bims-pideca 2026-08-02 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–08–02
sixteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Protocol for PI3K inhibitor-free differentiation and maturation of human iPSC-derived arterial- and venous-like endothelial cells.
Binding of RAS to PI3Kα regulates developmental and KRASG12D-induced lymphangiogenesis.
Dual control of PIP2 drives germline/soma segregation in Drosophila.
Dermatologic Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations from the PTEN Hamartoma Tumor Syndrome Dermatology Working Group.
Palmitoylation calibrates mitochondrial transport of insulin across the endothelium in insulin resistance.
Somatic PIK3CA and PTEN mutations with endothelial PI3K/AKT/mTOR activation in RAS-negative brain arteriovenous malformations.
Vessel Organoids Reveal FOXF1 Variant-Specific Regulation of Mesoderm and Capillary Development.
Live-Cell Imaging and Single-Cell Tracking to Monitor Clonal Dynamics and Fate Transitions in Human and Murine Intestinal Organoids.
Senotypes define the diverse landscape of senescent cells.
Inference of secreted protein signaling activities in intercellular communication.
scLEMBAS: Context-Aware Modeling of Signaling Pathway Activity at Single-Cell Resolution.
CXCL12/CXCR4 Governs Lymphatic Valve Formation Through Flow Dependent AKT/FOXO1/FOXC2 Activation.
Protocol for multiplexed quantification of fluorescent biosensor FRET efficiency using barcoded cells.
Twelve quick tips for AI-assisted coding in science.
Enhanced acetate uptake and metabolism in endothelial cells promote tumour angiogenesis and immunosuppression by increasing histone acetylation.
Genomic, epigenomic and transcriptomic regulation of cellular senescence.

STAR Protoc. 2026 Jul 30. pii: S2666-1667(26)00321-7. [Epub ahead of print]7(3): 104668

Protocol for PI3K inhibitor-free differentiation and maturation of human iPSC-derived arterial- and venous-like endothelial cells.

Oliwia N Mruk, Alexandra J Musk, Ralitsa R Madsen.

  Vascular malformations caused by genetic PI3K pathway activation are highly debilitating and hard to treat. Here, we present a PI3K inhibitor-free protocol to differentiate arterial and venous endothelial cells from human induced pluripotent stem cells (iPSCs) in 2D and 3D formats. We describe steps for iPSC culture, cell seeding on a synthetic matrix, defined media preparation, magnetic-activated cell sorting, and endothelial cell maturation under shear stress. We then detail procedures for determining cell density and culture duration for robust functional phenotyping.

Keywords:  Cell Biology; Cell Differentiation; Cell culture; Cell isolation; Developmental biology; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2026.104668
Dis Model Mech. 2026 Jul 30. pii: dmm.052932. [Epub ahead of print]

Binding of RAS to PI3Kα regulates developmental and KRASG12D-induced lymphangiogenesis.

Lorenzo M Fernandes, Jeffrey Tresemer, Angelica Vallejo, Alice Yao, Joshua P Scallan, Michael T Dellinger.

  Complex lymphatic anomalies (CLAs) are rare diseases characterized by the abnormal development of lymphatic vessels. CLAs can be caused by somatic activating mutations in KRAS (e.g., KrasG12D), which stimulate MAPK and PI3K signaling. While KRAS/MAPK signaling is known to play a critical role in CLA pathogenesis, the contribution of KRAS/PI3Kα signaling remains unclear. To investigate the role of RAS-activation of PI3Kα in CLAs, we analyzed mice carrying two missense mutations in the RAS-binding domain of p110α, the catalytic subunit of PI3Kα. These two mutations block the interaction between p110α and RAS but do not affect its kinase activity. Disruption of RAS-mediated PI3Kα activation in lymphatic endothelial cells reduced lymphatic vessel branching but did not affect lymphatic valve formation. In KrasG12D mutant mice, blocking RAS activation of p110α reduced the pathological enlargement of lymphatic vessels, but failed to prevent KrasG12D-induced lymphatic valve loss. Similar results were observed following p110α deletion in KrasG12D mutant mice. Together, these findings demonstrate that KrasG12D drives distinct disease phenotypes through separate downstream pathways. KRAS/PI3Kα signaling promotes pathological lymphatic vessel enlargement, whereas KRAS/MAPK signaling disrupts lymphatic valve formation.

