bims-cagime 2025-03-09 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–03–09
29 papers selected by
Kıvanç Görgülü, Technical University of Munich

To degrade or not to degrade: how phase separation modulates selective autophagy.
Evolutionary fingerprints of epithelial-to-mesenchymal transition.
MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia.
Adhesion strength of tumor cells predicts metastatic disease in vivo.
Ponsegromab for the Treatment of Cancer Cachexia.
DrBioRight 2.0: an LLM-powered bioinformatics chatbot for large-scale cancer functional proteomics analysis.
Multiplexed glycan immunofluorescence identification of pancreatic cancer cell subpopulations in both tumor and blood samples.
Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.
Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.
How pore formation in complex biological membranes is governed by lipid composition, mechanics, and lateral sorting.
Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.
The complex interplay between aging and cancer.
Tackling Cancer through Global Team Science.
Reproducible image-based profiling with Pycytominer.
Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy.
Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.
Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function?
Mapping the nanoscale organization of the human cell surface proteome reveals new functional associations and surface antigen clusters.
HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy.
Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
An AIE-active near-infrared molecular probe for migrasome labeling.
A novel radial co-culture microfluidic device for parallel and control detection of tumor cell invasiveness.
PhaSeDis: A Manually Curated Database of Phase Separation-Disease Associations and Corresponding Small Molecules.
Plasma miR-379 can predict treatment response to FOLFIRINOX and gemcitabine-nab-paclitaxel in advanced pancreatic cancer.
Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer.
The International Space Station has a unique and extreme microbial and chemical environment driven by use patterns.
Mechanical confinement triggers spreading and migration of immobile cells by deforming nucleus.
A cellular and molecular basis of leptin resistance.
Contractility-Driven Cell Motility against a Viscoelastic Resistance.

Autophagy. 2025 Mar 07.

To degrade or not to degrade: how phase separation modulates selective autophagy.

Mariya Licheva, Riccardo Babic, Jeremy Pflaum, Hector Mancilla, Florian Wilfling, Claudine Kraft.

  Selective macroautophagy/autophagy relies on newly formed double-membrane compartments, known as phagophores, to sequester and recycle diverse cellular components, including organelles, biomolecular condensates and protein aggregates, maturing into autophagosomes that fuse with the vacuole/lysosome. Autophagosomes originate at the cargo-vacuole/ER interface, where autophagy factors assemble into the phagophore assembly site (PAS). However, how autophagy proteins organize on the surface of structurally and biophysically different cargoes, and achieve spatial confinement at the PAS to support autophagosome formation remains unclear. Mechanisms governing cargo selection are also poorly understood. In this study, we demonstrate that receptor mobility, driven by low affinity cargo-receptor interactions, is crucial for rendering cellular structures degradable by autophagy. We show that cargo surface mobility, combined with the phase separation of scaffold proteins, drives the formation of early PAS precursors, termed "initiation hubs". These hubs dynamically rearrange at the cargo-vacuole/ER interface to promote autophagosome biogenesis, providing new insights into selective autophagy initiation.

Keywords:  Aggrephagy; Atg11/RB1CC1; autophagy; cargo receptor; initiation hub, phase separation

DOI:  https://doi.org/10.1080/15548627.2025.2476025
Nature. 2025 Mar 05.

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Luigi Perelli, Li Zhang, Sarah Mangiameli, Francesca Giannese, Krishnan K Mahadevan, Fuduan Peng, Francesca Citron, Hania Khan, Courtney Le, Enrico Gurreri, Federica Carbone, Andrew J C Russell, Melinda Soeung, Truong Nguyen Anh Lam, Sebastian Lundgren, Sujay Marisetty, Cihui Zhu, Desiree Catania, Alaa M T Mohamed, Ningping Feng, Jithesh Jose Augustine, Alessandro Sgambato, Giampaolo Tortora, Giulio F Draetta, Giovanni Tonon, Andrew Futreal, Virginia Giuliani, Alessandro Carugo, Andrea Viale, Michael P Kim, Timothy P Heffernan, Linghua Wang, Raghu Kalluri, Davide Cittaro, Fei Chen, Giannicola Genovese.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

DOI: https://doi.org/10.1038/s41586-025-08671-2
Cell Metab. 2025 Feb 26. pii: S1550-4131(25)00018-X. [Epub ahead of print]

MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia.

Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.

  Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.

Keywords:  ACKR3; MIF; adipose remodeling; adipose stem and progenitor cells; cancer cachexia

DOI:  https://doi.org/10.1016/j.cmet.2025.01.018
Cell Rep. 2025 Feb 28. pii: S2211-1247(25)00130-5. [Epub ahead of print] 115359

Adhesion strength of tumor cells predicts metastatic disease in vivo.

