLC tissues was comprehensively analyzed using bioinformatics tools, including the Universal Analysis of Cancer (UALCAN), The Cancer Genome Atlas (TCGA), UCSC-XENA, and Gene Expression Omnibus (GEO) databases. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were employed to assess LCN2 expression levels in NSCLC cell lines. The functional impact of LCN2 on NSCLC cells, including proliferation, apoptosis, and metastasis, were assessed through a series of in vitro assays, such as Cell Counting Kit-8 (CCK-8), EdU, wound healing, and transwell migration and invasion assays. An in vivo xenograft model was established to investigate the effects of LCN2 on tumor growth and metastasis. Additionally, the involvement of the JAK2/STAT3 signaling pathway was examined using western blotting and pharmacological inhibition with AG490.
    RESULTS: LCN2 was significantly upregulated in NSCLC tissues and cell lines, and its elevated expression correlated with poor prognosis. Functional analyses demonstrated that LCN2 knockdown suppressed NSCLC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, LCN2 was found to activate the JAK2/STAT3 pathway by interacting with SOCS3, and pharmacological blockade of this pathway effectively abrogated the oncogenic effects of LCN2 overexpression.
    CONCLUSIONS: This study identifies LCN2 as a potential oncogene in NSCLC, driving tumor progression through activation of the JAK2/STAT3 signaling pathway. These findings suggest that targeting LCN2 or its downstream signaling components may represent a promising therapeutic strategy for NSCLC.
    Keywords:  JAK2/STAT3 signaling pathway; Lipocalin-2; Metastasis; Non-small cell lung cancer; Progression
    DOI:  https://doi.org/10.1186/s12967-025-06418-1
  8. J Clin Invest. 2025 Apr 08. pii: e178806. [Epub ahead of print]
    Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
    Andrew C D'Lugos, Jeremy B Ducharme, Chandler S Callaway, Jose G Trevino, Carl Atkinson, Sarah M Judge, Andrew R Judge.
      Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross-sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild type (WT) mice, or mice with genetic deletion of the central complement component 3 (C3-/- mice). Compared to WT mice, C3-/- mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation is contributory to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.
    Keywords:  Cancer; Muscle; Muscle biology; Oncology; Proteomics
    DOI:  https://doi.org/10.1172/JCI178806
  9. J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]
    Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
    Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.
      Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.
    Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation
    DOI:  https://doi.org/10.1242/jcs.263688
  10. Sci Rep. 2025 Apr 11. 15(1): 12435
    MiR-204-5p mediates PERK inhibition to suppress growth and induce apoptosis in ovarian cancer through the eIF2α/ATF-4/CHOP pathway.
    Faranak Fallahian, Seyedeh Sara Ghorbanhosseini, Shekufe Rezghi Barez, Mahmoud Aghaei.
      The unfolded protein response (UPR) is crucial in maintaining cell survival during stressful conditions, but prolonged ER stress can lead to apoptosis. Based on the evidence acquired, it has been suggested that inhibiting the protein kinase RNA-like ER kinase (PERK) pathway, which constitutes an adaptive branch of UPR, may represent a viable approach for impeding the proliferation of neoplastic cells. This study assesses the influence of PERK inhibition mediated by miR-204-5p on the growth of ovarian cancer cell lines, OVCAR3 and SKOV3. We demonstrated that miR-204-5p significantly downregulated the expression of PERK at the RNA and protein levels. The suppression of PERK, mediated by miR-204-5p, significantly diminished cellular viability and enhanced apoptotic cell death in cells exposed to Tunicamycin (Tm). We ascertained that the inhibition of PERK by miR-204-5p decreased eukaryotic initiation factor 2alpha (eIF2α) phosphorylation. Moreover, activating transcription factor 4 (ATF4) and CCAAT-enhancer-binding homologous protein (CHOP) expression levels were notably elevated in response to miR-204-5p. The expression of Bax and caspase-12 was found to be upregulated, while the expression of Bcl-2 was reduced. This study is the first to demonstrate that silencing the PERK gene through miR-204-5p significantly inhibits cell growth and promotes ER-stress-induced apoptosis in ovarian cancer cells.
    Keywords:  Apoptosis; ER stress; MiR-204-5p; MicroRNA; Ovarian cancer; PERK
    DOI:  https://doi.org/10.1038/s41598-025-95883-1
  11. Nat Commun. 2025 Apr 04. 16(1): 3230
    Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
    Huanhuan Cai, Xueyuan Chen, Yan Liu, Yingbo Chen, Gechang Zhong, Xiaoyu Chen, Shuo Rong, Hao Zeng, Lin Zhang, Zelong Li, Aihua Liao, Xiangtai Zeng, Wei Xiong, Cihang Guo, Yanfang Zhu, Ke-Qiong Deng, Hong Ren, Huan Yan, Zeng Cai, Ke Xu, Li Zhou, Zhibing Lu, Fubing Wang, Shi Liu.
      Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.
    DOI:  https://doi.org/10.1038/s41467-025-58563-2
  12. Sci Rep. 2025 Apr 04. 15(1): 11574
    HIF-1 regulates mitochondrial function in bone marrow-derived macrophages but not in tissue-resident alveolar macrophages.
    Parker S Woods, Rengül Cetin-Atalay, Angelo Y Meliton, Kaitlyn A Sun, Obada R Shamaa, Kun Woo D Shin, Yufeng Tian, Benjamin Haugen, Robert B Hamanaka, Gökhan M Mutlu.
      HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state but can shift toward glycolysis under hypoxic conditions. Here, we generated mice with tamoxifen-inducible myeloid lineage cell specific deletion of Hif1a (Hif1afl/fl:LysM-CreERT2+/-) and from these mice, we isolated TR-AMs and bone marrow-derived macrophages (BMDMs) in which Hif1a is deleted. We show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity in Hif1a-/- BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. We conclude that HIF-1α regulates mitochondrial function in BMDMs but not in TR-AMs. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in different types of macrophages.
    Keywords:  Alveolar macrophage; Bone marrow-derived macrophage; HIF-1α; Inflammation; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1038/s41598-025-95962-3
  13. PLoS Biol. 2025 Apr 10. 23(4): e3003086
    A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth.
    Iratxe Zuazo-Gaztelu, David Lawrence, Ioanna Oikonomidi, Scot Marsters, Ximo Pechuan-Jorge, Catarina J Gaspar, David Kan, Ehud Segal, Kevin Clark, Maureen Beresini, Marie-Gabrielle Braun, Joachim Rudolph, Zora Modrusan, Meena Choi, Wendy Sandoval, Mike Reichelt, David C DeWitt, Pekka Kujala, Suzanne van Dijk, Judith Klumperman, Avi Ashkenazi.
      Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and regulated RNA decay. We discovered that some cancer cells surprisingly require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous IRE1 at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1's biological role and therapeutic targeting.
    DOI:  https://doi.org/10.1371/journal.pbio.3003086
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