Keywords:  And central conducting lymphatic anomaly; Complex lymphatic anomaly; Generalized lymphatic anomaly; Gorham-Stout disease; KRAS; Kaposiform lymphangiomatosis; Lymphangiogenesis; Lymphatic malformation; PIK3CA

DOI:  https://doi.org/10.1242/dmm.052932
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2604429123

Dual control of PIP2 drives germline/soma segregation in Drosophila.

Marcus D Kilwein, Liu Yang, Robert A Marmion, Char A Wynter, Akira Nakamura, Stanislav Y Shvartsman, Elizabeth R Gavis.

  Embryonic cell fate decisions require precise spatial coordination between competing lineage determinants. In the syncytial Drosophila embryo, primordial germ cells (PGCs) and posterior endoderm are specified at the posterior pole in overlapping domains, creating a conflict between germline and somatic fates. PGC formation depends on germ granules, which locally promote production of the phospholipid PIP2 at the posterior plasma membrane. PIP2 regulates actin dynamics leading to membrane protrusions that generate PGCs. We find that the posterior endoderm determinant, the receptor tyrosine kinase (RTK) Torso, antagonizes germ granule activity by activating phosphoinositide 3-kinase (PI3K) which converts PIP2 to PIP3. PIP3 prevents PGC formation, ensuring endoderm specification. Loss of Torso or PI3K expands the posterior PIP2 domain, increasing both the number and spatial extent of PGCs. Germ granules counteract this activity through production of the E3 ubiquitin ligase Germ cell-less (Gcl), which locally eliminates Torso and prevents PI3K-mediated PIP2 depletion at the posterior pole. In gcl mutants, PIP3 accumulates at the posterior membrane and PGC formation fails, a defect that can be partially rescued by targeted posterior expression of the PIP3 phosphatase Pten. Together, these findings demonstrate that mutual antagonism between germ granules and Torso signaling generates a PIP2/PIP3 boundary in the plasma membrane that governs the earliest germline-soma fate decision. Our work reveals how opposing maternal cues can be integrated at the level of membrane phospholipids to pattern cell fate during the earliest stages of development.

Keywords:  PI3K; PIP3; RTK signaling; endoderm; primordial germ cells

DOI:  https://doi.org/10.1073/pnas.2604429123
J Am Acad Dermatol. 2026 Jul 30. pii: S0190-9622(26)03206-8. [Epub ahead of print]

Dermatologic Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations from the PTEN Hamartoma Tumor Syndrome Dermatology Working Group.

Andrew Dhawan, Sarah Baitamouni, Darren Liu, Kristin Anthony, Francesco P Salamone, Iria Neri, Cheryl Bayart, Joan Tamburro.



Keywords:  Cowden syndrome; PHTS; PTEN hamartoma tumor syndrome; benign skin lesions; dermatologic manifestations; mTOR inhibitors; melanoma; oral papillomas; skin surveillance

DOI:  https://doi.org/10.1016/j.jaad.2026.07.095
bioRxiv. 2026 Jul 20. pii: 2026.07.14.738288. [Epub ahead of print]

Palmitoylation calibrates mitochondrial transport of insulin across the endothelium in insulin resistance.

Wei Zhang, Sangeeta Adak, Qiang Zhang, Gulinu Maimaituxun, Rong Xu, Guifang Dong, Avishek Debnath, Yixuan Wang, Srikanth Singamaneni, Xiaochao Wei, Clay F Semenkovich.

Impaired insulin transport across the endothelium contributes to insulin resistance, a poorly understood condition implicated in diabetes and many other chronic diseases. Insulin has been reported to undergo non-receptor-mediated endocytosis resembling fluid-phase uptake through unclear mechanisms. Here we show in mice with diet-induced insulin resistance that endothelial-specific deletion of the depalmitoylase acyl-protein thioesterase 1 (APT1) improved glucose tolerance and insulin sensitivity without affecting chronic inflammation or capillary structure. Endothelial APT1 deficiency increased interstitial insulin levels in mice confirmed by in-situ microneedle-based sampling. In cultured human microvascular cells, APT1 inhibition enhanced cell transport of high-dose insulin independent of the insulin receptor and canonical endocytic machinery. Unexpectedly, live-cell imaging revealed insulin rapidly localizing to mitochondria prior to endolysosomal trafficking, even at physiological insulin concentrations. APT1 inhibition delayed mitochondrial discharge of insulin to lysosomes. Cyclosporin A, an immunosuppressant known to affect mitochondrial function, preserved mitochondrial insulin content and promoted insulin transport in cultured cells, and enhanced interstitial insulin delivery in mice. Proteomic analysis revealed two palmitoylated proteins, PACS1 and YTHDF2, required for APT1-mediated mitochondrial-endolysosomal trafficking of insulin. A mitochondrial insulin shuttle in endothelial cells may participate in the physiological adaptation to hyperinsulinemia and its regulation by palmitoylation suggests a novel approach to insulin resistance.

