ID: 38838160
Title: Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis.
Abstract: Tissue stiffening is a predominant feature of fibrotic disorders, but the response of macrophages to changes in tissue stiffness and cellular context in fibrotic diseases remains unclear. Here, we found that the mechanosensitive ion channel Piezo1 was up-regulated in hepatic fibrosis. Macrophages lacking Piezo1 showed sustained inflammation and impaired spontaneous resolution of early liver fibrosis. Further analysis revealed an impairment of clearance of apoptotic cells by macrophages in the fibrotic liver. Macrophages showed enhanced efferocytosis when cultured on rigid substrates but not soft ones, suggesting stiffness-dependent efferocytosis of macrophages required Piezo1 activation. Besides, Piezo1 was involved in the efficient acidification of the engulfed cargo in the phagolysosomes and affected the subsequent expression of anti-inflammation genes after efferocytosis. Pharmacological activation of Piezo1 increased the efferocytosis capacity of macrophages and accelerated the resolution of inflammation and fibrosis. Our study supports the antifibrotic role of Piezo1-mediated mechanical sensation in liver fibrosis, suggesting that targeting PIEZO1 to enhance macrophage efferocytosis could induce fibrosis regression.

ID: 40429901
Title: Formation of Membrane Domains via Actin Waves: A Fundamental Principle in the Generation of Dynamic Structures in Phagocytes.
Abstract: Phagocytes carry out their functions by organizing new subcellular structures. During phagocytosis, macrophages internalize and degrade pathogens and apoptotic cells by forming the phagocytic cup and phagosome. Osteoclasts resorb bone by forming the sealing zone and ruffled border at the ventral membrane. This review explores the organizational principles of these dynamic structures. In in vitro frustrated phagocytosis, specifically 2D phagocytosis by macrophages, the activation of the Fcγ receptor generates multiple self-organized waves containing F-actin, Arp2/3, and phosphoinositides. The propagation of these circular actin waves segregates the inside from the outside, leading to the compartmentalization of the ventral membrane. As the actin wave passes, cortical actin is disrupted, and membrane remodeling occurs within the wave, creating a new membrane domain with high exocytic activity. These processes mirror the formation of the constriction zone in the phagocytic cup and phagosome during 3D phagocytosis. A similar mechanism may also contribute to the formation of the sealing zone and ruffled border in osteoclasts. Based on these observations, we propose that dynamic structures formed from actin waves are organized through the fractal integration of self-organized, oscillatory substructures, with F-actin treadmilling fueling their formation and maintenance.

ID: 40741709
Title: Depletion of endomembrane reservoirs drives phagocytic appetite exhaustion in macrophages.
Abstract: During phagocytosis, a phagocytic cup grows via F-actin remodeling and localized secretion to entrap a particle within a phagosome, which then fuses with endosomes and lysosomes to digest the particle, followed by phagosome resolution. As spatially limited systems, phagocytes have a maximal phagocytic capacity, at which point further uptake must be reduced. However, the processes responsible for phagocytic appetite exhaustion as phagocytes reach their maximal phagocytic capacity are poorly defined. We found that macrophages at their capacity have lower surface levels of Fcγ receptors but overexpression of these receptors did not increase their capacity, suggesting that receptor levels are not limiting. We found that surface membrane in-folding, membrane tension and cortical F-actin were all reduced in exhausted macrophages. Although this might contribute to appetite suppression, we also found that 'free' endosomes and lysosomes were severely depleted in exhausted macrophages. Consequently, focal exocytosis at sites of externally bound particles was reduced. In comparison, macrophages recovered their appetite if phagosome resolution was permitted. We propose that depletion of the endomembrane pools is a major determinant of phagocytic fatigue as macrophages reach their phagocytic capacity.

ID: 41071099
Title: Mechanosensitive ion channels as novel targets in osteoporosis.
Abstract: Osteoporosis is the most prevalent metabolic bone disease globally, leading to an increased risk of fractures. Recent advances in ion channel research have shed light on the importance of mechanosensitive ion channels as novel players in these pathophysiological processes. This perspective discusses the involvement of the mechanosensitive ion channels TREK-1, Piezo, and volume-regulated anion channels (VRACs) as potential novel pharmacological targets for the treatment of osteoporosis. TREK-1, a mechanosensitive K2P channel is important for maintaining the resting membrane potential in many cells, including osteoblasts and osteoclasts. K2P channels regulate osteoblast proliferation and differentiation, as well as osteoclast activity, potentially modulating bone remodeling in osteoporosis. Piezo channels influence osteoblast differentiation and osteoclast activity by modulating calcium influx, which is crucial for osteogenic signaling pathways, such as Wnt/β-catenin and ERK1/2. Piezo1 activation promotes bone formation, while its deficiency leads to impaired osteogenesis and increased bone resorption. Volume-regulated anion channels have been shown to be involved in osteoblast adaptation to mechanical stress and macrophage polarization, which indicates their importance for bone homeostasis. Chronic inflammation is a major contributor to osteoporosis progression. Evidence of ion channel involvement in this process has emerged in recent years. Specifically, macrophage function in osteoporosis seems to be linked to ion channel activity. Inflammatory polarization of macrophages is a key player in inflammation-induced bone loss and can be driven by mechanosensitive ion channels. Modulating these ion channels may provide new therapeutic opportunities. Given the complexity of ion channel interactions in bone cells and their regulatory role in bone remodeling, understanding their precise function in osteoporosis is essential. Targeted modulation of mechanosensitive ion channels holds promise as a novel therapeutic approach to mitigate inflammation-driven bone loss and improve bone density. Further research into their role in osteoclasts and macrophage-driven bone degradation will aid in developing innovative osteoporosis treatments. Osteoporosis is the most common bone disease worldwide. The exact reasons for why bones weaken is often not fully understood, which makes the development of targeted therapies difficult. Our article highlights a new perspective: certain proteins in bone cells, called mechanosensitive ion channels, may be key players in osteoporosis. These channels act like tiny “gates” in the cell membrane that open when cells are stretched, thereby regulating the activity of cells. They help bone cells and immune cells sense their environment and respond to changes. We focus on three groups of these channels: K2P channels influence how bone-building cells (osteoblasts) grow and how immune cells control inflammation. Piezo channels help bone cells sense mechanical forces and control immune cell behavior. Volume-regulated anion channel channels may help bone cells adapt to stress and regulate inflammatory signals. Because of their dual effect on mechanical and inflammatory signaling, changes/alterations in ion channel activity may contribute to bone loss in osteoporosis. Pharmacological targeting of these channels could therefore help to protect bone. Early studies suggest that drugs influencing mechanosensitive ion channels might one day prevent or slow down osteoporosis. More research is needed, but this approach opens exciting new possibilities for treatment.

