Table of Contents | | | | | | Diabetes mellitus—Progress and opportunities in the evolving epidemic | | E. Dale Abel, Anna L. Gloyn, Carmella Evans-Molina, Joshua J. Joseph, Shivani Misra, Utpal B. Pajvani, Judith Simcox, Katalin Susztak, Daniel J. Drucker | A comprehensive review of recent insights into the pathophysiology of type 1 and type 2 diabetes and their complications, highlighting recent advances in disease classification and the development of therapies that hold the promise to alter the course of this prevalent disorder. | |
| | Metabolic heterogeneity in humans | | Heather Christofk, Christian Metallo, Guanghui Liu, Joshua Rabinowitz, Lauren Sparks, David James | Recent advancements in technology, especially the emergence of single-cell technologies, genomic sequencing, metabolomics, and artificial intelligence, have enabled us to understand the distinct metabolic changes in different cell types, tissues, genders, disease states, ages, and populations. Six scientists whose work intersects with metabolism in various capacities tell us about their vision for human metabolic heterogeneity. | |
| | | Transforming obesity: The advancement of multi-receptor drugs | | Christine M. Kusminski, Diego Perez-Tilve, Timo D. Müller, Richard D. DiMarchi, Matthias H. Tschöp, Philipp E. Scherer | Recent advancements in obesity treatment, such as GLP-1-based polyagonists, offer significant weight reduction and beneficial effects on glycemia, the cardiovascular system, and adipose tissue. This review article discusses the recent advancements in multi-receptor drugs for treating obesity. | |
| | A metabolic balance of GLP-1 and NMDA receptors in the brain | | Jessica T.Y. Yue, Ameth N. Garrido, Tony K.T. Lam | Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature, Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDAR receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. | |
| | Digesting the complex metabolic effects of diet on the host and microbiome | | Rachel N. Carmody, Krista Varady, Peter J. Turnbaugh | The past half-century has delivered unprecedented insights into diet and its complex role in shaping the risk and treatment of metabolic disease. This Review discusses conceptual advances in molecular nutrition targeting the management of energy balance, including emerging dietary and pharmaceutical interventions and their interactions with the gut microbiome. | |
| | | Translating metabolic and cardiovascular research into effective treatments: What’s next? | | Juleen R. Zierath, Jolanda van der Velden, Ali Javaheri, Anthony Rosenzweig, Deborah M. Muoio, Erin E. Mulvihill, Tami A. Martino, Adil Rasheed, Xiao-Wei Chen, Zoltan P. Arany | The future of healthcare for cardiovascular diseases holds immense promise, not only based in new discoveries in cardiac metabolism but also in translating them to solutions for critical challenges faced by society. Here, ten scientists share their insights, shedding light on the future that lies ahead for this field. | |
| | | “Boosting” tumor immunity in elderly mice by hyperactivating dendritic cells | | Jiaqi Liu, Feng Shao | Immunosenescence poses a significant challenge to tumor immunotherapy in elderly individuals. In this issue of Cell, Zhivaki et al. elucidate that dendritic cells “hyperactivated” by specific adjuvants elicit TH1-skewed CD4+ T cell responses in a manner contingent on the NLRP3 inflammasome, which can eliminate tumors in aged mice. | |
| | | Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors | | Dania Zhivaki, Stephanie N. Kennedy, Josh Park, Francesco Boriello, Pascal Devant, Anh Cao, Kristin M. Bahleda, Shane Murphy, Cristin McCabe, Charles L. Evavold, Kate L. Chapman, Ivan Zanoni, Orr Ashenberg, Ramnik J. Xavier, Jonathan C. Kagan | Adjuvants known as hyperactivators can correct age-associated defects in dendritic cells, enabling anti-tumor T cell responses in old and young mice. The protective immunity elicited by hyperactive dendritic cells is driven by CD8+ T cells in young mice but directed by cytolytic CD4+ T cells in elderly mice. | |
