bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–04–06
35 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mapping STING.
  2. Peroxisomes mediate tissue repair.
  3. Invigorating discovery and clinical translation of aging biomarkers.
  4. Collaborative genome-wide association analysis with cryptography.
  5. IFNλ drives diarrhea.
  6. Publishers trial paying peer reviewers - what did they find?
  7. Brain implant translates thoughts to speech in an instant.
  8. A toolkit for seeing how the fly brain's visual system works.
  9. Taking flight.
  10. Are screens harming teens? What scientists can do to find answers.
  11. Efficient and accurate framework for genome-wide gene-environment interaction analysis in large-scale biobanks.
  12. Pathogen infection induces sickness behaviors through neuromodulators linked to stress and satiety in C. elegans.
  13. Pathways that limit differentiation of oligodendrocyte progenitors in the aging brain.
  14. How does the brain control consciousness? This deep-brain structure.
  15. They are what they eat.
  16. Quantitative characterization of tissue states using multiomics and ecological spatial analysis.
  17. Modulation of bone marrow haematopoietic stem cell activity as a therapeutic strategy after myocardial infarction: a preclinical study.
  18. Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.
  19. Exercise-induced anti-obesity effects in male mice generated by a FOXO1-KLF10 reinforcing loop promoting adipose lipolysis.
  20. Can we talk? The cryptic communications of hepatic stellate cells in lipid metabolism.
  21. The interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease.
  22. Building immune barriers.
  23. 23andMe plans to sell its huge genetic database: could science benefit?
  24. The best foods for healthy ageing - and the worst.
  25. Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity.
  26. Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery.
  27. Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes.
  28. Could the shingles vaccine help to prevent dementia?
  29. Macrophages promote nerve growth in both tumours and spinal cord.
  30. OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.
  31. CodonTransformer: a multispecies codon optimizer using context-aware neural networks.
  32. Aberrant gene expression prediction across human tissues.
  33. Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.
  34. Cell membranes sustain phospholipid imbalance via cholesterol asymmetry.
  35. Quantitative PET imaging and modeling of molecular blood-brain barrier permeability.
  1. Nat Immunol. 2025 Apr;26(4): 528
    Mapping STING.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-025-02128-4
  2. Nat Immunol. 2025 Apr;26(4): 528
    Peroxisomes mediate tissue repair.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-025-02130-w
  3. Nat Aging. 2025 Mar 31.
    Invigorating discovery and clinical translation of aging biomarkers.
    Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev.
      
    DOI:  https://doi.org/10.1038/s43587-025-00838-w
  4. Nat Genet. 2025 Apr 01.
    Collaborative genome-wide association analysis with cryptography.
      
    DOI:  https://doi.org/10.1038/s41588-025-02110-8
  5. Nat Immunol. 2025 Apr;26(4): 528
    IFNλ drives diarrhea.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-025-02129-3
  6. Nature. 2025 Mar 28.
    Publishers trial paying peer reviewers - what did they find?
    Holly Else.
      
    Keywords:  Publishing
    DOI:  https://doi.org/10.1038/d41586-025-00968-6
  7. Nature. 2025 Mar 31.
    Brain implant translates thoughts to speech in an instant.
    Miryam Naddaf.
      
    Keywords:  Brain; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01001-6
  8. Nature. 2025 Apr 02.
    A toolkit for seeing how the fly brain's visual system works.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00885-8
  9. Science. 2025 Apr 04. 388(6742): 118
    Taking flight.
    Melanie Ortiz Alvarez De La Campa.
      
    DOI:  https://doi.org/10.1126/science.adx8088
  10. Nature. 2025 Apr;640(8057): 7-8
    Are screens harming teens? What scientists can do to find answers.
      