ID: 41208482
Title: The MYO1F interactome reveals ASAP1, CD2AP and SH3KBP1 as novel adaptor proteins in podosomes and phagosomes.
Abstract: MYO1F, a long-tailed myosin of class I, is selectively expressed in immune cells and upregulated in microglia associated with neurodegenerative pathogenesis. Myosin motor functions are regulated by adaptor proteins that mediate cargo attachment and motor recruitment. To define the MYO1F interactome, we used in situ proximity labelling and proteomics in human myeloid cells. We identified a distinct SH3-domain-dependent adaptor module comprising CD2AP, ASAP1, SH3BP2 and SH3KBP1 (herein termed the CASS group of proteins). Interestingly, CD2AP is an Alzheimer's disease (AD) risk gene upregulated in the microglia of individuals with AD, which are implicated in phagocytic responses to amyloid-β. Structural modelling and mutagenesis confirmed multivalent proline-rich motif interactions between the CASS group of proteins and the MYO1F SH3 domain. Additional binding partners associate with the MYO1F pleckstrin homology (PH) domain. Immunofluorescence revealed colocalisation of MYO1F and the CASS group of proteins at actin-rich podosomes and phagocytic cups in macrophages and microglia. Functional assays demonstrated that MYO1F recruitment to the phagocytic cup requires motor activity and intact PH and SH3 domains. We provide the first MYO1F interactome identifying adaptor proteins for MYO1F in podosomes and during phagocytosis, offering new insights into its function in disease-associated microglia during neurodegeneration.

ID: 41214880
Title: Piezo1 Upregulation in Monocyte-Derived Macrophages Impairs Post-Myocardial Infarction Cardiac Repair via Defective Efferocytosis and Enhanced Ferroptosis.
Abstract: The regulation of macrophage function, particularly that of monocyte-derived macrophages (MoMs), by mechanical forces during myocardial infarction (MI) remains poorly understood. Consistently upregulated Piezo1 expression in cardiac macrophages and MoMs post-MI is found. Elevated Piezo1 expression in MoMs directly contributes to increased Piezo1 levels in cardiac macrophages. Myeloid cell-specific Piezo1-deficient mice (Piezo1Lyz2) exhibit significant improvements in ventricular function/remodeling after MI, accompanied by decreased apoptotic cardiomyocytes and decreased inflammation, increased numbers of macrophages, and increased border zone efferocytosis. In vitro, Piezo1 activation by Yoda1 increased oxygen-glucose deprivation (OGD)-induced ferroptosis and impaired MoM efferocytosis. Conversely, Piezo1 deficiency in MoMs decreases ferroptosis and increases efferocytosis. SLC7A11 is shown to mediate Piezo1-induced defective efferocytosis in MoMs. Piezo1 activation aggravated OGD-induced macrophage ferroptosis via Ca2+ influx followed by SLC15A3 upregulation. Piezo1 upregulated SLC7A11 in macrophages via a Ca2+/ATF4-dependent pathway. MoM-specific SLC7A11 knockdown significantly increases efferocytosis, reduces cardiomyocyte apoptosis and inflammation, and ameliorates post-MI left ventricular remodeling and function. In conclusion, early Piezo1 activation in MoMs is identified during MI, which governs the fate and function of recruited macrophages. These data establish an ischemic heart-bone marrow functional network and provide a novel therapeutic strategy in which MoM Piezo1 is targeted for post-MI heart repair.

ID: 41638907
Title: Syk activation during FcγR-mediated phagocytosis involves Syk palmitoylation and desulfenylation.
Abstract: The Syk tyrosine kinase acts downstream of several immune receptors such as the FcγR. Syk owns two SH2 domains that interact with biphosphorylated ITAMs of the FcγR upon phagocytosis. This results in the activation of Syk by autophosphorylation, triggering phosphorylation of several downstream targets, F-actin polymerization, and phagocytosis of the IgG-opsonized target. We found that Syk is S-acylated upon phagocytosis by macrophages. Palmitoylation is performed on a single Syk-Cys by the DHHC5 enzyme that specifically associates with Syk upon phagocytosis. Syk palmitoylation is important for Syk localization to the phagocytic cup, phosphorylation, and phagocytosis. We observed that another Syk-Cys residue, within a redox motif, is modified by sulfenylation. Nevertheless, Syk desulfenylation seems to occur during phagocytosis, when H2O2 production at the cup decreases, after 3.5 min of phagocytosis. Molecular dynamics studies indicated that desulfenylation increased the exposure of a loop within the Syk interdomain B. This could facilitate phosphorylation of key Syk-Tyr residues by upstream kinases. We thus propose an updated model for Syk activation during FcγR-mediated phagocytosis that involves both Syk palmitoylation and desulfenylation.

ID: 41950296
Title: A biophysical model of phagocytic cup dynamics: The effect of membrane tension.
Abstract: Phagocytosis is a fundamental cellular process by which cells engulf external particles, controlled by receptor-ligand binding and actin-driven membrane dynamics. While a number of mathematical models have been developed to describe this process, they often overlook membrane tension, a key physical parameter known to influence membrane deformation and cytoskeletal behaviour. To address this gap, we present an enhanced mathematical model of receptor motion during phagocytosis that explicitly incorporates the role of membrane tension. Further, we introduce a signalling component that is coupled to receptor dynamics via the membrane tension. We find that including tension results in fundamentally different engulfment behaviour, which is slower than that predicted by models without tension. In particular, unlike in the previous version of this model, we show that tension can lead to stalled engulfment, an experimentally-observed phenomenon known as frustrated phagocytosis. We also find that signalling is able to modify engulfment behaviour, especially at later stages, and is able to alter cup growth to become linear in time without the need for receptor drift as introduced in previous models. These findings offer new insights into the role of membrane tension and biophysical regulation in phagocytosis, with implications for immune function, cell motility and targeted drug delivery.

ID: 42094351
Title: Myo1e/f regulate phagocytic podosomes to promote efficient cup closure in macrophages.
Abstract: Phagocytosis requires coordinated remodeling of the actin cytoskeleton to generate protrusive and contractile forces that drive target engulfment. Class I myosins Myo1e and Myo1f (Myo1e/f) have been implicated in linking the plasma membrane to the actin network, but their specific roles during Fc-receptor-mediated phagocytosis remain unclear. Using CRISPR-edited RAW 264.7 macrophages lacking Myo1e and Myo1f, we show that double knockout (dKO) cells exhibit markedly reduced uptake of IgG-coated beads, a phenotype that is partially rescued by re-expression of either myosin. Lattice-light-sheet and confocal imaging revealed distinct F-actin architectures corresponding to the various stages of cup progression, including basal podosome-like adhesions, individual phagocytic podosomes (actin teeth) along the rim of the cup, and a contractile phagocytic ring formed by the reorganization of podosomes into a higher-order network. In Myo1e/f-deficient cells, podosome formation was diminished, actin teeth were largely absent, and the phagocytic ring formed prematurely, which was often accompanied by stalled cup progression and repeated engulfment attempts. Myo1e/f localized both to podosomes and to the inner surface of the phagocytic ring, non-muscle myosin II (NM2) localized to the outer surface, and the absence of Myo1e/f correlated with the diffuse distribution of NM2. In addition, Myo1e/f-deficient macrophages exhibited increased trogocytosis of antibody-opsonized HL-60 cells, indicating a shift from whole-target engulfment toward partial target ingestion. These results suggest that Myo1e/f coordinate spatial and temporal transitions between protrusive and contractile actin networks, thereby ensuring efficient phagocytic cup progression. Our findings highlight a dual role for Myo1e/f in adhesion regulation and force balance during macrophage phagocytosis.