| | The rate and nature of mitochondrial DNA mutations in human pedigrees | | Erla R. Árnadóttir, Kristján H.S. Moore, Valdís B. Guðmundsdóttir, S. Sunna Ebenesersdóttir, Kamran Guity, Hákon Jónsson, Kári Stefánsson, Agnar Helgason | This large-scale pedigree study of human mtDNA mutations reveals substantial selection against deleterious variants both before and after birth, characterizes extensive differences in mutability by position and allele, and shows that children only inherit around 3 units of mtDNA from their mothers. | |
| | Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony | | Matthias Eder, Olivier M.F. Martin, Natasha Oswal, Lucia Sedlackova, Cátia Moutinho, Andrea Del Carmen-Fabregat, Simon Menendez Bravo, Arnau Sebé-Pedrós, Holger Heyn, Nicholas Stroustrup | A multi-scale measurement and perturbation approach reveals intrinsic biological sources of inter-individual heterogeneity in gene expression, health, and lifespan. | |
| | Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale | | Ruiwen Zhang, Zhou He, Yajing Shi, Xiangkun Sun, Xinyu Chen, Guoquan Wang, Yizhou Zhang, Pan Gao, Ying Wu, Shuhan Lu, Junyi Duan, Shangwu Sun, Na Yang, Wei Fan, Kaitao Zhao, Bei Yang, Yuchen Xia, Yan Zhang, Ying Zhang, Hao Yin | AE is a genome editing tool that can efficiently and precisely engineer the chromosomal structure through duplication, expanding the landscape of precision genome editing from single genetic locus to the chromosomal scale. | |
| | Open-ST: High-resolution spatial transcriptomics in 3D | | Marie Schott, Daniel León-Periñán, Elena Splendiani, Leon Strenger, Jan Robin Licha, Tancredi Massimo Pentimalli, Simon Schallenberg, Jonathan Alles, Sarah Samut Tagliaferro, Anastasiya Boltengagen, Sebastian Ehrig, Stefano Abbiati, Steffen Dommerich, Massimiliano Pagani, Elisabetta Ferretti, Giuseppe Macino, Nikos Karaiskos, Nikolaus Rajewsky | | Open Access | Open-ST is an end-to-end experimental and computational workflow for do-it-yourself subcellular spatial transcriptomics in 2D or 3D at low cost. | |
| | Ring-shaped odor coding in the antennal lobe of migratory locusts | | Xingcong Jiang, Eleftherios Dimitriou, Veit Grabe, Ruo Sun, Hetan Chang, Yifu Zhang, Jonathan Gershenzon, Jürgen Rybak, Bill S. Hansson, Silke Sachse | | Open Access | Migratory locusts, genetically expressing the calcium sensor GCaMP6s in olfactory sensory neurons, have an unconventional, ring-shaped olfactory code of glomerular clusters in the antennal lobe, a pattern that occurs consistently throughout development. | |
| | | The primitive endoderm supports lineage plasticity to enable regulative development | | Madeleine Linneberg-Agerholm, Annika Charlotte Sell, Alba Redó-Riveiro, Marta Perera, Martin Proks, Teresa E. Knudsen, Antonio Barral, Miguel Manzanares, Joshua M. Brickman | | Open Access | Although generally considered a simple support tissue, extra-embryonic primitive endoderm has the capacity to regenerate a complete blastocyst and continue post-implantation development. | |
| | TERT activation targets DNA methylation and multiple aging hallmarks | | Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D. Lan, Shan Jiang, Kayla Nutsch, Brittney A. Beyer, Luke L. Lairson, Adam T. Boutin, Michael J. Bollong, Peter G. Schultz, Ronald A. DePinho | This study identifies a small molecule (TAC) that restores physiological levels of TERT throughout aged tissues, resulting in the rejuvenation of multiple tissues. Specifically, TAC administration in very aged mice alleviates multiple aging hallmarks such as cellular senescence and systemic inflammation, promotes new neuron formation with improved cognitive ability, enhances neuromuscular function, and is well tolerated with no evidence of toxicity. | |
