Am J Primatol. 2025 Jan;87(1):e23723. doi: 10.1002/ajp.23723.

ABSTRACT

It is under debate whether intersubjectivity-the capacity to experience a sense of togetherness around an action-is unique to humans. In humans, heavy tickling-a repeated body probing play that causes an automatic response including uncontrollable laughter (gargalesis)-has been linked to the emergence of intersubjectivity as it is aimed at making others laugh (self-generated responses are inhibited), it is often asymmetrical (older to younger subjects), and it elicits agent-dependent responses (pleasant/unpleasant depending on social bond). Intraspecific tickling and the related gargalesis response have been reported in humans, chimpanzees, and anecdotally in other great apes, potentially setting the line between hominids and other anthropoids. Here we investigated this phenomenon in bonobos and predicted that in this species (sharing with humans and chimpanzees the last common ancestor) the presence of tickling would be modulated depending on the players' age, play session initiators, and familiarity. In April-June 2018, we collected videos on play sessions-including tickling-on a bonobo group housed at La Vallée des Singes (France). We showed that tickling received decreased while tickling performed increased with age, with tickling being mostly directed from older to younger individuals. Moreover, tickling was mostly performed by the individuals that started the play interaction and most of it occurred in strongly bonded dyads, particularly mother-infant ones. Bonobo tickling features, especially age profile and social modulation, mirror those of heavy tickling in humans thus suggesting a common evolutionary origin and shared patterns of basic intersubjectivity in hominins.

PMID:39812349 | DOI:10.1002/ajp.23723

J Med Virol. 2025 Jan;97(1):e70130. doi: 10.1002/jmv.70130.

ABSTRACT

We investigated whether antibody concentrations measured in plasma using the Roche Elecsys® Anti-SARS-CoV-2 S assay (targeting the receptor binding domain, RBD) could estimate levels of Wuhan-Hu-1 and Omicron XBB.1.5 spike-directed antibodies with neutralizing ability (NtAb) or those mediating NK-cell activity. We analyzed 135 plasma samples from 39 vaccinated elderly nursing home residents. A strong correlation was found for NtAb against both Wuhan-Hu-1 (Rho = 0.73, p < 0.001) and Omicron XBB.1.5 (sub)variants (Rho = 0.73, p < 0.001). Moderate positive correlations were observed for NK-cell activity, based on lysosome-associated membrane protein 1 (LAMP1)-producing NK cells stimulated with Wuhan-Hu-1 (Rho = 0.43, p < 0.001) and Omicron XBB.1.5 spike proteins (Rho = 0.50, p < 0.001). Similarly, interferon-gamma (IFN-γ)-producing NK-cell frequencies showed moderate correlations (Wuhan-Hu-1: Rho = 0.43, p < 0.001; Omicron XBB.1.5: Rho = 0.50, p < 0.001). Random Forest models accurately predicted NtAb levels against Wuhan-Hu-1 (R2 = 0.72), though models for Omicron XBB.1.5 were less robust. Anti-RBD antibody concentrations of 4.73 and 5.02 log10 BAU/mL predicted high NtAb levels for Wuhan-Hu-1 and Omicron XBB.1.5, respectively. Antibody thresholds for predicting functional NK cell-mediated responses were 4.73 log10 and 4.54 log10 BAU/mL for Wuhan-Hu-1 and Omicron XBB.1.5, respectively. For LAMP1-producing NK cells, the thresholds were 4.94 and 4.75 log10 BAU/mL for Wuhan-Hu-1 and Omicron XBB.1.5, respectively. In summary, total anti-RBD antibody levels measured by the Roche assay may allow inference of NtAb levels and, to a lesser extent, Fc-mediated NK-cell responses against Omicron XBB.1.5.

PMID:39812228 | DOI:10.1002/jmv.70130

iScience. 2024 Dec 10;28(1):111569. doi: 10.1016/j.isci.2024.111569. eCollection 2025 Jan 17.