ID: 42223634
Title: PIEZO1 in Immune Cells: From Force to Function.
Abstract: As a professional mechanosensor, PIEZO1 converts mechanical stimuli-such as substrate stiffness, fluid shear stress, and membrane tension-into intracellular calcium influx, which in turn regulates a wide array of immune processes. The chapter details its significance across both innate and adaptive immunity, including T cell activation and migration, macrophage polarization, dendritic cell activation, natural killer cell cytotoxicity, neutrophil extracellular trap (NET) formation, and B cell antigen discrimination and class-switching to IgA. PIEZO1 emerges as a central regulator that fine-tunes immune responses by integrating signals from the cellular microenvironment, influencing inflammation, pathogen clearance, and metabolic reprogramming. Despite these advances, key questions remain regarding its role in chronic disease, autoimmunity, and cancer immunity. Targeting PIEZO1 presents a promising therapeutic strategy for conditions driven by mechanical stress and immune dysfunction, such as fibrosis, atherosclerosis, and solid tumours, potentially inaugurating a new era of mechano-immunotherapy.

ID: 42526292
Title: Spatial metabolic heterogeneity shapes CD8+ T cell function in cancer.
Abstract: Tumors are spatially heterogeneous ecosystems in which malignant, stromal, vascular, and immune cells interact within metabolically distinct niches. These localized microenvironments are shaped by factors such as nutrient availability, hypoxia, acidosis, and immunomodulatory metabolites, all of which strongly influence CD8⁺ T cell infiltration, migration, persistence, and effector function. Growing evidence indicates that spatial metabolic heterogeneity contributes to immune exclusion, T cell dysfunction, and resistance to immunotherapy. This has been accompanied by major advances in spatial metabolomics, particularly mass spectrometry imaging, which now enable the in situ mapping of metabolites within intact tissues. Combined with transcriptomic, proteomic, and imaging-based approaches, these technologies provide unprecedented insight into how metabolism is organized across tumors and how it shapes tumor-immune interactions. In this review, we discuss how metabolic zonation shapes CD8⁺ T cell function across primary tumors and metastatic lesions. We highlight emerging evidence linking localized metabolic programs to T cell exhaustion, impaired motility, and altered immune composition, and discuss therapeutic strategies aimed at improving T cell metabolic fitness, including metabolic modulation and engineering approaches relevant to immune checkpoint blockade and adoptive cell therapies. Finally, we consider the translational potential of spatial metabolomics for biomarker discovery and the development of precision immunometabolic oncology.

ID: 42531783
Title: Dual restoration of TGFβ1 and MerTK in macrophages alleviates atherosclerosis via enhanced efferocytosis and anti-inflammatory polarization.
Abstract: Although metabolic dysfunction-associated steatotic liver disease and atherosclerosis frequently coexist, no therapy concurrently targets both conditions. We previously observed that in such comorbidity settings, macrophages exhibit impaired efferocytosis and reduced anti-inflammatory polarization. In this study, we investigated whether simultaneously restoring these two defective macrophage functions could provide a unified therapeutic strategy both for hepatic and vascular pathology. To establish a comorbidity model featuring concurrent hepatic steatosis and atherosclerosis, we fed ApoE-/-mice a high-fat diet for 14 weeks. Moreover, we engineered bone marrow-derived macrophages to co-overexpress TGFβ1 and MerTK (MφSmart), thereby restoring anti-inflammatory properties and phagocytic capacity, then treated mice with control macrophages or MφSmart. TGFβ1 and MerTK overexpression in macrophages reprogrammed these cells toward an anti-inflammatory phenotype and endowed them with strong phagocytic capacity under lipid-loaded conditions. MφSmart reprogrammed macrophage injection into ApoE-/- mice alleviated inflammation locally in the plaque and liver. Consistent with the reduced inflammation, plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages. Mechanistically, the reprogrammed macrophages alleviated disease manifestations not only via direct inhibition of plaque inflammation but also by reshaping the inflammatory condition in the liver and plaque, where the transferred MφSmart predominantly accumulated. Macrophage-targeted dual-gene therapy overcomes the limitations of single-target approaches and achieves simultaneous therapeutic efficacy both in the liver and vasculature, establishing a preclinical proof-of-concept for multi-gene synergistic cell therapy in cardiometabolic disease.

ID: 42541333
Title: NLRC5-Deficient Macrophages Promote a Tumor-Permissive Phenotype via AXL- and MERTK-Mediated Efferocytosis.
Abstract: The innate immune protein NLRC5 plays a key role in cancer immune surveillance. Reduced NLRC5 expression is associated with a poor prognosis for many types of cancers. Previously, we showed that mice with a myeloid-specific deletion of Nlrc5 (Nlrc5mø-KO) develop gastric lymphoid lesions to Helicobacter infection resembling early-stage marginal zone lymphoma. We hypothesized that NLRC5 deficiency may promote a tumor-permissive microenvironment mediated by tumor-associated macrophages (TAMs). Consistent with this hypothesis, splenic macrophages from Helicobacter-infected Nlrc5mø-KO mice had upregulated expression of genes encoding the TAM receptor tyrosine kinases, Axl and Mertk. The levels of AXL and MERTK gene expression and MERTK phosphorylation were increased in NLRC5-/- THP-1 macrophages when compared with WT cells. In response to Helicobacter stimulation, Nlrc5-/- macrophages had significantly elevated anti-inflammatory responses (IL-10, TGF-β, Socs1, Socs3) compared with WT cells. Importantly, Nlrc5-/-macrophages showed enhanced efferocytosis and reduced antigen presentation to CD8+ T cells. Pretreatment of macrophages with AXL and MERTK inhibitors (R428, UNC2025) resulted in reduced efferocytosis and phosphorylation of downstream signaling molecules, STAT3 and ERK1/2. We propose that defective NLRC5 signaling in macrophages leads to tumor-permissive responses, thereby promoting the development of gastric lymphoid neogenesis to Helicobacter infection.