    Keywords:  Depression; Public health; Society
    DOI:  https://doi.org/10.1038/d41586-025-00991-7
  11. Nat Commun. 2025 Mar 29. 16(1): 3064
    Efficient and accurate framework for genome-wide gene-environment interaction analysis in large-scale biobanks.
    Yuzhuo Ma, Yanlong Zhao, Ji-Feng Zhang, Wenjian Bi.
      Gene-environment interaction (G×E) analysis elucidates the interplay between genetic and environmental factors. Genome-wide association studies (GWAS) have expanded to encompass complex traits like time-to-event and ordinal traits, which provide richer phenotypic information. However, most existing scalable approaches focus only on quantitative or binary traits. Here we propose SPAGxECCT, a scalable and accurate framework for diverse trait types. SPAGxECCT fits a genotype-independent model and employs a hybrid strategy including saddlepoint approximation (SPA) for accurate p value calculation, especially for low-frequency variants and unbalanced phenotypic distributions. We extend SPAGxECCT to SPAGxEmixCCT, which accounts for population stratification and is applicable to multi-ancestry or admixed populations. SPAGxEmixCCT can further be extended to SPAGxEmixCCT-local, which identifies ancestry-specific G×E effects using local ancestry. Through extensive simulations and real data analyses of UK Biobank data, we demonstrate that SPAGxECCT and SPAGxEmixCCT are scalable to analyze large-scale study cohort, control type I error rates effectively, and maintain power.
    DOI:  https://doi.org/10.1038/s41467-025-57887-3
  12. Nat Commun. 2025 Apr 03. 16(1): 3200
    Pathogen infection induces sickness behaviors through neuromodulators linked to stress and satiety in C. elegans.
    Sreeparna Pradhan, Gurrein K Madan, Di Kang, Eric Bueno, Adam A Atanas, Talya S Kramer, Ugur Dag, Jessica D Lage, Matthew A Gomes, Alicia Kun-Yang Lu, Jungyeon Park, Steven W Flavell.
      When animals are infected by a pathogen, peripheral sensors of infection signal to the brain to induce adaptive behavioral changes known as sickness behaviors. While the pathways that signal from the periphery to the brain have been intensively studied, how central circuits are reconfigured to elicit these behavioral changes is not well understood. Here we find that neuromodulatory systems linked to stress and satiety are recruited during chronic pathogen infection to alter the behavior of Caenorhabditis elegans. Upon infection by the bacterium Pseudomonas aeruginosa PA14, C. elegans decrease feeding, then display reversible bouts of quiescence, and eventually die. The ALA neuron and its neuropeptides FLP-7, FLP-24, and NLP-8, which control stress-induced sleep in uninfected animals, promote the PA14-induced feeding reduction. However, the ALA neuropeptide FLP-13 instead delays quiescence and death in infected animals. Cell-specific genetic perturbations show that the neurons that release FLP-13 to delay quiescence in infected animals are distinct from ALA. A brain-wide imaging screen reveals that infection-induced quiescence involves ASI and DAF-7/TGF-beta, which control satiety-induced quiescence in uninfected animals. Our results suggest that a common set of neuromodulators are recruited across different physiological states, acting from distinct neural sources and in distinct combinations to drive state-dependent behaviors.
    DOI:  https://doi.org/10.1038/s41467-025-58478-y
  13. Nat Aging. 2025 Apr 01.
    Pathways that limit differentiation of oligodendrocyte progenitors in the aging brain.
      
    DOI:  https://doi.org/10.1038/s43587-025-00848-8
  14. Nature. 2025 Apr 03.
    How does the brain control consciousness? This deep-brain structure.
    Smriti Mallapaty.
      