ABSTRACT

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist. Treatment with GVAX and anti-PD-1 led to increased CD8+ T cell activation and expression of cytoskeletal and extracellular matrix (ECM)-interacting components. Addition of CD137 agonist increased abundance of clonally expanded CD8+ T cells and increased immunosuppressive TREM2 signaling in tumor associated macrophages (TAMs), identified by comparison of ligand-receptor networks, corresponding to changes in metabolism and ECM interactions. These findings associate therapy with GVAX, anti-PD1, and CD137 agonist with enhanced CD8+ T cell function while inducing alternative immunosuppressive pathways in patients with PDAC.

PMID:39811671 | PMC:PMC11730579 | DOI:10.1016/j.isci.2024.111569

iScience. 2024 Dec 9;28(1):111521. doi: 10.1016/j.isci.2024.111521. eCollection 2025 Jan 17.

ABSTRACT

Cellular fitness depends on multiple phenotypes that must be balanced during evolutionary adaptation. For instance, coordinating growth and motility is critical for microbial colonization and cancer invasiveness. In bacteria, these phenotypes are controlled by local regulators that target single operons, as well as by global regulators that impact hundreds of genes. However, how the different levels of regulation interact during evolution is unclear. Here, we measured in Escherichia coli how CRISPR-mediated knockdowns of global and local transcription factors impact growth and motility in three environments. We found that local regulators mostly modulate motility, whereas global regulators jointly modulate growth and motility. Simulated evolutionary trajectories indicate that local regulators are typically altered first to improve motility before global regulators adjust growth and motility following their trade-off. These findings highlight the role of pleiotropic regulators in the adaptation of multiple phenotypes.

PMID:39811663 | PMC:PMC11731283 | DOI:10.1016/j.isci.2024.111521

iScience. 2024 Dec 9;28(1):111549. doi: 10.1016/j.isci.2024.111549. eCollection 2025 Jan 17.

ABSTRACT

Glial-vascular interactions are critical for the formation and maintenance of brain blood vessels and the blood-brain barrier (BBB) in mammals, but their role in the zebrafish BBB remains unclear. Using three glial gene promoters-gfap, glast, and glastini (a truncated glast)-we explored glial-vascular development in zebrafish. Sparse labeling showed fewer glial-vascular interactions at early stages, with glial coverage and contact area increasing with age. Stable transgenic lines for glast and glastini revealed similar developmental increases, starting at ∼30% coverage at 3 days post-fertilization (dpf) and peaking at ∼60% by 10 dpf, and consistently higher glial coverage in the forebrain and midbrain than in the hindbrain. Electron microscopy analyses showed similar progressive increases in glial-vascular interactions, with maximal coverage of ∼70% in adults-significantly lower than the ∼100% seen in mammals. These findings define the temporal and regional maturation of glial-vascular interactions in zebrafish and highlight differences from mammalian systems.

PMID:39811646 | PMC:PMC11731618 | DOI:10.1016/j.isci.2024.111549

ERJ Open Res. 2025 Jan 13;11(1):00486-2024. doi: 10.1183/23120541.00486-2024. eCollection 2025 Jan.

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease without effective non-invasive diagnostic and prognostic testing. It remains unclear whether vasodilators reverse inflammatory activation, a part of PAH pathogenesis. Single-cell profiling of inflammatory cells in blood could clarify these PAH mechanisms.

METHODS: We evaluated a University of Pittsburgh Medical Center cohort consisting of idiopathic PAH (iPAH) and systemic sclerosis-associated PAH (sscPAH) patients and non-PAH controls. We performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from controls (n=3) and from PAH patients (iPAH and sscPAH) naïve to treatment (n=4), PAH patients 3 months after phosphodiesterase-5 inhibitor (PDE5i) treatment (n=7) and PAH patients 3 months after PDE5i+macitentan treatment (n=6). We compared the transcriptomes of five PBMC subtypes from iPAH and sscPAH to observe their serial responses to treatments. Furthermore, we utilised network analysis to illuminate the altered connectivity of biological networks in this complex disease.