Madison A Kane, Katherine G Birmingham, Benjamin Yeoman, Neal Patel, Hayley Sperinde, Thomas G Molley, Pranjali Beri, Jeremy Tuler, Aditya Kumar, Sarah Klein, Somaye Zare, Anne Wallace, Parag Katira, Adam J Engler.

  Although only a fraction of tumor cells contribute to metastatic disease, no prognostic biomarkers currently exist to identify these cells. We show that a physical marker-adhesion strength-predicts metastatic potential in a mouse breast cancer model and that it may stratify human disease. Cells disseminating from murine mammary tumors are weakly adherent, and, when pre-sorted by adhesion, primary tumors created from strongly adherent cells exhibit fewer lung metastases than weakly adherent cells do. We demonstrate that admixed cancer lines can be separated by label-free adhesive signatures. When applied to murine metastatic tumors, adhesion retrospectively predicts metastatic disease with 100% specificity, 85% sensitivity, and area under the curve (AUC) of 0.94. Cells from human reduction mammoplasties have a higher adhesion strength versus resected human tumors, which may also be stratified between invasive and more indolent cancers. Thus, highly metastatic cells may have a distinct physical phenotype that may be a predictive marker of clinical outcomes.

Keywords:  CP: Cancer; CP: Cell biology; adhesion shear stress; epithelial cancer; fluid flow; heterogeneity

DOI:  https://doi.org/10.1016/j.celrep.2025.115359
N Engl J Med. 2025 Mar 06. pii: 10.1056/NEJMc2500502#sa1. [Epub ahead of print]392(10): 1035

Ponsegromab for the Treatment of Cancer Cachexia.

Inès Dufour, Laure B Bindels, Eric Goffin.

DOI: https://doi.org/10.1056/NEJMc2500502
Nat Commun. 2025 Mar 06. 16(1): 2256

DrBioRight 2.0: an LLM-powered bioinformatics chatbot for large-scale cancer functional proteomics analysis.

Wei Liu, Jun Li, Yitao Tang, Yining Zhao, Chaozhong Liu, Meiyi Song, Zhenlin Ju, Shwetha V Kumar, Yiling Lu, Rehan Akbani, Gordon B Mills, Han Liang.

Functional proteomics provides critical insights into cancer mechanisms, facilitating the discovery of novel biomarkers and therapeutic targets. We have developed a comprehensive cancer functional proteomics resource using reverse phase protein arrays, incorporating data from nearly 8000 patient samples from The Cancer Genome Atlas and approximately 900 samples from the Cancer Cell Line Encyclopedia. Our dataset includes a curated panel of nearly 500 high-quality antibodies, covering all major cancer hallmark pathways. To enhance the accessibility and analytic power of this resource, we introduce DrBioRight 2.0 ( https://drbioright.org ), an intuitive bioinformatic platform powered by state-of-the-art large language models. DrBioRight enables researchers to explore protein-centric cancer omics data, perform advanced analyses, visualize results, and engage in interactive discussions using natural language. By streamlining complex proteogenomic analyses, this tool accelerates the translation of large-scale functional proteomics data into meaningful biomedical insights.

DOI: https://doi.org/10.1038/s41467-025-57430-4
Sci Adv. 2025 Mar 07. 11(10): eadt0029

Multiplexed glycan immunofluorescence identification of pancreatic cancer cell subpopulations in both tumor and blood samples.

Braelyn Binkowski, Zachary Klamer, ChongFeng Gao, Ben Staal, Anna Repesh, Hoang-Le Tran, David M Brass, Pamela Bartlett, Steven Gallinger, Maria Blomqvist, J Bradley Morrow, Peter Allen, Chanjuan Shi, Aatur Singhi, Randall Brand, Ying Huang, Galen Hostetter, Brian B Haab.

Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays for early disease detection. We hypothesized that PDAC cell subpopulations could be identified by aberrant glycan signatures in both tumor tissue and blood samples. We used multiplexed glycan immunofluorescence to distinguish between PDAC and noncancer cell subpopulations within tumor tissue, and we developed hybrid glycan sandwich assays to determine whether the aberrant glycan signatures could be detected in blood samples. We found that PDAC cells were identified by signatures of glycans detected by four glycan-binding proteins (VVL, CA19-9, sTRA, and GM2) and that there are three types of glycan-defined PDAC tumors: sTRA type, CA19-9 type, and intermixed. In patient-matched tumor and blood samples, the PDAC tumor type could be determined by the aberrant glycans in the blood. As a result, the combined assays of aberrant glycan signatures were more sensitive and specific than any individual assay. Our results demonstrate a methodology to detect and stratify PDAC.

DOI: https://doi.org/10.1126/sciadv.adt0029
Nature. 2025 Mar 05.

Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.

