bims-medica 2026-05-24 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–05–24
thirteen papers selected by
Brett Chrest, Wake Forest University

Glutamine Metabolism: Role in Cancer Cell Proliferation and Survival.
Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming.
Introduction to Cancer Metabolism.
Shaping Human Health and Nutrition Through Innovations in Spatial Metabolism.
Cholinergic Ligand-dependent Modulation of Oxidative Phosphorylation Coupling in Digitonin-permeabilized BE(2)-C Neuroblastoma Cells.
Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications.
Tools and Technologies for Studying Cancer Metabolism.
Metabolic Checkpoint CPS1 Sustains TCA Anaplerosis via Urea Cycle in IDH-Mutant Gliomas.
Enzymatic oxygen reduction dominates overpotential-driven thermogenesis in mitochondria.
Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.
Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
Simultaneous determination of acylcarnitines, fatty acids, and amino acids by 3-nitrophenylhydrazine derivatization and ultra-high performance liquid chromatography/tandem mass spectrometry.
Mitochondria-Targeting Moieties Based on N-Tethered Pyridinium Cations.

Cancer Treat Res. 2026 ;195 45-78

Glutamine Metabolism: Role in Cancer Cell Proliferation and Survival.

Aganta Chakraborty, Sanket Pramanik, Shrabasti Mullick, Rajarshi Nath, Mohini Mondal, Radheshyam Pal, Sumel Ashique, Mayukh Jana.

  Glutamine is crucial for cancer cell proliferation and survival because it fuels the TCA cycle, provides building blocks for macromolecules, and helps maintain redox balance by supporting antioxidant pathways like glutathione production. Cancer cells often become dependent on glutamine, a phenomenon known as glutaminolysis, and use it to produce energy and essential molecules for rapid growth. This metabolic addiction makes glutamine metabolism a significant target for cancer therapies. In recent years, some therapeutic drugs targeting glutamine metabolism to treat cancer have been developed. However, such drugs are not sufficiently effective. Targeting metabolic reprogramming may be an effective strategy to enhance cancer treatment efficacy. Glutamine serves as a vital nutrient for cancer cells. Inhibiting glutamine metabolism has shown promise in preventing tumor growth both in vivo and in vitro through various mechanisms.

Keywords:  Cancer microenvironment; Glutamine metabolism; Redox balance; Signaling pathways; TCA cycle; Therapeutic targets; Tumor proliferation

DOI:  https://doi.org/10.1007/978-3-032-21861-2_3
Cancer Res. 2026 May 19.

Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming.

Ericka Vélez-Bonet, Kristyn Gumpper-Fedus, Kaylin M Chasser, Zachary A Hurst, Adaliz Torres-Rosado, Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Alexus Liette, Grace Vulic, Fouad Choueiry, Huan Zhang, Andrew Gold, Jiangjiang Zhu, Sue E Knoblaugh, Stacey Culp, Jeff S Volek, Zobeida Cruz-Monserrate.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity increases the risk of PDAC through metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese PDAC using genetically engineered mouse models (GEMMs). We hypothesized that KD may also prevent obesity-associated PDAC progression by altering body composition and cancer metabolism. Therefore, male PDAC GEMMs were subjected to diet-induced obesity (DIO) using high-fat diets or maintained on a low-fat diet (LFD) for 15 weeks. Mice were then randomized to continue the initial diets or switch to a KD or matched control diet for 6 weeks. Body weight and composition, glucose tolerance, ketone levels, pancreas histology, and tissue metabolomics were assessed. Furthermore, murine pancreas-derived organoids from DIO or LFD fed GEMMs were treated with a ketone body and analyzed using untargeted metabolomics. In obese PDAC GEMMs, KD delayed cancer progression independent of weight loss, an effect not observed in non-obese LFD-fed mice. KD-mediated PDAC suppression was associated with enrichment of pancreatic metabolic pathways that support non-glucose energy production. Ketone-treated organoids recapitulated a subset of the KD-associated metabolic differences observed in vivo, suggesting a direct metabolic effect on cancer cells. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC. The diet-cancer metabolic interactions highlight potential opportunities for dietary or metabolic interventions to prevent PDAC in high-risk obese populations.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2379
Cancer Treat Res. 2026 ;195 1-20

Introduction to Cancer Metabolism.