RESULTS: We defined differential gene expression and perturbed network connectivity in PBMCs of PAH patients following treatment with PDE5i or PDE5i+macitentan. Importantly, we identified significant reversal of inflammatory transcripts and pathways in the combined PAH patient cohort after vasodilator therapy in every PBMC type assessed. The "glucagon signalling in metabolic regulation" pathway in monocytes was reversed after vasodilator therapy via two independent analysis modalities.

CONCLUSION: Via a systems-biology approach, we define inflammatory reprogramming in the blood of PAH patients and the anti-inflammatory activity of vasodilators. Such findings establish diagnostic and prognostic blood-based tools for tracking inflammatory progression of PAH and response to therapy.

PMID:39811555 | PMC:PMC11726584 | DOI:10.1183/23120541.00486-2024

Cell Prolif. 2025 Jan 14:e13772. doi: 10.1111/cpr.13772. Online ahead of print.

ABSTRACT

Due to the similarity to human hepatocytes, porcine hepatocytes play an important role in hepatic research and drug evaluation. However, once hepatocytes were cultured in vitro, it was often prone to dedifferentiate, resulting in the loss of their characteristic features and normal functions, which impede their application in liver transplantation and hepatotoxic drugs evaluation. Up to now, this process has yet to be thoroughly investigated from the single-cell resolution and multi-omics perspective. In this study, we utilized 10× multiome technology to dissect the heterogeneity of porcine hepatocytes at different time points (Days 0, 1, 3, 5 and 7) during dedifferentiation. We comprehensively investigated cell heterogeneity, cellular dynamics, signalling pathways, potential gene targets, enhancer-driven gene regulatory networks, cell-cell communications of these cells and the conservation of mechanisms across species. We found that a series of critical signalling pathways driven by ERK, PI3K, Src and TGF-β were activated during this process, especially in the early stage of dedifferentiation. Based on these discoveries, we constructed a chemical combination targeting these pathways, which effectively inhibited the dedifferentiation of porcine hepatocytes in vitro. To validate the effectiveness of this combination, we transplanted such treated hepatocytes into FRGN mice, and the results demonstrated that these cells could effectively repopulate the liver and improve the survival of mice.

PMID:39810466 | DOI:10.1111/cpr.13772

Environ Sci Technol. 2025 Jan 14. doi: 10.1021/acs.est.4c10242. Online ahead of print.

ABSTRACT

Plants can recruit microorganisms to enhance soil arsenic (As) removal and nitrogen (N) turnover, but how microbial As methylation in the rhizosphere is affected by N biotransformation is not well understood. Here, we used acetylene reduction assay, arsM gene amplicon, and metagenome sequencing to evaluate the influence of N biotransformation on As methylation in the rhizosphere of Vetiveria zizanioides, a potential As hyperaccumulator. V. zizanioides was grown in mining soils (MS) and artificial As-contaminated soils (AS) over two generations in a controlled pot experiment. Results showed that the content of dimethylarsinic acid in the rhizosphere was significantly positively correlated with the rate of N fixation and the activity of nitrite reductase. The As-methylating species (e.g., Flavisolibacter and Paraflavitalea) were significantly enriched in the root-associated compartments in the second generation of MS and AS. Notably, higher abundance of genes involved in N fixation (nifD, nifK) and dissimilatory nitrate reduction to ammonium (narG/H, nirB/D/K/S) was detected in the second generation of MS than in the first generation. The metabolic pathway analysis further demonstrated that N fixing-stimulative and DNRA-stimulative As-methylating species could provide ammonium to enhance the synthesis of S-adenosyl-l-methionine, serving as methyl donors for soil As methylation. This study highlights two important N conversion-stimulative As-methylating pathways and has important implications for enhancing phytoremediation in As-contaminated soils.

PMID:39810418 | DOI:10.1021/acs.est.4c10242

Genome Biol. 2025 Jan 14;26(1):9. doi: 10.1186/s13059-024-03471-9.

ABSTRACT

BACKGROUND: Streptomyces is a highly diverse genus known for the production of secondary or specialized metabolites with a wide range of applications in the medical and agricultural industries. Several thousand complete or nearly complete Streptomyces genome sequences are now available, affording the opportunity to deeply investigate the biosynthetic potential within these organisms and to advance natural product discovery initiatives.