Jie Yang, Yumi Yamashita-Kanemaru, Benjamin I Morris, Annalisa Contursi, Daniel Trajkovski, Jingru Xu, Ilinca Patrascan, Jayme Benson, Alexander C Evans, Alberto G Conti, Aws Al-Deka, Layla Dahmani, Adnan Avdic-Belltheus, Baojie Zhang, Hanneke Okkenhaug, Sarah K Whiteside, Charlotte J Imianowski, Alexander J Wesolowski, Louise V Webb, Simone Puccio, Stefania Tacconelli, Annalisa Bruno, Sara Di Berardino, Alessandra De Michele, Heidi C E Welch, I-Shing Yu, Shu-Wha Lin, Suman Mitra, Enrico Lugli, Louise van der Weyden, Klaus Okkenhaug, Kourosh Saeb-Parsy, Paola Patrignani, David J Adams, Rahul Roychoudhuri.

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

DOI: https://doi.org/10.1038/s41586-025-08626-7
bioRxiv. 2025 Feb 17. pii: 2025.02.12.637975. [Epub ahead of print]

Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.

Oliver J Newsom, Lucas B Sullivan.

Fetal bovine serum (FBS) is a nearly ubiquitous, yet undefined additive in mammalian cell culture media whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS in culture. Here, we use a combination of live-cell imaging and liquid chromatography-mass spectrometry to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation and demonstrate that the serum metal and lipid components are crucial to sustaining proliferation in culture. Importantly, despite access to a wide range of lipid classes, albumin-bound lipids are the primary species consumed during cancer cell proliferation. Furthermore, we find that combinations of the additive ITS, containing necessary metals, and albumin-associated lipid classes are sufficient to replace FBS in culture media. We show that serum-free media enables sensitive quantification of lipid consumption dynamics during cell proliferation, which indicate that fatty acids (FA) are consumed through a mass-action mechanism, with minimal competition from other lipid classes. Finally, we find that pharmacologic disruption of FA activation and incorporation into the cellular lipidome reduces uptake from the environment and impairs cell proliferation. This work therefore identifies metabolic contributions of serum in cell culture settings and provides a framework for building cell culture systems that sustain cell proliferation without the variable and undefined contributions of FBS.

DOI: https://doi.org/10.1101/2025.02.12.637975
PNAS Nexus. 2025 Mar;4(3): pgaf033

How pore formation in complex biological membranes is governed by lipid composition, mechanics, and lateral sorting.

Leonhard J Starke, Christoph Allolio, Jochen S Hub.

  The primary function of biological membranes is to enable compartmentalization among cells and organelles. Loss of integrity by the formation of membrane pores would trigger uncontrolled depolarization or influx of toxic compounds, posing a fatal threat to living cells. How the lipid complexity of biological membranes enables mechanical stability against pore formation while, simultaneously, allowing for ongoing membrane remodeling is largely enigmatic. We performed molecular dynamics simulations of eight complex lipid membranes including the plasma membrane and membranes of the organelles endoplasmic reticulum, Golgi, lysosome, and mitochondrion. To quantify the mechanical stability of these membranes, we computed the free energy of transmembrane pore nucleation as well as the line tension of the rim of open pores. Our simulations reveal that complex biological membranes are remarkably stable, however, with the plasma membrane standing out as exceptionally stable, which aligns with its crucial role as a protective layer. We observe that sterol content is a key regulator for biomembrane stability, and that lateral sorting among lipid mixtures influences the energetics of membrane pores. A comparison of 25 model membranes with varying sterol content, tail length, tail saturation, and head group type shows that the pore nucleation free energy is mostly associated with the lipid tilt modulus, whereas the line tension along the pore rim is determined by the lipid intrinsic curvature. Together, our study provides an atomistic and energetic view on the role of lipid complexity in biomembrane stability.

Keywords:  Helfrich theory; lipid membranes; molecular dynamics simulations; pore formation

DOI:  https://doi.org/10.1093/pnasnexus/pgaf033
Cell. 2025 Feb 27. pii: S0092-8674(25)00145-X. [Epub ahead of print]

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.

Xiadi He, Qiwei Wang, Xin Cheng, Weihua Wang, Yutong Li, Yabing Nan, Jiang Wu, Bingqiu Xiu, Tao Jiang, Johann S Bergholz, Hao Gu, Fuhui Chen, Guangjian Fan, Lianhui Sun, Shaozhen Xie, Junjie Zou, Sheng Lin, Yun Wei, James Lee, John M Asara, Ke Zhang, Lewis C Cantley, Jean J Zhao.

  Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.

Keywords:  STAT1; immune response; protein modification; vitamin C; vitcylation

DOI:  https://doi.org/10.1016/j.cell.2025.01.043
Nat Aging. 2025 Mar 04.

The complex interplay between aging and cancer.

Lucrezia A Trastus, Fabrizio d'Adda di Fagagna.