ID: 42543371
Title: [Study on Huanglian Jiedu Decoction improving ox-LDL-induced LC3-related phagocytosis dysfunction in RAW264.7 macrophages by activating ERK5].
Abstract: To investigate whether the anti-atherosclerotic(AS) effect of Huanglian Jiedu Decoction(HLJDD) is associated with activation of extracellular signal-regulated kinase 5(ERK5) and the consequent improvement of microtubule-associated protein 1 light chain 3(LC3)-associated phagocytosis(LAP) dysfunction in macrophages. RAW264.7 cells were randomly divided into the normal control group, oxidized low-density lipoprotein(ox-LDL) group, HLJDD group, simvastatin(simva) group, and RAW264.7-ERK5 gene knockout(ERK5-KO) group. According to the experimental protocol, cells in each group were treated for 24 h with normal control rat serum, ox-LDL, HLJDD-containing serum, or simva-containing serum. Apoptotic Jurkat cells were added to each group and co-cultured for 90 min. After removal of the supernatant, LC3-Ⅱ labeling was performed to observe LAPosomes in macrophages, and the clearance of apoptotic Jurkat cells was assessed. The expression levels of phosphorylated(p)-ERK5, ERK5, LAP-related signaling molecules [T-cell immunoglobulin and mucin-domain-containing molecule-4(TIM-4), vacuolar protein sorting 34(VPS34), Beclin-1, RUN domain Beclin-1-interacting and cysteine-rich domain-containing protein(Rubicon), autophagy-related protein 5(ATG5), and autophagy-related protein 7(ATG7)], pro-inflammatory cytokines [interleukin-1β(IL-1β), interleukin-6(IL-6)], and anti-inflammatory cytokines [interleukin-10(IL-10), transforming growth factor-β(TGF-β)] were measured. RESULTS:: showed that, compared with the control group, the ox-LDL group exhibited decreased LAPosome percentage and reduced clearance of apoptotic cells, downregulated expression of p-ERK5, TIM-4, VPS34, Beclin-1, Rubicon, ATG5, and ATG7, increased IL-1β and IL-6 levels, and no significant changes in IL-10 or TGF-β expression. Compared with the ox-LDL group, the HLJDD and simva groups showed increased LAPosome percentage and enhanced apoptotic cell clearance, upregulated expression of p-ERK5, TIM-4, VPS34, Beclin-1, Rubicon, ATG5, and ATG7, decreased IL-1β and IL-6 levels, and increased IL-10 and TGF-β expression. Compared with the HLJDD group, the ERK5-KO group exhibited significantly reduced expression of ERK5 and p-ERK5, and all other indicators were reversed. In conclusion, HLJDD may ameliorate macrophage LAP dysfunction and exert anti-AS effects by activating ERK5.

ID: 42548808
Title: Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
Abstract: Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment and play critical roles in tumor progression, immune escape, and therapeutic response. Their functional plasticity is closely regulated by metabolic reprogramming, particularly glucose metabolism. Glucose-related pathways, including glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, and pyruvate/lactate metabolism, influence TAM polarization, cytokine production, phagocytosis, antigen presentation, and T cell interactions. In many tumors, enhanced glycolysis and lactate accumulation promote M2-like TAM polarization and suppress CD8+ T cell activity, whereas certain metabolic programs may support M1-like anti-tumor functions under specific conditions. This mini review summarizes major glucose metabolic pathways involved in TAM regulation, highlights their context-dependent pro- and anti-tumor roles, and discusses therapeutic strategies for reprogramming TAM metabolism to improve anti-tumor immunity and immunotherapy response.

ID: 42549352
Title: Magnetic Reprogramming of Macrophages Stimulates Phagocytosis of Breast Cancer Cells via a TRPC1-STING Inflammatory Axis.
Abstract: The reprogramming of tumor-associated macrophages (TAMs) from a pro-tumoral M2 to an anti-tumoral M1 phenotype is an attractive therapeutic strategy whose clinical translation is undermined by the systemic toxicity of currently available pharmacological approaches. Here, we demonstrate that non-invasive and localizable pulsed electromagnetic fields (PEMFs) induce macrophage reprogramming downstream of transient receptor potential canonical 1 (TRPC1) channel activation. Brief (10 min) PEMF exposure polarized macrophages toward an M1 phenotype by activating Stimulator of Interferon Genes (STING)-dependent NF-κB inflammatory pathways that were abolished by TRPC1 knockdown or inhibition. PEMF exposure directly enhanced the immunogenicity of breast cancer cells and modified macrophage-cancer crosstalk to promote M1 macrophage polarization and the attraction of STING-activated macrophages to the cancer cells. In co-cultures, PEMF exposure stimulated macrophage-mediated phagocytosis of cancer cells in a STING- and TRPC1-dependent manner. In spheroids, PEMFs induced the reprogramming of TAMs to an M1 status and selectively enhanced infiltration of M1 macrophages, resulting in STING-mediated phagocytosis of cancer cells. In mice, 2 weeks of twice-weekly PEMF exposure resorbed engrafted tumors and selectively eliminated cancer cells within tumors while promoting immune cell recruitment. PEMFs offer a non-invasive manner to locally reprogram TAMs within the tumor microenvironment to preferentially eliminate cancer cells.

ID: 42550039
Title: Innate immune recognition of Debaryomyces hansenii requires Dectin-1-Card9 signaling.
Abstract: Innate immune signaling plays a key role in host response to infection, yet the pattern recognition receptors that detect non-model gut-associated yeasts remain poorly defined. Here, we investigated macrophage sensing of Debaryomyces hansenii, a food-derived yeast that we found to be enriched within intestinal ulcers of Crohn disease (CD) patients. Using a cell surface receptor antibody screen of bone marrow-derived macrophages infected with a CD patient isolate of D. hansenii, we showed that D. hansenii-induced macrophage activation characterized by increased expression of co-stimulatory molecules, MHC-II, and pattern recognition receptors, including the C-type lectin receptor Dectin-1. Antibody blockade experiments showed both Dectin-1 and complement receptor 3 subunit CD11b were required for phagocytosis of D. hansenii, while Dectin-1 was uniquely required for production of the pro-inflammatory cytokine tumor necrosis factor (Tnf). CRISPR-Cas9-mediated deletion of Dectin-1 phenocopied antibody neutralization effects on phagocytosis. Furthermore, deletion of Dectin-1 or its downstream signaling adaptor molecule Card9 resulted in reduced Tnf secretion in response to D. hansenii. Dectin-1-mediated uptake of D. hansenii was observed in primary bone marrow-derived macrophage and dendritic cells, as well as across the spectrum of macrophage polarization states. Together, these findings define the role of Dectin-1-Card9 signaling axis in innate immune cell sensing of D. hansenii. These findings support the emerging relevance of innate immune recognition of a yeast in Crohn disease pathogenesis.