DOI: https://doi.org/10.64898/2026.07.14.738288
J Neuropathol Exp Neurol. 2026 Jul 25. pii: nlag054. [Epub ahead of print]

Somatic PIK3CA and PTEN mutations with endothelial PI3K/AKT/mTOR activation in RAS-negative brain arteriovenous malformations.

Yukiko Hata, Ryo Tanaka, Shojiro Ichimata, Satoshi Kuroda, Naoki Nishida.

  Somatic mutations affecting endothelial signaling pathways have emerged as important contributors to brain arteriovenous malformations (bAVMs). Although activating mutations in the RAS/MAPK pathway have been frequently reported, alternative molecular mechanisms remain incompletely understood. We describe 2 autopsy-confirmed bAVMs harboring somatic PIK3CA mutations, including one case with a concurrent PTEN alteration. Histologically, both lesions demonstrated typical bAVM architecture without unusual structural features. Immunohistochemical analysis revealed lesion-restricted activation of the PI3K/AKT/mTOR pathway in endothelial cells; adjacent normal vessels were negative. In contrast, ERK phosphorylation was focal and limited; targeted sequencing did not identify pathogenic RAS/MAPK mutations. These findings suggest dominant PI3K pathway activation with secondary or limited MAPK engagement. Variant allele frequencies were interpreted cautiously owing to whole-genome amplification from autopsy-derived tissue. In one case, prior Gamma Knife radiosurgery was considered to have contributed to the findings but histological features of radiation-associated vascular injury were not observed. Together, these findings support molecular heterogeneity in bAVMs and suggest that PIK3CA-driven PI3K pathway activation may contribute to vascular remodeling in RAS-negative lesions. Correlation of molecular alterations with pathway-specific endothelial activation highlights the value of integrated genetic and pathological assessment in bAVMs.

Keywords:  PI3K/AKT/mTOR pathway; PIK3CA mutation; PTEN alteration; RAS/MAPK signaling; cerebral arteriovenous malformation; endothelial activation; somatic mutation; vascular remodeling

DOI:  https://doi.org/10.1093/jnen/nlag054
bioRxiv. 2026 Jul 14. pii: 2026.07.12.737936. [Epub ahead of print]

Vessel Organoids Reveal FOXF1 Variant-Specific Regulation of Mesoderm and Capillary Development.

Nicole M Pek, Konrad Thorner, Minzhe Guo, Hayden Dennison, Tharushi Rajaguru, George Stan, Keishi Kishimoto, Robbert J Rottier, Darrell N Kotton, Aaron M Zorn, Mingxia Gu.

How allelic variants in lineage-regulating transcription factors drive diverging human developmental outcomes remains poorly understood. This is partly due to the lack of human model systems. Here, we used vessel organoids from human induced pluripotent stem cells (hiPSCs) to resolve variant-specific functions of Forkhead Box F1 (FOXF1), a critical regulator of mesoderm and vascular development. Using three patient-derived hiPSC lines harboring unique FOXF1 variants, we show that heterozygous variants cause capillary maldevelopment of varying severity. Single-nucleus multiomic analysis revealed variant-specific mechanisms - a severe variant impairs differentiation of nascent mesoderm to lateral plate mesoderm and disrupts vascular progenitor specification, while moderate variants permit mesoderm differentiation but rewire vascular progenitor states and function. Restoration of wild-type FOXF1 via lipid nanoparticle-mediated mRNA delivery rescued capillary formation in a variant- and developmental-stage-dependent manner. Together, these findings demonstrate that different variants disrupt stage-specific FOXF1 functions in human mesoderm-to-vascular development, underscoring the importance of variant-specific therapeutic strategies. HIGHLIGHTS Human vessel organoids reveal variant-specific roles of FOXF1 in mesoderm patterning and capillary development. Severe FOXF1 variant c.253T>A (p.F85I) impairs nascent mesoderm-to-lateral plate mesoderm differentiation and disrupts vascular progenitor specification. 'Moderate' FOXF1 variants differentially rewire endothelial and mural progenitor cell states and function. Lipid nanoparticle-mediated FOXF1 mRNA delivery rescues capillary formation in a variant- and developmental-stage-dependent manner.