RESULTS: We perform pangenome analysis on 2371 Streptomyces genomes, including approximately 1200 complete assemblies. Employing a data-driven approach based on genome similarities, the Streptomyces genus was classified into 7 primary and 42 secondary Mash-clusters, forming the basis for comprehensive pangenome mining. A refined workflow for grouping biosynthetic gene clusters (BGCs) redefines their diversity across different Mash-clusters. This workflow also reassigns 2729 known BGC families to only 440 families, a reduction caused by inaccuracies in BGC boundary detections. When the genomic location of BGCs is included in the analysis, a conserved genomic structure, or synteny, among BGCs becomes apparent within species and Mash-clusters. This synteny suggests that vertical inheritance is a major factor in the diversification of BGCs.

CONCLUSIONS: Our analysis of a genomic dataset at a scale of thousands of genomes refines predictions of BGC diversity using Mash-clusters as a basis for pangenome analysis. The observed conservation in the order of BGCs' genomic locations shows that the BGCs are vertically inherited. The presented workflow and the in-depth analysis pave the way for large-scale pangenome investigations and enhance our understanding of the biosynthetic potential of the Streptomyces genus.

PMID:39810189 | DOI:10.1186/s13059-024-03471-9

NPJ Syst Biol Appl. 2025 Jan 14;11(1):8. doi: 10.1038/s41540-024-00480-z.

ABSTRACT

Genome-scale metabolic models (GSMM) are commonly used to identify gene deletion sets that result in growth coupling and pairing product formation with substrate utilization and can improve strain performance beyond levels typically accessible using traditional strain engineering approaches. However, sustainable feedstocks pose a challenge due to incomplete high-resolution metabolic data for non-canonical carbon sources required to curate GSMM and identify implementable designs. Here we address a four-gene deletion design in the Pseudomonas putida KT2440 strain for the lignin-derived non-sugar carbon source, p-coumarate (p-CA), that proved challenging to implement. We examine the performance of the fully implemented design for p-coumarate to glutamine, a useful biomanufacturing intermediate. In this study glutamine is then converted to indigoidine, an alternative sustainable pigment and a model heterologous product that is commonly used to colorimetrically quantify glutamine concentration. Through proteomics, promoter-variation, and growth characterization of a fully implemented gene deletion design, we provide evidence that aromatic catabolism in the completed design is rate-limited by fumarase hydratase (FUM) enzyme activity in the citrate cycle and requires careful optimization of another fumarate hydratase protein (PP_0897) expression to achieve growth and production. A double sensitivity analysis also confirmed a strict requirement for fumarate hydratase activity in the strain where all genes in the growth coupling design have been implemented. Metabolic cross-feeding experiments were used to examine the impact of complete removal of the fumarase hydratase reaction and revealed an unanticipated nutrient requirement, suggesting additional functions for this enzyme. While a complete implementation of the design was achieved, this study highlights the challenge of completely inactivating metabolic reactions encoded by under-characterized proteins, especially in the context of multi-gene edits.

PMID:39809795 | DOI:10.1038/s41540-024-00480-z

Genome Res. 2025 Jan 14. doi: 10.1101/gr.279372.124. Online ahead of print.

ABSTRACT

Following amputation, zebrafish regenerate their injured caudal fin through lineage-restricted reprogramming. Although previous studies have charted various genetic and epigenetic dimensions of this process, the intricate gene regulatory programs shared by, or unique to, different regenerating cell types remain underinvestigated. Here, we mapped the regulatory landscape of fin regeneration by applying paired snRNA-seq and snATAC-seq on uninjured and regenerating fins. This map delineates the regulatory dynamics of predominant cell populations at multiple stages of regeneration. We observe a marked increase in the accessibility of chromatin regions associated with regenerative and developmental processes at 1 dpa, followed by a gradual closure across major cell types at later stages. This pattern is distinct from that of transcriptomic dynamics, which is characterized by several waves of gene upregulation and downregulation. We identified and in vivo validated cell-type-specific and position-specific regeneration-responsive enhancers and constructed regulatory networks by cell type and stage. Our single-cell resolution transcriptomic and chromatin accessibility map across regenerative stages provides new insights into regeneration regulatory mechanisms and serves as a valuable resource for the community.