Gomathi Mohan, Mukesh Meena, Manzer H Siddiqui, Gaurav Raturi, Pracheta Janmeda, Priya Chaudhary.

  The fact that tumor cells have a distinct metabolic phenotype from their normal equivalents is becoming more widely recognized. Tumor metabolism exhibits a complex ecological network due to the presence of multiple metabolic compartments interconnected through the transfer of catabolites. Tumor cells exhibit markedly elevated rates of metabolism for fatty acids, glutamine, acetate, hydroxybutyrate, pyruvate, lactate, and glucose compared to nontumor cells. Tumor cells can generate adenosine triphosphate (ATP) as the fundamental energy unit due to their metabolic flexibility and unpredictability, which aids in maintaining the redox balance and distributing resources to essential biosynthetic activities necessary for cell proliferation, growth, and survival. Experimental data indicate that cancer growth may be induced by metabolic cross talk between cell populations exhibiting distinct, synergistic metabolic characteristics. Thus, emphasizing the metabolic variations between tumor and normal cells presents a suitable approach for anticancer strategies. Cancer cells adapt their metabolism and influence the metabolic processes of surrounding cells within the microenvironment of the tumor to ensure their proliferation and survival. This process drives disease progression; specifically, we identify targetable metabolic weaknesses that can be intervened upon.

Keywords:  ATP; Cancer cells; Disease progression; Metabolic cross talk; Tumor metabolism

DOI:  https://doi.org/10.1007/978-3-032-21861-2_1
Annu Rev Nutr. 2026 May 19.

Shaping Human Health and Nutrition Through Innovations in Spatial Metabolism.

Craig W Vander Kooi, Matthew S Gentry, Ramon C Sun.

Spatial metabolomics has emerged as a transformative approach for understanding how metabolism is organized within tissues and how nutritional factors influence health and disease. By preserving the spatial context of metabolites within intact tissue architecture, techniques such as MALDI and DESI imaging mass spectrometry reveal metabolic heterogeneity that bulk analyses cannot capture. This review examines how spatial metabolomics advances nutrition research across multiple domains: from mapping nutrient distributions in foods to understanding how diet reshapes tissue metabolism in disease states. We highlight recent innovations, including single-cell-resolution imaging, 3D metabolome reconstruction, stable isotope tracing, and multiomics integration. Key applications demonstrate how dietary patterns drive glycogen accumulation in cancer, alter lipid zonation in fatty liver disease, and modulate brain metabolism through the gut-brain axis. These spatially resolved insights establish direct mechanistic links between nutrition, tissue metabolism, and disease pathogenesis.

DOI: https://doi.org/10.1146/annurev-nutr-062024-111053
J Vis Exp. 2026 Apr 28.

Cholinergic Ligand-dependent Modulation of Oxidative Phosphorylation Coupling in Digitonin-permeabilized BE(2)-C Neuroblastoma Cells.

Mohammad Golam Sabbir, Karin Hsiao.

The objective of this study was to assess oxidative phosphorylation (OXPHOS) function in cultured cells using defined substrate-inhibitor combinations while retaining cellular structure and cytosolic context lost in isolated mitochondrial preparations. Because intact cells are poorly permeable to several Krebs cycle intermediates, direct assessment of substrate-supported respiration through specific electron transport chain (ETC) entry points is limited. To overcome this, we applied digitonin-mediated selective plasma membrane permeabilization and performed extracellular flux analyzer-based coupling and electron flow assays in BE(2)-C neuroblastoma cells. To determine cell-type dependence, digitonin was empirically titrated in HEK293 cells and primary rat dorsal root ganglion (DRG) neurons using succinate + rotenone to isolate Complex II-IV-driven respiration. Succinate-supported respiration with Complex I inhibition showed increased Complex II-IV-driven oxygen (O₂) consumption in permeabilized compared with non-permeabilized cells, consistent with improved access of a membrane-impermeant substrate to mitochondria. In contrast, respiration supported by substrates that enter via endogenous transport pathways (e.g., pyruvate/malate) showed smaller differences between conditions. Using this platform to test muscarinic ligands, we observed agonist- versus antagonist-associated differences in O₂ consumption in the coupling assay, whereas the electron flow assay revealed minimal ligand-associated effects under the tested conditions. These findings indicate that detectable ligand effects were more prominent at the level of coupling-defined respiratory states than maximal electron transfer capacity. Overall, selective permeabilization expands substrate accessibility in cultured-cell bioenergetic assays and enables analysis of pharmacologic modulation of mitochondrial respiration.