Cancer is an age-related disease, but the interplay between cancer and aging is complex and their shared molecular drivers are deeply intertwined. This Review provides an overview of how different biological pathways affect cancer and aging, leveraging evidence mainly derived from animal studies. We discuss how genome maintenance and accumulation of DNA mutations affect tumorigenesis and tissue homeostasis during aging. We describe how age-related telomere dysfunction and cellular senescence intricately modulate tumor development through mechanisms involving genomic instability and inflammation. We examine how an aged immune system and chronic inflammation shape tumor immunosurveillance, fueling DNA damage and cellular senescence. Finally, as animal models are important to untangling the relative contributions of these aging-modulated pathways to cancer progression and to test interventions, we discuss some of the limitations of physiological and accelerated aging models, aiming to improve experimental designs and enhance translation.

DOI: https://doi.org/10.1038/s43587-025-00827-z
Cancer Discov. 2025 Mar 05. OF1-OF5

Tackling Cancer through Global Team Science.

Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Gemma M Balmer, David Scott.

Here, we discuss the seven new challenges set by Cancer Grand Challenges that are currently open for creative applications. We invite the research community to assemble global, interdisciplinary teams to tackle these challenges and ultimately change the way we think about, study, prevent, and treat cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0282
Nat Methods. 2025 Mar 03.

Reproducible image-based profiling with Pycytominer.

Erik Serrano, Srinivas Niranj Chandrasekaran, Dave Bunten, Kenneth I Brewer, Jenna Tomkinson, Roshan Kern, Michael Bornholdt, Stephen J Fleming, Ruifan Pei, John Arevalo, Hillary Tsang, Vincent Rubinetti, Callum Tromans-Coia, Tim Becker, Erin Weisbart, Charlotte Bunne, Alexandr A Kalinin, Rebecca Senft, Stephen J Taylor, Nasim Jamali, Adeniyi Adeboye, Hamdah Shafqat Abbasi, Allen Goodman, Juan C Caicedo, Anne E Carpenter, Beth A Cimini, Shantanu Singh, Gregory P Way.

Advances in high-throughput microscopy have enabled the rapid acquisition of large numbers of high-content microscopy images. Next, whether by deep learning or classical algorithms, image analysis pipelines commonly produce single-cell features. To process these single cells for downstream applications, we present Pycytominer, a user-friendly, open-source Python package that implements the bioinformatics steps key to image-based profiling. We demonstrate Pycytominer's usefulness in a machine-learning project to predict nuisance compounds that cause undesirable cell injuries.

DOI: https://doi.org/10.1038/s41592-025-02611-8
Cell Rep. 2025 Mar 01. pii: S2211-1247(25)00159-7. [Epub ahead of print]44(3): 115388

Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy.

Paulo Pereira, Joshua Panier, Marc Nater, Michael Herbst, Anna Laura Calvanese, Hakan Köksal, Héctor Castañón, Virginia Cecconi, Paulino Tallón de Lara, Steve Pascolo, Maries van den Broek.

  Metastases arise from disseminated cancer cells (DCCs) that detach from the primary tumor and seed distant organs. There, quiescent DCCs can survive for an extended time, a state referred to as metastatic dormancy. The mechanisms governing the induction, maintenance, and awakening from metastatic dormancy are unclear. We show that the differentiation of dormancy-inducing CD8+ T cells requires CD4+ T cell help and that interferon (IFN)γ directly induces dormancy in DCCs. The maintenance of metastatic dormancy, however, is independent of T cells. Instead, awakening from dormancy requires an inflammatory signal, and we identified CD4+ T cell-derived interleukin (IL)-17A as an essential wake-up signal for dormant DCCs in the lungs. Thus, the induction of and awakening from metastatic dormancy require an external stimulus, while the maintenance of dormancy does not rely on continuous surveillance by lymphocytes.

Keywords:  CP: Cancer; CP: Immunology; IFNγ; IL-17A; breast cancer; metastatic dormancy

DOI:  https://doi.org/10.1016/j.celrep.2025.115388
Nature. 2025 Mar 05.

Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.

Laetitia Coassolo, Niels B Danneskiold-Samsøe, Quennie Nguyen, Amanda Wiggenhorn, Meng Zhao, David Cheng-Hao Wang, David Toomer, Jameel Lone, Yichao Wei, Aayan Patel, Irene Liparulo, Deniz Kavi, Lianna W Wat, Saranya Chidambaranathan Reghupaty, Julie Jae Kim, Tina Asemi, Ewa Bielczyk-Maczynska, Veronica L Li, Maria Dolores Moya-Garzon, Nicole A J Krentz, Andreas Stahl, Danny Hung-Chieh Chou, Liqun Luo, Katrin J Svensson.

Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1)1,2. However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight.