    Keywords:  Brain; Neuroscience; Psychology
    DOI:  https://doi.org/10.1038/d41586-025-01021-2
  15. Sci Immunol. 2025 Apr 04. 10(106): eadx7179
    They are what they eat.
    Asha Pillai.
      The viability of ingested bacterial pathogens can alter the metabolic program and cytokine secretion of macrophages.
    DOI:  https://doi.org/10.1126/sciimmunol.adx7179
  16. Nat Genet. 2025 Apr 01.
    Quantitative characterization of tissue states using multiomics and ecological spatial analysis.
    Daisy Yi Ding, Zeyu Tang, Bokai Zhu, Hongyu Ren, Alex K Shalek, Robert Tibshirani, Garry P Nolan.
      The spatial organization of cells in tissues underlies biological function, and recent advances in spatial profiling technologies have enhanced our ability to analyze such arrangements to study biological processes and disease progression. We propose MESA (multiomics and ecological spatial analysis), a framework drawing inspiration from ecological concepts to delineate functional and spatial shifts across tissue states. MESA introduces metrics to systematically quantify spatial diversity and identify hot spots, linking spatial patterns to phenotypic outcomes, including disease progression. Furthermore, MESA integrates spatial and single-cell multiomics data to facilitate an in-depth, molecular understanding of cellular neighborhoods and their spatial interactions within tissue microenvironments. Applying MESA to diverse datasets demonstrates additional insights it brings over prior methods, including newly identified spatial structures and key cell populations linked to disease states. Available as a Python package, MESA offers a versatile framework for quantitative decoding of tissue architectures in spatial omics across health and disease.
    DOI:  https://doi.org/10.1038/s41588-025-02119-z
  17. Nat Cell Biol. 2025 Apr 02.
    Modulation of bone marrow haematopoietic stem cell activity as a therapeutic strategy after myocardial infarction: a preclinical study.
    Jasmin Rettkowski, Mari Carmen Romero-Mulero, Indranil Singh, Carolin Wadle, Jan Wrobel, Diana Chiang, Natalie Hoppe, Julian Mess, Katharina Schönberger, Maria-Eleni Lalioti, Karin Jäcklein, Beatriz SilvaRego, Timon Bühler, Noémie Karabacz, Mirijam Egg, Helen Demollin, Nadine Obier, Yu Wei Zhang, Claus Jülicher, Anne Hetkamp, Martin Czerny, Michael-Jason Jones, Hana Seung, Ritika Jain, Constantin von Zur Mühlen, Alexander Maier, Achim Lother, Ingo Hilgendorf, Peter van Galen, Antonia Kreso, Dirk Westermann, Alejo E Rodriguez-Fraticelli, Timo Heidt, Nina Cabezas-Wallscheid.
      Myocardial infarction (MI) is a major global health concern. Although myeloid cells are crucial for tissue repair in emergency haematopoiesis after MI, excessive myelopoiesis can exacerbate scarring and impair cardiac function. Bone marrow (BM) haematopoietic stem cells (HSCs) have the unique capability to replenish the haematopoietic system, but their role in emergency haematopoiesis after MI has not yet been established. Here we collected human sternal BM samples from over 150 cardiac surgery patients, selecting 49 with preserved cardiac function. We show that MI causes detrimental transcriptional and functional changes in human BM HSCs. Lineage tracing experiments suggest that HSCs are contributors of pro-inflammatory myeloid cells infiltrating cardiac tissue after MI. Therapeutically, enforcing HSC quiescence with the vitamin A metabolite 4-oxo-retinoic acid dampens inflammatory myelopoiesis, thereby modulating tissue remodelling and preserving long-term cardiac function after MI.
    DOI:  https://doi.org/10.1038/s41556-025-01639-4
  18. Nat Commun. 2025 Mar 28. 16(1): 3038
    Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.
    Kuo Du, David S Umbaugh, Wang Liuyang, Ji Hye Jun, Rajesh K Dutta, Seh Hoon Oh, Niansheng Ren, Qiaojuan Zhang, Dennis C Ko, Ana Ferreira, Jon Hill, Guannan Gao, Steven S Pullen, Vaibhav Jain, Simon Gregory, Manal F Abdelmalek, Anna Mae Diehl.
      Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in male mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.
    DOI:  https://doi.org/10.1038/s41467-025-57616-w
  19. Nat Commun. 2025 Apr 01. 16(1): 3111
    Exercise-induced anti-obesity effects in male mice generated by a FOXO1-KLF10 reinforcing loop promoting adipose lipolysis.
    Jie-Ying Zhu, Min Chen, Wang-Jing Mu, Hong-Yang Luo, Yang Li, Shan Li, Lin-Jing Yan, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo.
      Exercise combats obesity and metabolic disorders, but the underlying mechanism is incompletely understood. KLF10, a transcription factor involved in various biological processes, has an undefined role in adipose tissue and obesity. Here, we show that exercise facilitates adipocyte-derived KLF10 expression via SIRT1/FOXO1 pathway. Adipocyte-specific knockout of KLF10 blunts exercise-promoted white adipose browning, energy expenditure, fat loss, glucose tolerance in diet-induced obese male mice. Conversely, adipocyte-specific transgenic expression of KLF10 in male mice enhanced the above metabolic profits induced by exercise. Mechanistically, KLF10 interacts with FOXO1 and facilitates the recruitment of KDM4A to form a ternary complex on the promoter regions of Pnpla2 and Lipe genes to promote these key lipolytic genes expression by demethylating H3K9me3 on their promoters, which facilitates lipolysis to defend against obesity in male mice. As a downstream effector responding to exercise, adipose KLF10 could act as a potential target in the fight against obesity.
    DOI:  https://doi.org/10.1038/s41467-025-58467-1
  20. Cell Metab. 2025 Apr 01. pii: S1550-4131(25)00111-1. [Epub ahead of print]37(4): 794-796
    Can we talk? The cryptic communications of hepatic stellate cells in lipid metabolism.
    Scott L Friedman.
      The contributions of signals generated by hepatic stellate cells that regulate hepatocyte lipid and glucose homeostasis are largely unexplored. The article by Hansen et al. introduces a novel role of plasmalemma vesicle-associated protein (PLVAP), a membrane protein expressed by hepatic stellate cells, in regulating these pathways in hepatocytes during fasting.
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.008
  21. Nat Genet. 2025 Apr 01.
    The interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease.
    Sílvia Vilarinho.
      