PMID:39809530 | DOI:10.1101/gr.279372.124

Bioresour Technol. 2025 Jan 12:132064. doi: 10.1016/j.biortech.2025.132064. Online ahead of print.

ABSTRACT

Pinene is a plant volatile monoterpenoid which is used in the fragrance, pesticide, and biofuel industries. Although α-pinene has been synthesized in microbial cell factories, the low synthesis efficiency has thus far limited its production. In this study, the cell growth and α-pinene production of the engineered yeast were decoupled by a dynamic regulation strategy, resulting in a 101.1-fold increase in α-pinene production compared to the control. By enhancing the mevalonate pathway and expanding the cytosolic acetyl-CoA pool, α-pinene production was further increased. Overexpression of the transporter Sge1 resulted in a redistribution of global gene transcription, leading to an increased flux of α-pinene synthesis. By optimizing the aeration flow rate in 3-L bioreactors, the α-pinene production reached 1.8 g/L, which is the highest reported α-pinene production in cell factories. Our research provides insights and fundamentals for the efficient synthesis of monoterpenoids in microbial cell factories.

PMID:39809385 | DOI:10.1016/j.biortech.2025.132064

Dev Cell. 2025 Jan 9:S1534-5807(24)00771-8. doi: 10.1016/j.devcel.2024.12.032. Online ahead of print.

ABSTRACT

Reactivation of cell division is crucial for the regeneration of damaged tissues, which is a fundamental process across all multicellular organisms. However, the mechanisms underlying the activation of cell division in plants during regeneration remain poorly understood. Here, we show that single-cell endodermal ablation generates a transient change in the local mechanical pressure on neighboring pericycle cells to activate patterned cell division that is crucial for tissue regeneration in Arabidopsis roots. Moreover, we provide strong evidence that this process relies on the phytohormone ethylene. Thus, our results highlight a previously unrecognized role of mechano-chemical control in patterned cell division during regeneration in plants.

PMID:39809282 | DOI:10.1016/j.devcel.2024.12.032

Biomed Pharmacother. 2025 Jan 13;183:117829. doi: 10.1016/j.biopha.2025.117829. Online ahead of print.

ABSTRACT

Soluble guanylate cyclase (sGC) stands as a pivotal regulatory element in intracellular signalling pathways, mediating the formation of cyclic guanosine monophosphate (cGMP) and impacting diverse physiological processes across tissues. Increased formation of reactive oxygen species (ROS) is widely recognized to modulate cGMP signalling. Indeed, oxidatively damaged, and therefore inactive sGC, contributes to poor vascular reactivity and more severe neurological damage upon stroke. However, the specific involvement of cGMP in redox signalling remains elusive. Here, we demonstrate a significant cGMP-dependent reduction of reactive oxygen and nitrogen species upon sGC activation under hypoxic conditions, independent of any potential scavenger effects. Importantly, this reduction is directly mediated by downregulating NADPH oxidase (NOX) 4 and 5 during reperfusion. Using an in silico simulation approach, we propose a mechanistic link between increased cGMP signalling and reduced ROS formation, pinpointing NF-κB1 and RELA/p65 as key transcription factors regulating NOX4/5 expression. In vitro studies revealed that p65 translocation to the nucleus was reduced in hypoxic human microvascular endothelial cells following sGC activation. Altogether, these findings unveil the intricate regulation and functional implications of sGC, providing valuable insights into its biological significance and ultimately therapeutic potential.

PMID:39809128 | DOI:10.1016/j.biopha.2025.117829

Comput Biol Med. 2025 Jan 13;186:109665. doi: 10.1016/j.compbiomed.2025.109665. Online ahead of print.