DOI: https://doi.org/10.1038/s41586-025-08683-y
J Lipid Res. 2025 Feb 26. pii: S0022-2275(25)00025-2. [Epub ahead of print] 100765

Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function?

Graeme I Lancaster, Andrew J Murphy.

Ferroptosis is an iron-dependent form of cell death driven by the excessive peroxidation of poly-unsaturated fatty acids (PUFAs) within membrane phospholipids (PLs). Ferroptosis is a hallmark of many diseases and preventing or inducing ferroptosis has considerable therapeutic potential. Like other forms of cell death, the pathological importance and therapeutic potential of ferroptosis is well appreciated. However, while cell death modalities such as apoptosis and necroptosis have critical physiological roles, such as in development and tissue homeostasis, whether ferroptosis has important physiological roles is largely unknown. In this regard, key questions for field are: Is ferroptosis used for physiological processes? Are certain cell-types purposely adapted to be either resistant or sensitive to ferroptosis to be able to function optimally? Do physiological perturbations such as aging and diet impact ferroptosis susceptibility? Herein, we have reviewed emerging evidence that supports the idea that being able to selectively and controllably induce or resist ferroptosis is essential for development and cell function. While several factors regulate ferroptosis, it appears that the ability of cells and tissues to control their lipid composition, specifically the abundance of PLs containing PUFAs, is crucial for cells to be able to either resist or be sensitized to ferroptosis. Finally, aging and diets enriched in specific PUFAs lead to an increase in cellular PUFA levels which may sensitize cells to ferroptosis. Such changes may impact the pathogenesis of diseases where ferroptosis is involved.

DOI: https://doi.org/10.1016/j.jlr.2025.100765
bioRxiv. 2025 Feb 17. pii: 2025.02.12.637979. [Epub ahead of print]

Mapping the nanoscale organization of the human cell surface proteome reveals new functional associations and surface antigen clusters.

Brendan M Floyd, Elizabeth L Schmidt, Nicholas A Till, Jonathan L Yang, Pinyu Liao, Benson M George, Ryan A Flynn, Carolyn R Bertozzi.

The cell surface is a dynamic interface that controls cell-cell communication and signal transduction relevant to organ development, homeostasis and repair, immune reactivity, and pathologies driven by aberrant cell surface phenotypes. The spatial organization of cell surface proteins is central to these processes. High-resolution fluorescence microscopy and proximity labeling have advanced studies of surface protein associations, but the spatial organization of the complete surface proteome remains uncharted. In this study, we systematically mapped the surface proteome of human T-lymphocytes and B-lymphoblasts using proximity labeling of 85 antigens, identified from over 100 antibodies tested for binding to surface-exposed proteins. These experiments were coupled with an optimized data-independent acquisition mass spectrometry workflow to generate a robust dataset. Unsupervised clustering of the resulting interactome revealed functional modules, including well-characterized complexes such as the T-cell receptor and HLA class I/II, alongside novel clusters. Notably, we identified mitochondrial proteins localized to the surface, including the transcription factor TFAM, suggesting previously unappreciated roles for mitochondrial proteins at the plasma membrane. A high-accuracy machine learning classifier predicted over 6,000 surface protein associations, highlighting functional associations such as IL10RB's role as a negative regulator of type I interferon signaling. Spatial modeling of the surface proteome provided insights into protein dispersion patterns, distinguishing widely distributed proteins, such as CD45, from localized antigens, such as CD226 pointing to active mechanisms of regulating surface organization. This work provides a comprehensive map of the human surfaceome and a resource for exploring the spatial and functional dynamics of the cell membrane proteome.

DOI: https://doi.org/10.1101/2025.02.12.637979
Cell. 2025 Feb 25. pii: S0092-8674(25)00156-4. [Epub ahead of print]

HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy.

Qinqin Jiang, David A Braun, Karl R Clauser, Vijyendra Ramesh, Nitin H Shirole, Joseph E Duke-Cohan, Nancy Nabilsi, Nicholas J Kramer, Cleo Forman, Isabelle E Lippincott, Susan Klaeger, Kshiti M Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, Yijia Jiang, Rong Li, Sudeepa Syamala, Suzanna Rachimi, Eva K Verzani, Jonathan D Stevens, William J Lane, Sabrina Y Camp, Kevin Meli, Melissa B Pappalardi, Zachary T Herbert, Xintao Qiu, Paloma Cejas, Henry W Long, Sachet A Shukla, Eliezer M Van Allen, Toni K Choueiri, L Stirling Churchman, Jennifer G Abelin, Cagan Gurer, Gavin MacBeath, Richard W Childs, Steven A Carr, Derin B Keskin, Catherine J Wu, William G Kaelin.

  Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.