    DOI:  https://doi.org/10.1038/s41588-025-02151-z
  22. Nat Immunol. 2025 Apr;26(4): 528
    Building immune barriers.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-025-02127-5
  23. Nature. 2025 Mar 31.
    23andMe plans to sell its huge genetic database: could science benefit?
    Celeste Biever.
      
    Keywords:  Business; Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-01004-3
  24. Nature. 2025 Apr;640(8057): 11
    The best foods for healthy ageing - and the worst.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00879-6
  25. Immunity. 2025 Mar 26. pii: S1074-7613(25)00123-2. [Epub ahead of print]
    Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity.
    Motonao Osaki, Shimon Sakaguchi.
      Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation in vitro. In vivo, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.
    Keywords:  CD80; CD86; CTLA-4; M1 and M2 macrophage; Th1 and Th2 immunity; Treg cells; allergy; autoimmunity; co-stimulation; cytotoxic T-lymphocyte-associated antigen-4; eosinophil; inflammation resolution; mCTLA-4; membrane CTLA-4; regulatory T cells; sCTLA-4; soluble CTLA-4; tissue repair; tumor immunity
    DOI:  https://doi.org/10.1016/j.immuni.2025.03.004
  26. Nat Commun. 2025 Mar 31. 16(1): 3089
    Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery.
    Xiaotao Zhang, Huaming Li, Yichen Gu, An Ping, Jiarui Chen, Qia Zhang, Zhouhan Xu, Junjie Wang, Shenjie Tang, Rui Wang, Jianan Lu, Lingxiao Lu, Chenghao Jin, Ziyang Jin, Jianmin Zhang, Ligen Shi.
      Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism, and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation.
    DOI:  https://doi.org/10.1038/s41467-025-58254-y
  27. Science. 2025 Apr 04. 388(6742): 52-59
    Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes.
    Jorge Diego Martin-Rufino, Alexis Caulier, Seayoung Lee, Nicole Castano, Emily King, Samantha Joubran, Marcus Jones, Seth R Goldman, Uma P Arora, Lara Wahlster, Eric S Lander, Vijay G Sankaran.
      Most phenotype-associated genetic variants map to noncoding regulatory regions of the human genome, but their mechanisms remain elusive in most cases. We developed a highly efficient strategy, Perturb-multiome, to simultaneously profile chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of master transcription factors (TFs). We examined the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within TF-sensitive accessible chromatin regions in erythroid differentiation, although representing <0.3% of the genome, show a ~100-fold enrichment for blood cell phenotype heritability, which is substantially higher than that for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.
    DOI:  https://doi.org/10.1126/science.ads7951
  28. Nature. 2025 Apr 02.
    Could the shingles vaccine help to prevent dementia?
    Anupam B Jena.
      