DOI: https://doi.org/10.3791/69789
Redox Biol. 2026 May 16. pii: S2213-2317(26)00222-3. [Epub ahead of print]94 104224

Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications.

Christos Chinopoulos.

  Respiratory chain limitation is a recurrent but spatially heterogeneous state in solid tumors, driven by hypoxic subregions, electron transport chain defects, and signaling- or therapy-imposed respiratory inhibition. Restricted electron flow supports an ETC-linked MRS state characterized by accumulation of reduced electron carriers and configuration-dependent reactive oxygen species formation. This review describes how electron transport chain limitation remodels posttranslational modifications through (i) oxygen partitioning and substrate control of oxygen-dependent dioxygenases -considering that respiratory complex IV is the dominant intracellular molecular oxygen sink, thus shaping its availability for hydroxylation and demethylation reactions- and (ii) redox backpressure that shifts NAD(P)+/NAD(P)H balance, perturbs acyl-CoA and citric acid cycle metabolite pools, and rewires protonmotive force-linked matrix chemistry and thiol buffering. These constraints are predicted to remodel lysine acylations, HIF hydroxylation, histone and DNA methylation, cysteine-centered redox PTMs, phosphorylation networks, ubiquitin-dependent proteostasis, ADP-ribosylation, and lactylation. Together, these relationships support a site- and context-dependent PTM-routing state in which the position of respiratory chain limitation and the local tumor environment shape which PTM chemistries become rate-limiting, adaptive, or growth-restrictive.

Keywords:  Dioxygenases; Hypoxia; NAD(+)/NADH ratio; Reverse electron transfer; Sirtuins; Ubiquinone

DOI:  https://doi.org/10.1016/j.redox.2026.104224
Cancer Treat Res. 2026 ;195 237-247

Tools and Technologies for Studying Cancer Metabolism.

Ayush Madan, Subhajit Mandal, Soukat Chandra, Joy Das, Biplab Debnath.

  Tools for studying cancer metabolism include mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy for metabolomics, metabolic imaging (PET, MRI, MRS) for in vivo analysis, and metabolic flux analysis (MFA) with stable isotope tracers to track metabolic pathways. Other technologies involve microfluidic systems for simulating tumor environments and fluorescence-activated cell sorting (FACS)-based methods for analyzing immune cell metabolism. Multiple analytical platforms that facilitate the detection of metabolites in cells and living organisms have been utilized to study cancer metabolism. In this section, we will discuss how these techniques have contributed to the study of cancer metabolism and how they have led to advances in our understanding of metabolic reprogramming and biological phenotypes.

Keywords:  Analytical platforms; Cancer metabolism; Metabolites

DOI:  https://doi.org/10.1007/978-3-032-21861-2_12
Cancer Lett. 2026 May 21. pii: S0304-3835(26)00369-1. [Epub ahead of print] 218606

Metabolic Checkpoint CPS1 Sustains TCA Anaplerosis via Urea Cycle in IDH-Mutant Gliomas.

Hao Xu, Licheng Zhang, Minjie Fu, Hui Yang, Ruixin Wu, Jun Ma, Muyuan You, Jinsen Zhang, Kun Lv, Yonghe Wu, Dan Ye, Wei Hua.

  Isocitrate dehydrogenase-mutant (IDH-MUT) gliomas exhibit distinct metabolic profile marked by 2-hydroxyglutarate (2-HG) accumulation at the expense of α-ketoglutarate. How these tumors maintain the tricarboxylic acid (TCA) cycle, however, remained unclear. We conducted comprehensive metabolomic profiling using clinical cohorts, cell lines, and patient-derived organoids (PDOs). The metabolic dynamics of TCA and urea cycles were interrogated using stable isotope tracing with 13C-aspartate, U5-13C-15N-aspartate, 15NH4Cl and 15N-glutamate. The functional role of carbamoyl-phosphate synthase 1 (CPS1), the key enzyme of the urea cycle, was validated through inhibition experiments in vitro, in vivo and in PDO model, followed by seahorse respirometry and electron microscopy. Metabolomic profiling of two glioma cohorts consistently showed elevated urea cycle metabolites in IDH-MUT tumors. We identified CPS1 as a metabolic checkpoint sustaining TCA cycle through half urea cycle (from ammonia to arginine). Of note, CPS1 upregulation drove fumarate anaplerosis to sustain TCA flux in IDH-MUT gliomas. Thus, CPS1 inhibition not only reduced fumarate levels but also decreased oncometabolite 2-HG both in vitro and in vivo. Consistently, CPS1 inhibition impaired mitochondrial respiration and suppressed tumor growth in vitro, in vivo and in PDOs. Taken together, metabolic checkpoint CPS1 orchestrates half urea cycle to replenish the TCA cycle in IDH-MUT gliomas. Targeting CPS1 represents a promising metabolic therapeutic target for this glioma subtype.