ID: 42550891
Title: Adenosine 2A receptor drives microglial efferocytosis to accelerate white matter repair and functional recovery after stroke.
Abstract: Although reperfusion therapy effectively restores blood flow to occluded brain arteries after ischemic stroke, many patients develop persistent white matter injury, a major contributor to long-term neurological disability. Currently, there are few approved clinical therapies that specifically target white matter repair to enhance functional recovery after stroke. We demonstrated that microglial adenosine 2A receptor (A2AR) is essential for spontaneous white matter regeneration after ischemic injury in mice. Deletion of A2AR in microglia specifically impaired chronic-phase repair without altering the severity of acute ischemic injury. Pharmacological activation of A2AR signaling with blood-brain barrier-permeable agonistic micelles during the early reperfusion phase enhanced white matter structural repair and led to sustained improvements in cognitive and sensorimotor function in mice. Mechanistically, A2AR activation promoted microglial efferocytosis of apoptotic cells and myelin debris in the lesioned white matter, thereby limiting secondary necrosis-induced inflammation, enhancing neurotrophic factor release, and establishing a reparative microenvironment conducive to oligodendrocyte precursor cell differentiation and remyelination. Moreover, A2AR signaling engaged HIF1α-dependent metabolic reprogramming to increase glycolysis, thereby providing the energetic support required for efficient and sustained efferocytosis. Together, these findings identify A2AR as a critical regulator of microglia-mediated white matter repair and a promising therapeutic target for enhancing regeneration after stroke.

ID: 42554945
Title: GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.
Abstract: Dysregulation of brain cholesterol homeostasis is increasingly recognized as a critical driver of Alzheimer's disease (AD) pathogenesis. G protein-coupled receptor 146 (GPR146) has emerged as a pivotal regulator of systemic cholesterol metabolism; however, its role in the central nervous system and AD remains elusive. Here, we report that GPR146 deficiency in mice modulates ERK/PKA signaling without affecting baseline physiology or general behavior. Following intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)42 oligomers, GPR146 was associated with altered Aβ42-evoked ERK/PKA/Akt signaling both in vivo and in vitro. Mechanistically, Gpr146 ablation potentiated microglial Aβ phagocytosis, which correlated with the transcriptional upregulation of phagocytic receptors, including TREM2, GPR34, P2Y6, and CR3, alongside increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, GPR146 deficiency was linked to elevated levels of blood-brain barrier (BBB)-associated markers Cldn-5 and Glut-1 protein levels, while attenuating Aβ‑induced inflammatory responses in brain endothelial cells. At the metabolic level, GPR146 knockout modulated the expression of key enzymes governing glucose (GLUT1, GLUT3, G6PD, PFK, HK) and lipid (HMGCS1, ACACA, FASN, SCD1) metabolism and markedly reduced Aβ‑elicited lipid droplet accumulation in the cortex and hippocampus. Collectively, our findings establish GPR146 as a novel neurometabolic regulator whose deficiency correlates with enhanced Aβ phagocytosis, maintenance of BBB-associated proteins, and altered cerebral metabolism, thereby presenting a potential therapeutic axis for early AD intervention.

ID: 42555194
Title: Engineering Morphological Anisotropy to Control the In Vivo Transport Dynamics, Clearance, and Biodistribution of Silica Nanocarriers.
Abstract: Shape governs function across scales in nature, from streamlined bacteria to biconcave red blood cells that navigate capillary flow. Inspired by these bio-geometries, we explore how nanoscale anisotropy can be engineered to control the dynamic transport and biodistribution of synthetic nanocarriers in the body. We fabricate anisotropic silica nanocapsules with precisely tunable asymmetry to dissect shape effects on nano-bio interactions under physiological flow. Under shear flow in vitro, increasing anisotropy markedly reduced cellular uptake, whereas this effect was much less pronounced under static conditions, revealing strong flow-shape coupling. In vivo, highly anisotropic nanocapsules exhibit prolonged circulation, with a 2.8-fold longer half-life than spherical counterparts and significantly reduced sequestration by the liver, spleen, and circulating blood cells. Mechanistic analyses attributed these effects to decreased phagocytic internalization by Kupffer cells, splenic macrophages, and circulating monocytes. Computational fluid dynamics simulations corroborated this phenomenon, demonstrating that greater anisotropy shifts particle trajectories away from vessel walls toward the central flow stream, lowering the chances of cellular interception. Together, these results establish nanoscale anisotropy as a critical determinant of nanoparticle transport, immune recognition, and clearance under flow. Anisotropy engineering therefore provides a nature-inspired framework for designing long-circulating, immune-evasive nanocarriers with improved therapeutic performance.

ID: 42555352
Title: Circulating cochlin LCCL domain binds to dying cells and enhances efferocytosis.
Abstract: Clearance of dead cells by efferocytosis is a critical process for homeostasis, notably by limiting inflammation. Defective efferocytosis has been associated with autoimmune, neurodegenerative, and cardiovascular diseases, as well as chronic infections, making its regulation a potential therapeutic target. Here, we identify circulating cochlin LCCL (Limulus factor C, Cochlin, and Lgl1) domain as a regulator of efferocytosis. Using cell binding assay for recombinant cochlin LCCL domain, we establish its tropism for dead or dying cells of both immune and non-immune lineages from murine and human origins. By three independent functional assays, we demonstrate that endogenous and exogenous cochlin LCCL domain enhances macrophage efferocytosis in vitro and in vivo in lipopolysaccharide (LPS)-induced inflammation and intranasal Pseudomonas aeruginosa infection, to a similar extent as the efferocytosis promoter GAS6. Our findings provide a role of cochlin LCCL domain in the regulation of efferocytosis, alongside its already described pro-inflammatory role, as an immunomodulator for host response and homeostasis.

ID: 42558291
Title: IL-33 promotes efferocytosis by peritoneal macrophages by a mechanism associated with rapid granulocyte IL-13 production.
Abstract: Resolution of inflammation is an active process that requires efferocytosis, the engulfment of apoptotic cells by macrophages, mediated by receptors such as MerTK. IL-33 is an alarmin that initiates type 2 immune responses, including increased production of IL-13, which promotes MerTK expression. The ability of IL-33 to promote efferocytosis in vivo was examined. Intraperitoneal administration of IL-33 to mice increased local MerTK+ macrophage numbers within 48h. MerTK+ macrophages were not similarly induced by free mitochondria, an alternative cell damage associated signal. Efferocytotic activity was increased rapidly in response to apoptotic thymocytes in IL-33-treated mice. The established inducer of MerTK expression, IL-13, was detected in peritoneal lavage fluid shortly after IL-33 administration. Peritoneal eosinophils expressed the IL-33 receptor and demonstrated both intracellular IL-13 by flow cytometry and significantly increased Il13 transcript expression following IL-33 treatment. In contrast, neither elevated IL-13 expression nor IL-13 protein secretion was observed in peritoneal lymphocyte populations within the first 6 hours after IL-33 administration. Primary cultures of bone marrow-derived mouse mast cells and eosinophils demonstrated IL-13 protein responses to IL-33 administration within 6 h. Mast cell-deficient Cpa3-Cre; Mcl-1fl/fl mice had significantly reduced IL-13 levels in the peritoneal cavity 3 hours after IL-33 administration when compared with mast cell-containing littermates. In contrast, IL-33-treated eosinophil-deficient ΔdblGATA mice had similar levels of IL-13 at this time point as wild type controls. These data demonstrate that IL-33 promotes MerTK expression, critical for efferocytosis by macrophages, by a process associated with an early rapid local increase in IL-13 production to which mast cells are a substantial early contributor. These findings contribute to our understanding of clinical situations where elevated soluble IL-33 receptor (sST2) and/or lower mast cell numbers are associated with worse clinical outcome.