DOI: https://doi.org/10.64898/2026.07.12.737936
J Vis Exp. 2026 Jul 10.

Live-Cell Imaging and Single-Cell Tracking to Monitor Clonal Dynamics and Fate Transitions in Human and Murine Intestinal Organoids.

Xuan Zheng, Daniel Krueger, Johan H van Es, Hans Clevers.

The intestinal epithelium undergoes rapid self-renewal through stem cell division, cell differentiation, and migration. Understanding how individual cells commit to specific fates and how clonal dynamics emerge within this tissue requires methods that capture cellular behavior in real time and at single-cell resolution. Intestinal organoids recapitulate key features of epithelial self-organization and cell-type diversity, making them a powerful system for studying these processes in a controlled setting. Here we present a protocol for long-term confocal live-cell imaging (up to 72 h) and single-cell tracking in human and murine intestinal organoids, built around two complementary reporter strategies. First, we describe the generation of mosaic organoids by combining differentially labeled cell populations, enabling single-cell resolution of membrane-localized and cytoskeletal reporters that cannot otherwise be attributed to individual cells in a dense epithelium. Second, we use cell-type-specific fate reporters (MUC2 for goblet cells and DEFA5 for Paneth cells) to monitor secretory cell type transitions in real time. The protocol covers organoid culture, mosaic organoid formation, sample preparation with strategies to minimize phototoxicity, image acquisition over several days, and semi-automated single-cell tracking using OrganoidTracker, which reconstructs cell trajectories and lineages over time. While demonstrated in intestinal organoids, this framework is readily adaptable to other epithelial organoid systems, including gastric, pancreatic, and colonic models, broadening its utility for studies of epithelial biology, homeostasis, and disease.

DOI: https://doi.org/10.3791/72058
Nat Aging. 2026 Jul 29.

Senotypes define the diverse landscape of senescent cells.

Marissa J Schafer, Nathan Basisty, Ann V Hertzel, Alexandra N Rindone, Jennifer H Elisseeff, Vidyani Suryadevara, Constantin Aliferis, Paul D Robbins, Laura J Niedernhofer, Karl N Miller, Peter D Adams, Vilas Menon, Hemali Phatnani, Joao F Passos, Birgit Schilling, Simon Melov, Nicola Neretti, Darren J Baker.

Cellular senescence was initially defined in vitro as a stable cell-cycle arrest that occurs after repeated replication, but it is now recognized as a heterogeneous state shaped by cell type, species, senescence-inducing stress, tissue microenvironment and time. To organize this complexity, we propose the term 'senotype' to classify senescent cells by their inputs, molecular features and functional effects. We outline a practical framework incorporating: (1) cell identity and context; (2) inducing mechanism; (3) temporal stage; (4) multimodal molecular and structural features; and (5) physiological or pathological functions. Experimentally defined senotypes can serve as references for interpreting tissue-derived senotypes, where parameters may be incomplete. Senotypes should be anchored in combinations of core hallmarks (that is, durable cell-cycle arrest, altered secretory profiles, macromolecular or organelle damage, disrupted homeostasis) rather than single markers. Advances in single-cell, spatial, proteomic and computational methods enable rigorous senotype characterization, improving consistency and accelerating development of targeted senotherapeutics.

DOI: https://doi.org/10.1038/s43587-026-01148-5
Nat Methods. 2026 Jul 30.

Inference of secreted protein signaling activities in intercellular communication.

Beibei Ru, Lanqi Gong, Emily Yang, Seongyong Park, George Zaki, Kenneth Aldape, Lalage Wakefield, Peng Jiang.