Keywords:  ERV; HIF; cancer vaccine; ccRCC; immunopeptidomic; immunotherapy; kidney cancer; neoantigen

DOI:  https://doi.org/10.1016/j.cell.2025.01.046
Nat Metab. 2025 Mar 06.

Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.

Trine S Nicolaisen, Aslak E Lyster, Kim A Sjøberg, Daniel T Haas, Christian T Voldstedlund, Anne-Marie Lundsgaard, Jakob K Jensen, Ea M Madsen, Casper K Nielsen, Mads Bloch-Ibenfeldt, Nicolai J Wewer Albrechtsen, Adam J Rose, Natalie Krahmer, Christoffer Clemmensen, Erik A Richter, Andreas M Fritzen, Bente Kiens.

Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.

DOI: https://doi.org/10.1038/s42255-025-01236-7
Biomaterials. 2025 Feb 27. pii: S0142-9612(25)00132-2. [Epub ahead of print]319 123213

An AIE-active near-infrared molecular probe for migrasome labeling.

Jie Cui, Fei Zhang, Dong Jiang, Boqi Liu, Han Zhang, Niu Niu, Dingyuan Yan, Guangjie Song, Xue Li, Li Yu, Dong Wang, Ben Zhong Tang.

  Migrasomes, newly identified organelles, play crucial roles in various physiological and pathological activities, including embryogenesis, immune responses, wound healing, and metastasis of cancer cells. Migrasome visualization is essential for the deep exploration of migrasome biology. Despite the reported labeling methods based on migrasome marker proteins, a simple and convenient method for migrasome labeling is more desirable compared to the complicated transfection technique. Here, an aggregation-induced emission (AIE) based near-infrared (NIR) molecular probe named TTCPy was presented, which can bind to the phospholipid on migrasomes and light up migrasomes with a turn-on NIR fluorescence. TTCPy allows for high-performance imaging of migrasomes in both live cells and living chorioallantoic membranes via simple and rapid staining. Moreover, TTCPy achieves live-cell super-resolution imaging of migrasomes, affording remarkedly improved spatial resolution and signal-to-background ratio. This work offers a simple yet powerful tool for migrasome visualization and will contribute to the booming hotspot of migrasome biology.

Keywords:  Aggregation-induced emission; Migrasome labeling; Near-infrared fluorescence; Super-resolution imaging

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123213
Spectrochim Acta A Mol Biomol Spectrosc. 2025 Feb 21. pii: S1386-1425(25)00248-3. [Epub ahead of print]334 125942

A novel radial co-culture microfluidic device for parallel and control detection of tumor cell invasiveness.

Shuo Chen, Shuai Yue, Wei Ba, Jin Fang.

  Metastasis is responsible for the majority of cancer-related deaths, and tumor cell invasion is a critical step in the cancer metastatic cascade. Traditional invasion analysis using transwell assays and immunodeficient mouse models struggles to control tumor microenvironment factors, such as various biochemical signals and cell types. A microfluidic chip system has emerged as an important tool for invasion analysis, but the simultaneous parallel and controlled experiments within the same group of tumor cells remain challenging. Here, we developed a new three-dimensional co-culture microfluidic device to investigate tumor invasion. This device consists of three concentric circles and is divided into four identical regions. Each region includes a tumor cell region, an invasion channel and a co-culture channel. Additionally, the four identical regions allow for four specific groups of parallel or control analysis surrounding the same group of tumor cells. Thus, our device enables the comparison of invasion among the same group of cells under different conditions, avoiding the discrepancies in invasion that arise when the treatment factors differ across different groups of tumor cells. Using experimental examinations and numerical simulations, we verified the capability of the device for parallel and controlled analysis of tumor invasion in response to different stimuli, including chemokines, drugs and cellular factors secreted from co-cultured cells. Furthermore, we found that in a co-culture environment with cancer-associated fibroblasts, the invasiveness of LoVo cells and their resistance to 5-fluorouracil treatment were enhanced. This innovative approach allows for easy, parallel and controlled assays to study tumor cell invasion with the advantages of multiplexing and simplicity. The method provides straightforward, repeatable control over cell-biochemical signals and cell-cell interactions, making it a valuable tool for accurately evaluating tumor invasion in metastasis studies.

Keywords:  Cancer-associated fibroblasts; Co-culture; Microfluidic chip; Parallel and control; Tumor invasion

DOI:  https://doi.org/10.1016/j.saa.2025.125942
Genomics Proteomics Bioinformatics. 2025 Mar 04. pii: qzaf014. [Epub ahead of print]

PhaSeDis: A Manually Curated Database of Phase Separation-Disease Associations and Corresponding Small Molecules.

Taoyu Chen, Guoguo Tang, Tianhao Li, Zhining Yanghong, Chao Hou, Zezhou Du, Kaiqiang You, Liwei Ma, Tingting Li.