ID: 42558661
Title: Cutaneous Intravascular Large B-Cell Lymphoma Presenting as Hemophagocytic Lymphohistiocytosis.
Abstract: Intravascular large B-cell lymphoma (IVLBCL) is an uncommon and aggressive subtype of non-Hodgkin lymphoma defined by the proliferation of large malignant B cells confined within small blood vessels. This neoplasm can present with different nonspecific symptoms, including fever, altered mental status, livedoid skin rashes, hepatosplenomegaly, and cytopenias, often complicating its diagnosis. The main categories are classical (formerly designated as Western), hemophagocytic variant (formerly designated as Asian), and primary cutaneous IVLBCL. A distinctly severe manifestation is hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome characterized by exaggerated immune activation and macrophage activation manifested by phagocytosis of hematopoietic cells including neutrophils, red blood cells, and platelets. We describe a 72-year-old female who presented with features reminiscent of an autoinflammatory syndrome including fever and hyperferritinemia followed by clinical features concerning for HLH. She developed a reticulated skin rash. Following skin biopsy, a diagnosis was rendered of IVLBCL complicated by HLH. The pathophysiology and other aspects of the literature pertaining to IVLBCL and HLH are reviewed.

ID: 42559550
Title: Nanoplastics Impair Neuroimmune Integrity Via Cellular Retention and Multiple Organelle Stress.
Abstract: The biological persistence of nanoplastics (NPs) has raised growing concern regarding their potential to accumulate in human tissues yet their impact on neuroimmune cellular function remains largely undefined. Here, we investigated the neuroimmune effects of polystyrene NPs (100, 200, and 1000nm; 10 and 100μg/mL) across neuronal (SH-SY5Y, PCNs) and immune cells (THP1, macrophages). Cellular responses were assessed through analyses of cytotoxicity, immunocytochemistry and cytokine profiling. NPs exposure did not induce acute cytotoxicity but promoted persistent intracellular retention accompanied by lysosomal dysfunction, dysregulated autophagic flux, ER stress, and constrained mitochondrial function, thereby inducing a sublethal multi-organelle stress response. Macrophages exhibited greater vulnerability consistent with phagocytic burden, while inflammatory challenge further enhanced NPs uptake, reinforcing intracellular persistence. In contrast, neurons showed limited extracellular cytokine secretion yet accumulated intracellular IL-1β, suggesting low-grade inflammatory activation. Such responses were recapitulated in PCNs, supporting translational relevance across neuronal models. The cumulative nature of these observations suggests that NPs exposure may give rise to previously unrecognized accumulation-related pathologies, a phenomenon we term "plasticoma" as a conceptual framework, to describe the preferential deposition of non-degradable plastic particles within cells, to frame and stimulate future investigations into NP accumulation and pathology. These findings position NPs as potential determinant of neuroimmune dysfunction and highlight the importance of strategies aimed at mitigating their biological accumulation.

ID: 42561943
Title: C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.
Abstract: C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.

ID: 42562887
Title: Metabolic-epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment.
Abstract: The tumor microenvironment exerts profound metabolic and epigenetic pressures that shape the plasticity of innate immune cells, influencing their capacity to promote or suppress tumor progression. Emerging evidence highlights the intricate interplay between metabolic reprogramming and epigenetic modifications in macrophages, neutrophils, and other innate immune populations within the tumor microenvironment. Tumor-derived metabolites, hypoxia, and nutrient availability dynamically regulate chromatin accessibility, histone modifications, and DNA methylation patterns, thereby driving context-dependent immune phenotypes. Notably, metabolic rewiring can imprint long-lasting epigenetic changes, a phenomenon known as innate immune memory, which alters subsequent immune responses. Here, we discuss how key metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, govern innate immune cell fate and function via epigenetic mechanisms. We also highlight recent advances in epigenomic profiling that have unveiled distinct chromatin landscapes associated with innate immune dysfunction across cancer types. Finally, we explore emerging therapeutic strategies that target the metabolic-epigenetic axis to restore innate immune surveillance and enhance immunotherapy efficacy. A deeper understanding of this metabolic-epigenetic crosstalk could reveal novel avenues for modulating innate immunity in cancer therapy.

ID: 42563266
Title: Nanomaterial Strategies for Pulmonary Delivery of Immunotherapeutics in Lung Cancer Treatment.
Abstract: Organ-selective immunomodulation is increasingly viewed as a route to improve the therapeutic index of cancer immunotherapy, yet most agents are still delivered systemically, where limited tumor exposure and immune-related toxicities remain common. The lung is an attractive site for local intervention because it is directly accessible and immunologically specialized. However, effective pulmonary delivery is constrained by mucociliary clearance, airway mucus, alveolar macrophage uptake, and epithelial barriers. Nanomaterials can be rationally engineered to address these constraints, increasing pulmonary retention and concentrating immunotherapeutics within the lung tumor microenvironment while reducing systemic burden. This Review summarized the key physiological barriers for pulmonary immunotherapeutic delivery and discusses how nanomaterial properties shape deposition, retention, cellular partitioning, and downstream immune activation. We critically evaluate representative inhalable platforms across major immunotherapeutic modalities, including vaccines, immune checkpoint blockade, innate immune agonists (e.g., STING agonists), cytokine regulation, and emerging in situ immune-cell engineering strategies. We also highlight translational considerations. Together, these advances support inhalable immunotherapeutic nanomedicines as a complementary approach to current lung cancer treatment and a broader framework for pulmonary immune modulation.

ID: 42563401
Title: A multi-stage deep learning framework for half-detector truncation and metal artifact reduction in CBCT.
Abstract: Cone-beam computed tomography (CBCT) is widely utilized for its high spatial resolution and compact design. However, image quality is often compromised in the half-detector (HD) geometry, where data truncation arising from the offset detector configuration coexists with metal artifacts caused by metallic implants. These artifacts interact synergistically, leading to severe image degradation that conventional correction methods fail to address. We propose a multi-stage deep learning framework, HD-TMAR, to systematically decompose and correct combined truncation and metal artifacts in HD CBCT. The proposed framework adopts a multi-stage restoration strategy comprising three stages: (1) Sinogram Correction, which explicitly isolates the artifact residuals from the projection data and synergizes them with structural prior-normalized features to systematically suppress global truncation biases and metal artifacts; (2) Merging and Reconstruction, which employs a specialized overlapping patching and selective replacement strategy to accurately reconstruct the truncated regions and metal traces; and (3) Image Refinement, where ImgNet further enhances the reconstructed image to restore fine anatomical textures. Experiments using realistic simulation datasets demonstrated that the proposed method achieved the highest qualitative fidelity and quantitative metrics compared to previous deep learning MAR methods. The framework effectively suppressed severe artifacts while preserving dental morphology, whereas comparative methods suffered from secondary artifacts or blurring. HD-TMAR successfully disentangles complex artifact interactions. By synergizing sinogram-domain correction with image-domain refinement, the framework demonstrates promising potential for clinical application in enhancing the diagnostic performance of HD CBCT systems in the presence of metallic implants.