Keywords:  CPS1; IDH mutation; glioma; metabolism; urea cycle

DOI:  https://doi.org/10.1016/j.canlet.2026.218606
Chem Sci. 2026 Mar 30.

Enzymatic oxygen reduction dominates overpotential-driven thermogenesis in mitochondria.

Nuning Anugrah Putri Namari, Mo Yan, Junji Nakamura, Kotaro Takeyasu.

Understanding how chemical energy dissipates as heat in non-equilibrium redox systems is a fundamental problem in physical chemistry. While this phenomenon is well described in electrochemical systems such as fuel cells, its role in biological enzymatic systems remains underexplored. Mitochondrial thermogenesis has long been attributed to proton leakage, which correlates with heat generation but lacks a clearly defined physical mechanism. In fact, catalytic reactions-whether occurring on inorganic electrodes or in biological enzymes-inevitably require finite overpotentials, and quantifying these losses demands a site-specific kinetic descriptor. To this end, we introduce the electron transfer frequency (ETF), directly analogous to the turnover frequency (TOF) in heterogeneous catalysis, as a means to analyze enzymatic electron-transfer processes at the single-site level. Using ETF as the central descriptor, we develop a chemistry-based framework that models intracellular heat production as the dissipation of Gibbs free energy through enzymatic overpotentials in the mitochondrial electron transport chain, analogous to Joule heat in fuel cells. By treating each respiratory complex as a resistive kinetic step and calibrating the model with experimentally measured electrochemical parameters, we estimate that 45-71% of respiration energy is dissipated as heat. Among these, complex IV alone contributes over 70% of the total dissipation, establishing it as the primary thermogenic site. This framework reproduces reported heat-to-respiration ratios across diverse cell types and demonstrates that overpotential dissipation, rather than proton leakage, represents a major and quantifiable pathway of heat generation. More broadly, it shows that analytical principles of electrocatalysis can be predictively extended to biological redox systems, establishing a common physical chemistry basis for energy dissipation in both.

DOI: https://doi.org/10.1039/d5sc06693j
Nature. 2026 May 20.

Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.

Ram P Chakrabarty, Jonathan G Van Vranken, Yuki Aoi, Taylor A Poor, Gregory S McElroy, Karthik Vasan, Shimaa H A Soliman, Marta Iwanaszko, Rogan A Grant, Benjamin C Howard, Colleen R Reczek, Anjali D Chandel, Michael Kahl, Zhaofa Xu, Kathryn A Helmin, Qiushi Jin, Dongmei Wang, Peng Gao, Jenna L E Blum, Zachary L Sebo, Feng Yue, Yongchao C Ma, Shawn M Davidson, Steven P Gygi, Samuel E Weinberg, Benjamin D Singer, SeungHye Han, Ali Shilatifard, Navdeep S Chandel.

L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria2. Thus, L-2-HG is often classified as a toxic metabolite2-5. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.

DOI: https://doi.org/10.1038/s41586-026-10564-x
Sci Immunol. 2026 May 29. 11(119): eaef0098

Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.

Sofía C Khouili, Elena Priego, Ignacio Heras-Murillo, Gillian Dunphy, Annalaura Mastrangelo, Sarai Martínez-Cano, Vanessa Nuñez, Manuel Rodrigo-Tapias, Adrián Belinchón-García, Johan Garaude, Salvador Iborra, Navdeep S Chandel, Patricia González-Rodríguez, Michel Enamorado, David Sancho.

Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD+/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD+/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD+/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD+-driven redox metabolism, and antigen cross-presentation.