ABSTRACT

BACKGROUND: Effective drugs for tendinopathy are lacking, resulting in significant morbidity and re-tearing rate after operation. Applying systems biology to identify new applications for current pharmaceuticals can decrease the duration, expenses, and likelihood of failure associated with the development of new drugs.

METHODS: We identify tendinopathy signature genes employing a transcriptomics database encompassing 154 clinical tendon samples. We then proposed a systems biology based drug prediction strategy that encompassed multiplex transcriptional drug prediction, systematic review assessment, deep learning based efficacy prediction and Mendelian randomization (MR). Finally, we evaluated the effects of drug target using gene knockout mice.

RESULTS: We demonstrate that sirolimus is a repurposable drug for tendinopathy, supported by: 1) Sirolimus achieves top ranking in drug-gene signature-based multiplex transcriptional drug efficacy prediction, 2) Consistent evidence from systematic review substantiates the efficacy of sirolimus in the management of tendinopathy, 3) Genetic prediction indicates that plasma proteins inhibited by mTOR (the target of sirolimus) are associated with increased tendinopathy risk. The effectiveness of sirolimus is further corroborated through in vivo testing utilizing tendon tissue-specific mTOR gene knockout mice. Integrative pathway enrichment analysis suggests that mTOR inhibition can regulate heterotopic ossification-related pathways to ameliorate clinical tendinopathy.

CONCLUSIONS: Our study assimilates knowledge of system-level responses to identify potential drugs for tendinopathy, and suggests sirolimus as a viable candidate. A systems biology approach could expedite the repurposing of drugs for human diseases that do not have well-defined targets.

PMID:39809087 | DOI:10.1016/j.compbiomed.2025.109665

JCO Clin Cancer Inform. 2025 Jan;9:e2300248. doi: 10.1200/CCI.23.00248. Epub 2025 Jan 14.

ABSTRACT

PURPOSE: Perfusion modeling presents significant opportunities for imaging biomarker development in breast cancer but has historically been held back by the need for data beyond the clinical standard of care (SoC) and uncertainty in the interpretability of results. We aimed to design a perfusion model applicable to breast cancer SoC dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) series with results stable to low temporal resolution imaging, comparable with published results using full-resolution DCE-MRI, and correlative with orthogonal imaging modalities indicative of biophysical markers.

METHODS: Subsampled high-temporal-resolution DCE-MRI series were run through our perfusion model and resulting fits were compared for consistency. The fits were also compared against previously published results from institutions using the full resolution series. The model was then evaluated on a separate cohort for validity of biomarker indications. Finally, the model was used as a fundamental part of predicting response to neoadjuvant chemotherapy (NACT).

RESULTS: Temporally subsampled DCE-MRI series yield perfusion fit variations on the scale of 1% of the tumor median value when input frames are varied. Fits generated from pseudoclinical series are within the variation range seen between imaging sites (ρ = 0.55), voxel-wise. The model also demonstrates significant correlations with orthogonal positron emission tomography imaging, indicating potential for use as a biomarker proxy. Specifically, using the perfusion fits as the grounding for a biophysical simulation of response, we correctly predict the pathologic complete response status after NACT in 15 of 18 patients, for an accuracy of 0.83, with a specificity and sensitivity of 0.83 as well.

CONCLUSION: Clinical DCE-MRI data may be leveraged to provide stable perfusion fit results and indirectly interrogate the tumor microenvironment. These fits can then be used downstream for prediction of response to NACT with high accuracy.

PMID:39808751 | DOI:10.1200/CCI.23.00248

ACS Synth Biol. 2025 Jan 14. doi: 10.1021/acssynbio.4c00290. Online ahead of print.