  Biomacromolecules form membraneless organelles through liquid-liquid phase separation in order to regulate the efficiency of particular biochemical reactions. Dysregulation of phase separation might result in pathological condensation or sequestration of biomolecules, leading to diseases. Thus, phase separation and phase separating factors may serve as drug targets for disease treatment. Nevertheless, such associations have not yet been integrated into phase separation related databases. Therefore, based on MloDisDB, a database for membraneless organelle factor-disease association previously developed by our lab, we constructed PhaSeDis, the phase separation-disease association database. We increased the number of phase separation entries from 52 to 185, and supplemented the evidence provided by the original article verifying the phase separation nature of the factors. Moreover, we included the information of interacting small molecules with low-throughput or high-throughput evidence that might serve as potential drugs for phase separation entries. PhaSeDis strives to offer comprehensive descriptions of each entry, elucidating how phase separating factors induce pathological conditions via phase separation and the mechanisms by which small molecules intervene. We believe that PhaSeDis would be very important in the application of phase separation regulation in treating related diseases. PhaSeDis is available at http://mlodis.phasep.pro.

Keywords:  Biomolecular condensation; Database; Disease; Phase separation; Small molecule

DOI:  https://doi.org/10.1093/gpbjnl/qzaf014
J Liq Biopsy. 2024 Sep;5 100152

Plasma miR-379 can predict treatment response to FOLFIRINOX and gemcitabine-nab-paclitaxel in advanced pancreatic cancer.

Lenka N C Boyd, Mahsoem Ali, Jisce R Puik, Annalisa Comandatore, Laura Ginocchi, Laura L Meijer, Rutger-Jan Swijnenburg, Roberta Tartarini, Tessa Y S Le Large, Luca Morelli, Ingrid Garajova, Marc G Besselink, Andrea Mambrini, Johanna W Wilmink, Adam E Frampton, Hanneke W M van Laarhoven, Elisa Giovannetti, Geert Kazemier.

   Background: Novel biomarkers, such as plasma microRNAs (miRs), are needed to help guide clinical decision-making for the type of chemotherapy to use in patients with advanced pancreatic ductal adenocarcinoma (PDAC). This study assessed the ability of plasma miRs to predict optimal treatment response from FOLFIRINOX or gemcitabine-nab-paclitaxel in these patients.
Methods: Next-generation sequencing (NGS) was performed for biomarker discovery in pre-treatment plasma samples from advanced PDAC patients subsequently treated with FOLFIRINOX (n = 12) or gemcitabine-nab-paclitaxel (n = 12). Selected candidate biomarkers were validated in 40 patients with advanced PDAC using RT-qPCR. Cox regression was then used to assess the predictive value of plasma miRs for either FOLFIRINOX or gemcitabine-nab-paclitaxel.
Results: In the validation cohort, high plasma miR-379 expression was strongly predictive of treatment response (Pinteraction = 0.0004). Overall survival (OS) was significantly better with FOLFIRINOX vs. gemcitabine-nab-paclitaxel in those patients with lower plasma miR-379 expression (hazard ratio, 0.32 [95% confidence interval, 0.08 to 0.98]; P = 0.046). However, gemcitabine-nab-paclitaxel was associated with superior OS in patients with higher plasma miR-379 (hazard ratio, 0.28 [0.10 to 0.86]; P = 0.027). In contrast, miR-127, miR-155, and miR-200 showed no predictive value for treatment response for either chemotherapy regimen (P interaction = 0.12, P interaction = 0.83 and P interaction = 0.12, respectively).
Conclusions: Plasma miR-379 appears clinically useful as a predictive biomarker to identify which patients with advanced PDAC benefit most from treatment with FOLFIRINOX or gemcitabine-nab-paclitaxel. Further validation in larger studies and clinical trials is now warranted.

Keywords:  FOLFIRINOX; Gemcitabine-nab-paclitaxel; Pancreatic ductal adenocarcinoma; microRNA; predictive biomarker

DOI:  https://doi.org/10.1016/j.jlb.2024.100152
bioRxiv. 2025 Feb 22. pii: 2025.02.17.638725. [Epub ahead of print]

Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer.

Ahmed Mahmoud, Philip H Choi, Christine Sukhwa, Jura Pintar, Henry Walch, Nan Zhao, Jonathan Bermeo, Sebastian Chung, Manisha Raghavan, Samhita Bapat, Qingwen Jiang, Georgios Karagkounis, Julia Meredith, Michael Giarrizzo, Canan Firat, Andrea Cercek, Michael B Foote, Nikolaus Schultz, Walid K Chatila, Garrett M Nash, Jinru Shia, Francisco Sanchez-Vega, Steven Larson, Arvin C Dar, Neal Rosen, Karuna Ganesh.

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRAS MULTI -ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.