| | STING orchestrates the neuronal inflammatory stress response in multiple sclerosis | | Marcel S. Woo, Christina Mayer, Lars Binkle-Ladisch, Jana K. Sonner, Sina C. Rosenkranz, Artem Shaposhnykov, Nicola Rothammer, Volodymyr Tsvilovskyy, Svenja M. Lorenz, Lukas Raich, Lukas C. Bal, Vanessa Vieira, Ingrid Wagner, Simone Bauer, Markus Glatzel, Marcus Conrad, Doron Merkler, Marc Freichel, Manuel A. Friese | | Open Access | Inflammation and glutamate excitotoxicity are the major drivers of neuronal cell death in multiple sclerosis (MS). This study identifies neuronal STING as a central regulator of inflammation-induced neurodegeneration by integrating (1) interferon and (2) glutamate-evoked intracellular calcium signaling to induce ferroptotic cell death, offering a target for treating MS-related neurodegeneration. | |
| | NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation | | Balamurugan Sundaram, Nagakannan Pandian, Hee Jin Kim, Hadia M. Abdelaal, Raghvendra Mall, Omkar Indari, Roman Sarkar, Rebecca E. Tweedell, Emily Q. Alonzo, Jonathon Klein, Shondra M. Pruett-Miller, Peter Vogel, Thirumala-Devi Kanneganti | | Open Access | NLRC5 is an innate immune sensor that drives inflammatory cell death in response to NAD+ depletion. NLRC5 interacts with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms in mammalian cells, similar to those in plants. NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target. | |
| | Therapeutic potential of co-signaling receptor modulation in hepatitis B | | Francesco Andreata, Chiara Laura, Micol Ravà, Caroline C. Krueger, Xenia Ficht, Keigo Kawashima, Cristian G. Beccaria, Federica Moalli, Bianca Partini, Valeria Fumagalli, Giulia Nosetto, Pietro Di Lucia, Ilaria Montali, José M. Garcia-Manteiga, Elisa B. Bono, Leonardo Giustini, Chiara Perucchini, Valentina Venzin, Serena Ranucci, Donato Inverso, Marco De Giovanni, Marco Genua, Renato Ostuni, Enrico Lugli, Masanori Isogawa, Carlo Ferrari, Carolina Boni, Paola Fisicaro, Luca G. Guidotti, Matteo Iannacone | | Open Access | In this study, we traced the trajectory and fate of dysfunctional HBV-specific CD8+ T cells and analyzed the modulation of co-signaling receptors following hepatocellular priming. We identified 4-1BB agonism as the most promising strategy to convert these cells into antiviral effectors for treating chronic HBV infections. | |
| | A metabolomics pipeline highlights microbial metabolism in bloodstream infections | | Jared R. Mayers, Jack Varon, Ruixuan R. Zhou, Martin Daniel-Ivad, Courtney Beaulieu, Amrisha Bhosle, Nathaniel R. Glasser, Franziska M. Lichtenauer, Julie Ng, Mayra Pinilla Vera, Curtis Huttenhower, Mark A. Perrella, Clary B. Clish, Sihai D. Zhao, Rebecca M. Baron, Emily P. Balskus | | Open Access | An iterative, comparative metabolomics pipeline identifies microbial-specific, targetable metabolic pathways that are active during bloodstream infection (BSI). | |
| | | An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms | | Thomas M. Hart, Nicole D. Sonnert, Xiaotian Tang, Reetika Chaurasia, Paige E. Allen, Jason R. Hunt, Curtis B. Read, Emily E. Johnson, Gunjan Arora, Yile Dai, Yingjun Cui, Yu-Min Chuang, Qian Yu, M. Sayeedur Rahman, M. Tays Mendes, Agustin Rolandelli, Pallavi Singh, Abhai K. Tripathi, Choukri Ben Mamoun, Melissa J. Caimano, Justin D. Radolf, Yi-Pin Lin, Volker Fingerle, Gabriele Margos, Utpal Pal, Raymond M. Johnson, Joao H.F. Pedra, Abdu F. Azad, Jeanne Salje, George Dimopoulos, Joseph M. Vinetz, Jason A. Carlyon, Noah W. Palm, Erol Fikrig, Aaron M. Ring | A curated yeast display library expressing 3,324 human extracellular and secreted proteins was probed with 82 diverse pathogen samples, resulting in a foundational database of 1,303 putative interactions that sheds light on potential mechanisms of pathogenesis. |
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