ID: 42563416
Title: A 3D model of human hand anatomy using contrast imaging and muscle architecture visualization.
Abstract: Diffusible iodine-based contrast-enhanced microCT (DiceCT) enables three-dimensional visualization of mineralized and soft tissues while preserving their spatial relationships in situ. We present a DiceCT-based digital atlas of a human hand from a consented female donor through the University of Missouri Gift of Body program, scanned at 48.8 μm resolution following Lugol's iodine staining. Bones, tendons, intrinsic muscles, neurovascular structures, the flexor retinaculum and carpal tunnel, and dorsal digital expansions were manually segmented to generate labeled multiplanar sections and three-dimensional reconstructions. The dataset resolves epidermal ridge detail on the palmar surface while capturing structures, including the carpal tunnel contents, extensor mechanism, neurovasculature, palmar fat pads, and metacarpophalangeal sesamoids. Reconstructions demonstrate relevant relationships among the median nerve, flexor tendons, and flexor retinaculum, the ulnar nerve within Guyon's canal and the radial artery within the anatomical snuffbox. Distal digital arterial anastomoses are visible near the terminal tufts, and radial artery branches supplying the dorsal and distal scaphoid poles provide context for scaphoid vascular vulnerability. Muscle volumes and physiological cross-sectional areas were calculated using all fascicles within each intrinsic muscle. Flexor pollicis brevis and adductor pollicis exhibited comparatively large relative physiological cross-sectional areas, whereas the lumbricals had the smallest values, consistent with previous architectural estimates. By documenting whole-hand anatomy and within-individual muscle architecture non-destructively, this atlas provides a high-fidelity resource for anatomical education, documentation of anatomical variation, clinical interpretation, and generation of anatomically consistent biomechanical models. These results support DiceCT as a platform bridging anatomical research, clinical translation, and pedagogical access to donor-specific human anatomy.

ID: 42563592
Title: Waist-to-Body Mass Index Ratio and Risk of Musculoskeletal Disease in Type 2 Diabetes: A Cohort and PhIP-Seq Analysis.
Abstract: Musculoskeletal complications in type 2 diabetes (T2DM) are inadequately captured by body mass index (BMI). Waist-to-BMI ratio (WBR) may better reflect adverse body composition. We examined cross-sectional and longitudinal associations between WBR and musculoskeletal disorders in T2DM. This two-phase study was conducted within an ongoing hospital-based cohort at the First Affiliated Hospital of Fujian Medical University (Fuzhou, China). The cross-sectional analysis included 4157 adults with T2DM recruited between March 2012 and August 2023 (54.3% men; mean age 59.4 ± 10.3 years), using data from their first assessment. Associations of waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), BMI and WBR with osteopenia, sarcopenia, sarcopenic osteopenia (SOs), sarcopenic obesity (SOb) and fractures were evaluated. The prospective cohort comprised a longitudinal subset enrolled between March 2012 and June 2022, ensuring at least 1 year of follow-up prior to administrative censoring in August 2023. A total of 440 individuals (57.0% men; mean age 59.7 ± 9.7 years) were followed for a median of 34.0 months (20.0-57.0). Associations between time-dependent WBR and incident outcomes were assessed using Cox models. A nested exploratory analysis was conducted within the cohort. Thirty participants with extreme annualised WBR change (ΔWBR/yr) were selected. Baseline serum samples collected at enrolment, prior to outcome occurrence, were analysed using phage immunoprecipitation sequencing (PhIP-Seq). Cross-sectionally, WBR was negatively correlated with bone mineral density and appendicular skeletal muscle mass index and positively correlated with osteopenia, sarcopenia, SOs, SOb and fractures (all p < 0.01), whereas BMI, WC, WHtR and WHR showed weaker associations. After adjustment, higher WBR was independently associated with osteopenia (men: OR 1.723, 95% CI 1.614-1.840; women: OR 1.420, 1.348-1.495), sarcopenia (men: OR 4.779, 4.165-5.484; women: OR 2.991, 2.683-3.334), SOs (men: OR 6.261, 5.314-7.377; women: OR 4.336, 3.753-5.010), SOb (men: OR 4.737, 3.975-5.646; women: OR 4.652, 3.715-5.825) and fractures (men: OR 1.236, 1.093-1.397; women: OR 1.103, 1.003-1.213; all p < 0.05). Prospectively, higher time-dependent WBR predicted incident osteopenia (HR 1.365, 95% CI 1.024-1.820), sarcopenia (HR 1.282, 1.086-1.512), SOs (HR 1.408, 1.176-1.686), SOb (HR 1.634, 1.262-2.116) and fractures (HR 1.369, 1.029-1.821). PhIP-Seq analysis identified differential autoantibody reactivity related to muscle structural organisation and cytoskeletal regulation, while bone-related differences were enriched in Wnt signalling and hormone-related pathways. Higher WBR and longitudinal increases were independently associated with osteopenia, sarcopenia, sarcopenic phenotypes and fractures in individuals with T2DM.

ID: 42564069
Title: The new era of MASH pharmacotherapy: a comprehensive review of FDA-approved and emerging agents.
Abstract: Metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis (NASH), is a progressive liver disease and a leading cause of cirrhosis and liver-related mortality worldwide, affecting approximately 3%-5% of the global adult population and up to 30%-40% of individuals with type 2 diabetes mellitus (T2DM) or those attending dedicated diabetes and endocrine centers. For decades, treatment was limited to lifestyle interventions. The years 2024 and 2025 marked a paradigm shift with the first-ever FDA approvals of pharmacologic agents for MASH. This comprehensive narrative review synthesizes the evidence for newly approved and emerging pharmacotherapies for MASH, addressing the mechanisms of action, pivotal clinical trial data, efficacy, safety profiles, and place in therapy for resmetirom and semaglutide. It also discusses key agents including pioglitazone, saroglitazar, and vitamin E, and evaluates the non-invasive testing (NIT) toolkit-including FIB-4, VCTE, shear wave elastography, MRE, and ELF-in the context of a structured, risk-stratified clinical algorithm. Resmetirom (Rezdiffra), a THR-β agonist, achieved MASH resolution in 26%-30% versus 10% placebo and fibrosis improvement in 24%-26% versus 14% placebo at 52 weeks in the MAESTRO-NASH trial. Semaglutide 2.4 mg (Wegovy) demonstrated a 28.7% delta over placebo in MASH resolution in the ESSENCE trial. Pioglitazone has additional evidence for reducing the FIB-4 index in real-world studies. Saroglitazar, a PPAR-α/γ dual agonist approved in India, has shown significant reductions in ALT, liver fat, and metabolic parameters in Phase 2 studies and is advancing to Phase 2b. Shear wave elastography is a clinically important alternative to VCTE for fibrosis staging, particularly in patients with obesity, and offers value in resolving discordant FIB-4/VCTE results. The approval of resmetirom and semaglutide marks a new era in MASH management. A risk-stratified algorithmic approach using NITs guides patient selection, with liver biopsy reserved for specific clinical scenarios. The therapeutic landscape is rapidly evolving, with saroglitazar and combination approaches representing key frontiers.