DOI: https://doi.org/10.1101/2025.02.17.638725
Cell. 2025 Feb 21. pii: S0092-8674(25)00108-4. [Epub ahead of print]

The International Space Station has a unique and extreme microbial and chemical environment driven by use patterns.

Rodolfo A Salido, Haoqi Nina Zhao, Daniel McDonald, Helena Mannochio-Russo, Simone Zuffa, Renee E Oles, Allegra T Aron, Yasin El Abiead, Sawyer Farmer, Antonio González, Cameron Martino, Ipsita Mohanty, Ceth W Parker, Lucas Patel, Paulo Wender Portal Gomes, Robin Schmid, Tara Schwartz, Jennifer Zhu, Michael R Barratt, Kathleen H Rubins, Hiutung Chu, Fathi Karouia, Kasthuri Venkateswaran, Pieter C Dorrestein, Rob Knight.

  Space habitation provides unique challenges in built environments isolated from Earth. We produced a 3D map of the microbes and metabolites throughout the United States Orbital Segment (USOS) of the International Space Station (ISS) with 803 samples collected during space flight, including controls. We find that the use of each of the nine sampled modules within the ISS strongly drives the microbiology and chemistry of the habitat. Relating the microbiology to other Earth habitats, we find that, as with human microbiota, built environment microbiota also align naturally along an axis of industrialization, with the ISS providing an extreme example of an industrialized environment. We demonstrate the utility of culture-independent sequencing for microbial risk monitoring, especially as the location of sequencing moves to space. The resulting resource of chemistry and microbiology in the space-built environment will guide long-term efforts to maintain human health in space for longer durations.

Keywords:  3D mapping; International Space Station; built environment; culture independent; extraterrestrial habitat; indoor environment; metabolome; metabolomics; microbiome; surface swab

DOI:  https://doi.org/10.1016/j.cell.2025.01.039
Biomaterials. 2025 Feb 25. pii: S0142-9612(25)00128-0. [Epub ahead of print]320 123209

Mechanical confinement triggers spreading and migration of immobile cells by deforming nucleus.

Ran Rao, Haoxiang Yang, Kailong Qiu, Min Xu, Hao Liu, Jinghao Shen, Weihao Wang, Runjie Nie, Huan Chen, Hongyuan Jiang.

  Cells in vivo are often subject to the challenge of spatial confinement from neighboring cells and extracellular matrix (ECM) that are usually adhesive and deformable. Here, we showed that confinement makes initially quiescent round cells on soft adhesive substrates spread and migrate, exhibiting a phenotype similar to that of cells on unconfined stiff substrates. Interestingly, the confinement-induced cell spreading and migration exist widely in many cell types, and depend on formins, cell contractility and endonuclear YAP-TEAD interaction. Finally, we demonstrated the nucleus is a mechanosensor independent of ECM rigidity, and its flattening alone is sufficient to trigger YAP nuclear translocation, assembly of focal adhesions and stress fibers, cell spreading and migration. Thus, our findings revealed a new inside-out mechanism through which the nucleus directly detects and responds to external mechanical confinement, and could have important implications for cell migration in crowded micro-environments during cancer metastasis, wound healing and embryonic development.

Keywords:  Cell spreading; Inside-out mechanism; Mechanical confinement; Mechanosensor; Migration; Nucleus

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123209
Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00001-4. [Epub ahead of print]37(3): 723-741.e6

A cellular and molecular basis of leptin resistance.

Bowen Tan, Kristina Hedbacker, Leah Kelly, Zhaoyue Zhang, Alexandre Moura-Assis, Ji-Dung Luo, Joshua D Rabinowitz, Jeffrey M Friedman.

  Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin's actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.

Keywords:  POMC; diet-induced obesity; leptin; leptin resistance; mTOR; rapamycin

DOI:  https://doi.org/10.1016/j.cmet.2025.01.001
Phys Rev Lett. 2025 Feb 14. 134(6): 068401

Contractility-Driven Cell Motility against a Viscoelastic Resistance.

Tapas Singha, Pierre Sens.

We study a model of contraction-based cell motility inside a microchannel to investigate the regulation of cell polarization and motion by the mechanical resistance of the environment. A positive feedback between the asymmetry of the acto-myosin cortex density and cell motion gives rise to spontaneous symmetry breaking and motility beyond a threshold contractility that depends on the resistance of extracellular medium. In highly viscous environments, we predict bistability under moderate contractility, so that symmetry breaking needs to be activated. In viscoelastic environments, we find the possibility for periodic oscillations in cortex density polarization and velocity. At the boundary between viscous and viscoelastic environments, the cell may cross, bounce back, or become trapped, depending on the viscoelastic relaxation time. These results are summarized in phase diagrams obtained by combining linear stability analysis and numerical simulations.

DOI: https://doi.org/10.1103/PhysRevLett.134.068401