DOI: https://doi.org/10.1126/sciimmunol.aef0098
J Chromatogr A. 2026 May 15. pii: S0021-9673(26)00434-6. [Epub ahead of print]1782 467105

Simultaneous determination of acylcarnitines, fatty acids, and amino acids by 3-nitrophenylhydrazine derivatization and ultra-high performance liquid chromatography/tandem mass spectrometry.

Hamidreza Ardalani, Srinivas Reddy Dannarm, Peter Spégel.

  Acylcarnitines (ACs) play a pivotal role in metabolism, most notably by facilitating the transport of fatty acids (FAs) into mitochondria for β-oxidation, a key step in cellular energy production. Dysregulation of AC, FA, and amino acid (AA) levels has been linked to various metabolic disorders, including cardiovascular diseases, neurodegenerative conditions, and cancer. Consequently, monitoring these metabolites in blood samples provides valuable insights into metabolic health and disease progression. In this study, we developed a method for the quantification of carnitine, seven ACs, fifteen FAs, and thirteen AAs in human serum using reversed-phase ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). By employing 3-nitrophenylhydrazine (3-NPH) derivatization, we achieved high detectability for ACs, with limits of detection (LODs) ranging from 0.01-0.27 ng/mL for ACs, 0.22-1.76 ng/mL for FAs and 0.17-18.25 ng/mL for AAs. Recovery rates ranged from 92-126% for ACs, 56-116% for FAs and 86-115% for AAs. Inter- and intra-day precision were below 20% for all metabolites except two FAs. This method provides a reliable and sensitive tool for the simultaneous analysis of ACs, FAs, and AAs in serum, with potential applications in clinical diagnostics and metabolic research.

Keywords:  Acylcarnitine; Amino acids; Fatty acids; LC-MS/MS; Nitrophenylhydrazine

DOI:  https://doi.org/10.1016/j.chroma.2026.467105
Angew Chem Int Ed Engl. 2026 May 20. e7158257

Mitochondria-Targeting Moieties Based on N-Tethered Pyridinium Cations.

Ivan Džajić, Natalija Trunkelj, Jernej Repas, Maša Kandušer, Lara Smrdel, Stane Pajk, Lovro Žiberna, Irena Mlinarič-Raščan, Bostjan Markelc, Tim Bozic, Masa Omerzel, Tanja Jesenko, Maja Cemazar, Katja Kološa, Bojana Žegura, Miha Virant, Matic Lozinšek, Hai M Nguyen, Joshua A Nasburg, Heike Wulff, Maxime Gueguinou, Valerije Vrček, Veronica Carpanese, Ildiko Szabo, Luis A Pardo, Tihomir Tomašič, Lucija Peterlin Mašič, Andrej Emanuel Cotman.

  Mitochondria-targeting moieties (MTMs) are molecular fragments designed to deliver covalently tethered functional cargo to mitochondria, providing a modular strategy for chemical biology tools, imaging agents, and mitochondria-targeted therapies. Phosphonium- or nitrogen cation-based MTMs are not inert vectors and exhibit intrinsic bioactivity on mitochondrial and cellular levels to various extents. Here, we systematically evaluated a panel of N+-based cations to determine how structural features influence subcellular distribution and inherent bioactivity. Live-cell imaging of fluorescent dye conjugates revealed that 3,5-diphenylpyridinium (DPPy+) exhibits cellular uptake and mitochondrial targeting comparable to the benchmark triphenylphosphonium (TPP+), whereas conjugates with unsubstituted pyridinium preferentially accumulate in lysosomes. Profiling of inert cargo derivatives showed that DPPy+ has lower intrinsic activity on mitochondrial membrane potential and oxidative phosphorylation, as well as on cellular respiration and viability than TPP+. The combination of efficient mitochondrial delivery and low intrinsic bioactivity translated to bioactive cargo: a Kv1.3 inhibitor conjugate with DPPy+ induced apoptosis in cancer cell lines and demonstrated improved cancer selectivity relative to the TPP+ conjugate in pancreatic organoid models. These results position lipophilic pyridinium cations as effective TPP+ surrogates with enhanced biocompatibility for mitochondria-targeted therapeutic and diagnostic agents, while revealing the structure-dependent competing lysosomal accumulation of permanent nitrogen cations.

Keywords:  cancer; cations; fluorescent probes; medicinal chemistry; mitochondria

DOI:  https://doi.org/10.1002/anie.7158257