    Keywords:  Alzheimer's disease; Medical research; Public health; Vaccines
    DOI:  https://doi.org/10.1038/d41586-025-00861-2
  29. Nat Rev Immunol. 2025 Mar 28.
    Macrophages promote nerve growth in both tumours and spinal cord.
    Austeja Baleviciute, Sebastien Talbot.
      
    DOI:  https://doi.org/10.1038/s41577-025-01164-3
  30. Nat Struct Mol Biol. 2025 Mar 28.
    OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.
    Hugo Sepulveda, Xiang Li, Leo J Arteaga-Vazquez, Isaac F López-Moyado, Melina Brunelli, Lot Hernández-Espinosa, Xiaojing Yue, J Carlos Angel, Caitlin Brown, Zhen Dong, Natasha Jansz, Fabio Puddu, Aurélie Modat, Jamie Scotcher, Páidí Creed, Patrick H Kennedy, Cindy Manriquez-Rodriguez, Samuel A Myers, Robert Crawford, Geoffrey J Faulkner, Anjana Rao.
      O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1-OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET-OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.
    DOI:  https://doi.org/10.1038/s41594-025-01505-9
  31. Nat Commun. 2025 Apr 03. 16(1): 3205
    CodonTransformer: a multispecies codon optimizer using context-aware neural networks.
    Adibvafa Fallahpour, Vincent Gureghian, Guillaume J Filion, Ariel B Lindner, Amir Pandi.
      Degeneracy in the genetic code allows many possible DNA sequences to encode the same protein. Optimizing codon usage within a sequence to meet organism-specific preferences faces combinatorial explosion. Nevertheless, natural sequences optimized through evolution provide a rich source of data for machine learning algorithms to explore the underlying rules. Here, we introduce CodonTransformer, a multispecies deep learning model trained on over 1 million DNA-protein pairs from 164 organisms spanning all domains of life. The model demonstrates context-awareness thanks to its Transformers architecture and to our sequence representation strategy that combines organism, amino acid, and codon encodings. CodonTransformer generates host-specific DNA sequences with natural-like codon distribution profiles and with minimum negative cis-regulatory elements. This work introduces the strategy of Shared Token Representation and Encoding with Aligned Multi-masking (STREAM) and provides a codon optimization framework with a customizable open-access model and a user-friendly Google Colab interface.
    DOI:  https://doi.org/10.1038/s41467-025-58588-7
  32. Nat Commun. 2025 Mar 29. 16(1): 3061
    Aberrant gene expression prediction across human tissues.
    Florian R Hölzlwimmer, Jonas Lindner, Georgios Tsitsiridis, Nils Wagner, Francesco Paolo Casale, Vicente A Yépez, Julien Gagneur.
      Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compile an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 49 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE show mild predictive ability (1-1.6% average precision). Leveraging these and further variant annotations, we next train AbExp, a model that yields 12% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues leads to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.
    DOI:  https://doi.org/10.1038/s41467-025-58210-w
  33. J Exp Med. 2025 Jun 02. pii: e20242282. [Epub ahead of print]222(6):
    Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.
    Miho Tanaka, Lotus Lum, Kenneth H Hu, Piyush Chaudhary, Savannah Hughes, Cecilia Ledezma-Soto, Bushra Samad, Daphne Superville, Kenneth Ng, Arun Chumber, Ciara Benson, Zoe N Adams, Kelly Kersten, Oscar A Aguilar, Lawrence Fong, Alexis J Combes, Matthew F Krummel, Melissa Q Reeves.
      Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of "hot" and "cold" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a "dominant cold" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.
    DOI:  https://doi.org/10.1084/jem.20242282
  34. Cell. 2025 Mar 26. pii: S0092-8674(25)00270-3. [Epub ahead of print]
    Cell membranes sustain phospholipid imbalance via cholesterol asymmetry.
    Milka Doktorova, Jessica L Symons, Xiaoxuan Zhang, Hong-Yin Wang, Jan Schlegel, Joseph H Lorent, Frederick A Heberle, Erdinc Sezgin, Edward Lyman, Kandice R Levental, Ilya Levental.
      Membranes are molecular interfaces that compartmentalize cells to control the flow of nutrients and information. These functions are facilitated by diverse collections of lipids, nearly all of which are distributed asymmetrically between the two bilayer leaflets. Most models of biomembrane structure and function include the implicit assumption that these leaflets have similar abundances of phospholipids. Here, we show that this assumption is generally invalid and investigate the consequences of lipid abundance imbalances in mammalian plasma membranes (PMs). Using lipidomics, we report that cytoplasmic leaflets of human erythrocyte membranes have >50% overabundance of phospholipids compared with exoplasmic leaflets. This imbalance is enabled by an asymmetric interleaflet distribution of cholesterol, which regulates cellular cholesterol homeostasis. These features produce unique functional characteristics, including low PM permeability and resting tension in the cytoplasmic leaflet that regulates protein localization.
    Keywords:  cholesterol; lipid asymmetry; lipid diffusion; membrane packing; membrane structure; peripheral protein; permeability; phospholipid; plasma membrane; protein-membrane interactions
    DOI:  https://doi.org/10.1016/j.cell.2025.02.034
  35. Nat Commun. 2025 Mar 30. 16(1): 3076
    Quantitative PET imaging and modeling of molecular blood-brain barrier permeability.
    Kevin J Chung, Yasser G Abdelhafez, Benjamin A Spencer, Terry Jones, Quyen Tran, Lorenzo Nardo, Moon S Chen, Souvik Sarkar, Valentina Medici, Victoria Lyo, Ramsey D Badawi, Simon R Cherry, Guobao Wang.
      Neuroimaging of blood-brain barrier permeability has been instrumental in identifying its broad involvement in neurological and systemic diseases. However, current methods evaluate the blood-brain barrier mainly as a structural barrier. Here we developed a non-invasive positron emission tomography method in humans to measure the blood-brain barrier permeability of molecular radiotracers that cross the blood-brain barrier through its molecule-specific transport mechanism. Our method uses high-temporal resolution dynamic imaging and kinetic modeling for multiparametric imaging and quantification of the blood-brain barrier permeability-surface area product of molecular radiotracers. We show, in humans, our method can resolve blood-brain barrier permeability across three radiotracers and demonstrate its utility in studying brain aging and brain-body interactions in metabolic dysfunction-associated steatotic liver inflammation. Our method opens new directions to effectively study the molecular permeability of the human blood-brain barrier in vivo using the large catalogue of available molecular positron emission tomography tracers.
    DOI:  https://doi.org/10.1038/s41467-025-58356-7
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