ABSTRACT

Naturally evolved and synthetically designed forms of compartmentalization benefit encapsulated function by increasing local concentrations of substrates and protecting cargo from destabilizing environments and inhibitors. Crucial to understanding the fundamental principles of compartmentalization are experimental systems enabling the measurement of the permeability rates of small molecules. Here, we report the experimental measurement of the small-molecule permeability of a 40 nm icosahedral bacterial microcompartment shell. This was accomplished by heterologous loading of light-producing luciferase enzymes and kinetic measurement of luminescence using stopped-flow spectrophotometry. Compared to free enzyme, the luminescence signal kinetics was slower when the luciferase was encapsulated in bacterial microcompartment shells. The results indicate that substrates and products can still exchange across the shell, and modeling of the experimental data suggest that a 50× permeability rate increase occurs when shell vertices were vacant. Overall, our results suggest design considerations for the construction of heterologous bacterial microcompartment shell systems and compartmentalized function at the nanoscale.

PMID:39808735 | DOI:10.1021/acssynbio.4c00290

Proc Natl Acad Sci U S A. 2025 Jan 21;122(3):e2409724122. doi: 10.1073/pnas.2409724122. Epub 2025 Jan 14.

ABSTRACT

ADAR is highly expressed and correlated with poor prognosis in hepatocellular carcinoma (HCC), yet the role of its constitutive isoform ADARp110 in tumorigenesis remains elusive. We investigated the role of ADARp110 in HCC and underlying mechanisms using clinical samples, a hepatocyte-specific Adarp110 knock-in mouse model, and engineered cell lines. ADARp110 is overexpressed and associated with poor survival in both human and mouse HCC. It creates an immunosuppressive microenvironment by inhibiting total immune cells, particularly cytotoxic GZMB+CD8+ T cells infiltration, while augmenting Treg cells, MDSCs, and exhausted CD8+ T cells ratios. Mechanistically, ADARp110 interacts with SNRPD3 and RNPS1 to stabilize CD24 mRNA by inhibiting STAU1-mediated mRNA decay. CD24 protects HCC cells from two indispensable mechanisms: macrophage phagocytosis and oxidative stress. Genetic knockdown or monoclonal antibody treatment of CD24 inhibits ADARp110-overexpressing tumor growth. Our findings unveil different mechanisms for ADARp110 modulation of tumor immune microenvironment and identify CD24 as a promising therapeutic target for HCCs.

PMID:39808660 | DOI:10.1073/pnas.2409724122

J Clin Invest. 2025 Jan 14:e186035. doi: 10.1172/JCI186035. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present the first comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (an S6K inhibitor) in CRC cell lines and mouse- and patient-derived organoids (PDOs). Tissue microarrays from CRC patients confirmed that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of PDOs in precision medicine in metastatic CRC.

PMID:39808497 | DOI:10.1172/JCI186035

Appl Microbiol Biotechnol. 2025 Jan 14;109(1):7. doi: 10.1007/s00253-024-13402-0.

ABSTRACT

Process intensification and simplification in biopharmaceutical manufacturing have driven the exploration of advanced feeding strategies to improve culture performance and process consistency. Conventional media design strategies, however, are often constrained by the stability and solubility challenges of amino acids, particularly in large-scale applications. As a result, dipeptides have emerged as promising alternatives. Despite extensive research on amino acids, dipeptide supplementation in Chinese hamster ovary (CHO) cell-based manufacturing has received comparatively less attention. In this review, we critically analyze challenges associated with amino acids prone to instability and poor solubility (e.g., glutamine, cysteine, and tyrosine), and explore the potential of dipeptides to address these limitations. We explore the intricate mechanisms of dipeptide transport and enzymatic cleavage, highlighting how chemical properties, stereoisomerism, and competitive metabolites influence their utilization. Notably, while most dipeptides exhibit enhanced solubility, their stabilization effects and culture performance remain variable, underlining the need for rational design. To guide future innovations, we propose tailored dipeptide strategies derived for specific biomanufacturing needs by integrating multi-omics analysis, metabolic flux modeling, and artificial intelligence (AI) modeling. KEY POINTS : •Explored dipeptides as a solution to amino acid instability and poor solubility, enhancing cell culture performance. •Discussed transporter kinetics and cleavage enzymes influencing dipeptide utilization in biomanufacturing. •Suggested various design strategies for identifying appropriate dipeptide pairs to improve bioprocess efficiency.

PMID:39808320 | DOI:10.1007/s00253-024-13402-0