The human genome encodes ~1,900 secreted proteins, many of which mediate intercellular communication. Secreted proteins do not act cell-autonomously, limiting systematic approaches to characterize their functions. Here we introduce SecAct (Secreted Activity, https://secact.ccr.cancer.gov ), a computational framework that infers the signaling activities of 1,170 human secreted proteins from spatial, single-cell and bulk transcriptomic data. The inference model harnesses precomputed intercellular signaling signatures trained on 1,258 spatial transcriptomics samples spanning 37 cancer types. Transcriptomics data from antisecreted protein therapies validate SecAct's accuracy in predicting the repression of secreted protein activity following treatment. For spatial and single-cell transcriptomics data, SecAct provides interactive modules for analyzing secreted protein-mediated cell-cell communication. Applying SecAct to 54 cancer immunotherapy cohorts comprising 5,174 patients, we identified secreted proteins associated with tumor immunity. In vivo experiments validated lymphocyte antigen 86 (LY86), whose function in cancer was previously unknown, as an antitumor regulator.

DOI: https://doi.org/10.1038/s41592-026-03172-0
bioRxiv. 2026 Jul 22. pii: 2026.07.20.739670. [Epub ahead of print]

scLEMBAS: Context-Aware Modeling of Signaling Pathway Activity at Single-Cell Resolution.

Hratch M Baghdassarian, Nikolaos Meimetis, Olof Nordenstorm, Brian A Joughin, Avlant Nilsson, Douglas A Lauffenburger.

Cells sense and integrate extracellular cues through intracellular signaling networks that reshape transcription factor activity to dictate cellular responses. Signaling activity is difficult to decipher: it is non-linear, and it contains extensive feedback and crosstalk. Furthermore, the same perturbation can elicit markedly different responses depending on context (e.g., cell type, disease state, and tissue microenvironment) such that identical stimuli produce diverse responses in multicellular populations. Consequently, there is a vast combinatorial space of complex interactions and context-dependent responses that necessitate computational models. Computational models of single-cell perturbation responses are demonstrated to predict cellular responses, but are often limited in mechanistic insight. Prior knowledge networks offer a route to bridge predictive capability and interpretability. Here we present scLEMBAS, a context-aware, gray-box neural network that models signaling pathway activity at single-cell resolution while preserving mechanistic grounding. scLEMBAS encodes a prior-knowledge network of protein-protein interactions as a recurrent neural network whose learnable edge weights correspond to signaling interaction strengths. It also captures context and individual cell variance through compositional bias terms. An adversarial approach allows the model to answer a single-cell counterfactual - what a given cell's TF activity would be under a different perturbation or context - while involving mechanistic rather than simply relational information. Across two scRNA-seq datasets spanning single- and multi-perturbation settings, scLEMBAS accurately predicts out-of-distribution combinations of perturbation and context. Capturing population variance across individual cells enables the model to predict cell subtype specific perturbation responses, despite being agnostic to such labels. Beyond prediction, scLEMBAS' learned parameters are biologically interpretable: learned edge weights carry information beyond network topology and "self-prune" spurious interactions, while the categorical bias nominates proteins associated with cell-type-specific perturbation states. Overall, scLEMBAS enables quantitative dissection of how signaling pathway activity is reshaped by perturbation within specific cellular contexts.

DOI: https://doi.org/10.64898/2026.07.20.739670
bioRxiv. 2026 Jul 22. pii: 2026.07.21.739861. [Epub ahead of print]

CXCL12/CXCR4 Governs Lymphatic Valve Formation Through Flow Dependent AKT/FOXO1/FOXC2 Activation.

Long Nguyen Hoang Do, Jingjing Pang, Esteban Delgado, Liam Flynn, Hongxia Liu, Xiaolei Liu.

Background: Lymphatic valves are specialized structures within lymphatic vessels that ensure unidirectional lymph transport. Defective lymphatic valve formation is associated with lymphedema, a chronic disease characterized by impaired lymph drainage and the accumulation of protein-rich interstitial fluid. Lymphatic valves form during late embryonic stages in mice, with oscillatory shear stress implicated in regulating the molecular mechanisms which control lymphatic valve formation. However, the molecular mechanisms governing lymphatic valve formation remain incompletely understood. Although CXCR4 is regulated by shear stress in blood vessels, whether CXCL12/CXCR4 signaling regulates lymphatic valve formation and the underlying molecular mechanisms remain unknown.
Methods: To investigate the roles of CXCR4 in the regulation of lymphatic valve development, we utilized lymphatic endothelial cell (LEC)-specific Cxcr4 knockout ( Flt4CreER T2 , Cxcr4 f/f ) mice. To determine the source of CXCL12, major ligand for CXCR4 in the mesentery, we used global Cxcl12 -/-, and Cxcl12-DsRed knock-in/knockout (KIKO) reporter mice, as well as conditional Cxcl12 knockout mouse lines. To determine the molecular mechanisms by which CXCL12/CXCR4 regulates lymphatic valve development, primary human dermal LECs were exposed to oscillatory shear stress (OSS) to mimic valve-associated flow, followed by analysis of downstream signaling pathways and valve related gene expression.
Results: LEC-specific loss of CXCR4 displayed impaired lymphatic valve development. Flt4CreER T2 , Cxcr4 f/f mice showed a significant reduction in valve numbers in embryonic mesenteric lymphatic vessels. Similarly, reduced valve numbers were observed in Cxcl12-/- embryos, indicating CXCL12/CXCR4 is required for embryonic mesentery collecting lymphatic valve formation. Cxcl12-DsRed KIKO mice revealed that blood vessels, opposed to nerves, were the major source of CXCL12 in the embryonic mesentery. In align with this finding, EC-specific Cxcl12 deletion recapitulated defective valve phenotypes observed in Cxcl12 -/- embryos. Mechanistically, CXCR4 knockdown in primary human dermal LECs attenuated OSS induced phosphorylation of AKT and FOXO1, leading to increased nuclear localization of FOXO1 and reduced expression of FOXC2, an essential transcription factor governing lymphatic valve development. Consistent with these findings, lymphatic valves of LEC- Cxcr4 deficient mice exhibited increased FOXO1 nuclear localization. Importantly, pharmacological activation of AKT reduced FOXO1 nuclear accumulation and restored lymphatic valve numbers in LEC- Cxcr4 deficient mesenteric lymphatic vessels.
Conclusions: Our findings reveal CXCL12/CXCR4 signaling acts as a critical regulator of lymphatic valve development. CXCL12/CXCR4 signaling integrates into the flow dependent AKT/FOXO1/FOXC2 signaling axis to coordinate lymphatic valve development and morphogenesis. Taken together, our study uncovers a previously unknown role of CXCL12/CXCR4 signaling pathway in the regulation of lymphatic valve development. Targeting CXCL12/CXCR4/AKT/FOXO1 axis may represent a promising therapeutic strategy for improving lymphatic valve development to improve lymphatic function for the treatment of lymphedema.

DOI: https://doi.org/10.64898/2026.07.21.739861
STAR Protoc. 2026 Jul 30. pii: S2666-1667(26)00409-0. [Epub ahead of print]7(3): 104756

Protocol for multiplexed quantification of fluorescent biosensor FRET efficiency using barcoded cells.

Jhen-Wei Wu, Yichu Xu, Yun Chen, Jr-Ming Yang, Chuan-Hsiang Huang.

  Genetically encoded fluorescent biosensors frequently use Förster resonance energy transfer (FRET) between donor and acceptor fluorescent proteins (FPs) as readouts for monitoring molecular activities in live cells. Here, we present a protocol for determining FRET efficiency through the simultaneous imaging of multiple FRET biosensors alongside donor and acceptor FPs using spectrally orthogonal fluorescent cell barcodes. We describe steps for culturing and transfecting cells, acquiring and analyzing images, and calculating FRET efficiency. This approach facilitates simultaneous analysis of multiple FRET biosensors. For complete details on the use and execution of this protocol, please refer to Wu et al.1.

Keywords:  Biotechnology and bioengineering; Cell Biology; Microscopy; Single Cell

DOI:  https://doi.org/10.1016/j.xpro.2026.104756
PLoS Comput Biol. 2026 Jul;22(7): e1014428

Twelve quick tips for AI-assisted coding in science.

Eric W Bridgeford, Iain Declan Campbell, Zijiao Chen, Zhicheng Lin, Harrison Ritz, Joachim Vandekerckhove, Russell A Poldrack.

While AI coding tools have demonstrated potential to accelerate software development, their use in scientific computing raises critical questions about code quality and scientific validity. In this paper, we provide twelve practical tips for AI-assisted coding that balance the capabilities of AI with the demands of scientific and methodological rigor. We address how AI can be leveraged strategically throughout the development cycle with four key themes: problem preparation and understanding, managing context and interaction, testing and validation, and code quality assurance and iterative improvement. These principles serve to emphasize maintaining human agency in coding decisions, establishing robust validation procedures, and preserving the domain expertise essential for methodologically sound research. These tips are intended to help researchers harness AI's transformative potential for faster software development while ensuring that their code meets the standards of reliability, reproducibility, and scientific validity that research integrity demands.

DOI: https://doi.org/10.1371/journal.pcbi.1014428
Gut. 2026 Jul 31. pii: gutjnl-2026-338754. [Epub ahead of print]

Enhanced acetate uptake and metabolism in endothelial cells promote tumour angiogenesis and immunosuppression by increasing histone acetylation.

Jie-Ying Chen, Yu-Chen Ji, Chen-Hui Wu, Jun-Guang Chen, Hui-Xian Zeng, Chen Xie, Jian-Hong Fang, Shi-Mei Zhuang.

   BACKGROUND: Acetate is the metabolic precursor of acetyl-coenzyme A (CoA), fuelling histone acetylation.
OBJECTIVE: We aimed to investigate whether the acetate-acetylation axis is hijacked in tumour endothelial cells (TECs) to govern hepatocellular carcinoma (HCC) progression.
DESIGN: The endothelial acetate-acetylation axis and its impact on malignant phenotypes and anticancer therapy were systematically dissected using clinical specimens, primary endothelial cells (ECs) from HCC (tumour endothelial cells, TECs) or non-tumour liver tissues (non-tumour endothelial cells, NECs), EC lines and diverse mouse models.
RESULTS: Compared with NECs, TECs showed elevation of acetate transporter (monocarboxylate transporter 1, MCT1), metabolic enzyme ACSS2 and H3K27ac. Acetate was highly enriched within tumour and surrounding parenchyma, and correlated positively with tumour angiogenesis. Functionally, acetate or hepatoma-conditioned media increased endothelial H3K27ac and EC migration, which were attenuated by inhibiting MCT1 or ACSS2. Notably, acetate-treated ECs, but not acetate alone, drived CD8+ T cell exhaustion and regulatory T cell (Treg) expansion. In mouse hepatoma allograft models, acetate administration increased H3K27ac levels in TECs, driving angiogenesis, tumour growth and metastasis, while reducing CD8+ T cells and expanding Tregs. Mechanistically, acetate orchestrated pro-angiogenic and immunosuppressive transcriptional programmes in ECs via histone acetylation. Therapeutically, pharmacological ACSS2 inhibition, EC-targeting simACSS2-liposomes and adeno-associated virus (AAV)-TIE2-shmACSS2 all decreased H3K27ac levels in TECs, inhibited angiogenesis, increased CD8+ T cells and reduced Tregs. Crucially, ACSS2 inhibition synergised with anti-programmed cell death protein 1 (PD-1) to alleviate immunosuppression, curb angiogenesis and suppress tumour progression.
CONCLUSION: Hepatic acetate accumulation and concomitant MCT1/ACSS2 upregulation in TECs drives endothelial epigenetic remodelling, thus fuelling angiogenesis, immunosuppression and HCC progression. Targeting this metabolic-epigenetic axis represents a novel approach to potentiate HCC therapy and sensitise immunotherapy.

Keywords:  ANGIOGENESIS; CANCER IMMUNOBIOLOGY; EPIGENETICS; HEPATOCELLULAR CARCINOMA; LIVER METABOLISM

DOI:  https://doi.org/10.1136/gutjnl-2026-338754
Nat Rev Genet. 2026 Jul 29.

Genomic, epigenomic and transcriptomic regulation of cellular senescence.

Rahagir Salekeen, Tra L Kieu, Paul D Robbins, Laura J Niedernhofer, Linshan Laux.

Cellular senescence is a complex, highly regulated cell state induced by cellular damage and stress. Senescence is central to many areas of biology, with roles in tumour suppression, tissue regeneration, antiviral defence and diverse age-related pathologies. Senescence is characterized by stable cell cycle arrest, metabolic alterations, chromatin remodelling and the secretion of pro-inflammatory and tissue-modifying factors that are collectively termed the senescence-associated secretory phenotype. Recent technological advances, including new genetic models, single-cell and spatial multi-omics platforms and machine-learning approaches, promise to enable the phenotyping, tracing and manipulation of senescent cells with unprecedented precision and resolution. This Review defines our current understanding of the genetic pathways that regulate senescence induction, maintenance, propagation and heterogeneity, including the DNA damage response, non-genotoxic stress pathways, epigenetic changes and cell-cell communication. We also emphasize key challenges in distinguishing senescence from other cell fates and the need for next-generation biomarkers to capture the varied phenotypes and functions of senescent cells.

DOI: https://doi.org/10.1038/s41576-026-00982-y