ID: 42564115
Title: Radiomics-based high-resolution CT analysis for differentiating primary tumor sources of pulmonary metastases.
Abstract: To evaluate machine learning models based on HRCT radiomic features for distinguishing breast and colorectal cancer pulmonary metastases, and interpret the optimal model to aid clinical decision-making. This retrospective study enrolled 85 patients with pathologically confirmed pulmonary metastases. After radiomic feature extraction, the cohort was divided into a training set (n=59) and an independent test set (n=26) at a 7:3 ratio via stratified sampling. Data were processed with Z-score normalization, variance thresholding and PCA (45 principal components). Five classifiers were constructed: LR, linear SVM, RF, XGBoost and LightGBM. Model stability and performance were assessed by 5-fold stratified cross-validation and independent test validation. The 45 principal components accounted for 99.92% of cumulative variance. LR showed optimal performance, with a test AUC of 0.9821, classification accuracy of 84.62%, and a mean cross-validation AUC of 0.9606 (95% CI: 0.8887-0.9895). The small training-test AUC difference (0.0179) indicated no severe overfitting. SVM ranked second (test AUC = 0.9405), while XGBoost and RF exhibited significant overfitting and LightGBM underfitting. The model's decision relied on key texture features; only GLSZM non-uniformity differed significantly between groups, consistent with their pathophysiological characteristics. The PCA-reduced and regularization-optimized LR model has excellent generalization, stability and clinical interpretability in differentiating pulmonary metastases from breast and colorectal cancers. This study preliminarily highlights the potential of LR in high-dimensional small-sample scenarios, and provides a foundational methodological reference for future large-scale multicenter diagnostic research.

ID: 42564117
Title: Effects of immunosuppression on tracheal mucosal responses after infection with Mycoplasma gallisepticum in vaccinated and unvaccinated chickens.
Abstract: Vaccination is the most common method used to control infection caused by Mycoplasma gallisepticum in chickens. However, concurrent immunosuppression may compromise vaccine efficacy. This study investigated the effect of immunosuppression induced by either chicken anaemia virus (CAV) or infectious bursal disease virus (IBDV), administered prior to or following vaccination with the M. gallisepticum live vaccine strain ts-304 (Vaxsafe MG304), on tracheal host responses to subsequent challenge with virulent M. gallisepticum. Tracheal responses were assessed by genome-wide transcriptional profiling in these groups and compared across unvaccinated-unchallenged, unvaccinated-challenged, vaccinated-unchallenged and vaccinated-challenged groups that had not been exposed to CAV or IBDV. Immunosuppression resulted in significant differences in tracheal transcriptional responses compared to immunocompetent groups, irrespective of the timing of infection with CAV or IBDV. Differences in transcription were more pronounced in the IBDV-infected groups than the CAV-infected groups. Functional interrogation of differentially transcribed genes revealed adverse effects of M. gallisepticum on extracellular and intracellular signalling, cell communication, cellular actin dynamics, formation of the cellular cytoskeleton, and cellular metabolic pathways in the tracheal mucosa of immunosuppressed groups. In addition, there were indications of down-regulation of both innate and adaptive immune responses, including cytokine signalling, antigen processing presentation, and immune cell receptor signalling in the immunosuppressed groups. Specifically, findings indicated that infection with CAV impaired pro-inflammatory and adaptive T-cell responses in the tracheal mucosa. The findings implied that the primary immune response induced post-vaccination and the secondary immune response induced post-challenge with virulent M. gallisepticum were both affected by infection with these two viruses. Coupled with previous observations of reduced antibody titres against M. gallisepticum, and increased rates of recovery of virulent M. gallisepticum in both CAV- and IBDV-infected groups, the significant transcriptional changes detected in the current study highlighted the roles of both cell-mediated (CMI) and humoral immunity (HI) in vaccine-induced protection, as CAV mainly affects CMI and IBDV mainly affects HI. These findings will assist in identifying the mechanisms underlying the reduced efficacy of live attenuated mycoplasma vaccines in immunosuppressed animals.

ID: 42564178
Title: Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance.
Abstract: Immune checkpoint blockade has transformed cancer therapy, yet many tumors remain intrinsically resistant or acquire resistance after initial response. Increasing evidence indicates that this failure is not determined solely by PD-1, PD-L1, CTLA-4, or T-cell exhaustion, but also by metabolically suppressive states within the tumor microenvironment. Tumor-derived metabolites can function as metabolic immune checkpoints by limiting effector immune activity, promoting regulatory or myeloid suppressive compartments, and weakening immunotherapy efficacy. This mini review summarizes recent experimental evidence showing how lactate, adenosine, tryptophan-derived metabolites, and nucleotide-derived metabolites shape immune escape and resistance to immune checkpoint blockade. Lactate links tumor glycolysis to Treg recruitment, impaired T-cell function, and lactylation-associated therapeutic resistance. The CD73-adenosine axis suppresses CD8+ T cells and natural killer cells while reinforcing regulatory and myeloid immune programs. Tryptophan-derived metabolites extend beyond the classical IDO1-kynurenine-AhR pathway to involve non-classical checkpoints such as Siglec-15 and broader kynurenine/indole/serotonin networks. Emerging evidence further identifies nucleotide-derived UDP signaling as a driver of macrophage-mediated immunosuppression. Finally, we discuss how targeting metabolic checkpoints in combination with immune checkpoint blockade may improve therapeutic responses. Defining the spatial and cellular contexts of metabolite-mediated immune suppression may enable more precise strategies to overcome immunotherapy resistance.

ID: 42564594
Title: Impact of a Structured MRI Reporting Template on the Completeness of Primary Rectal Cancer Staging Reports: A Retrospective Audit.
Abstract: High-resolution pelvic magnetic resonance imaging (MRI) is essential for local staging of primary rectal carcinoma and for communicating surgically relevant risk factors before multidisciplinary treatment planning. Free-text MRI reports may describe the primary tumor but may inconsistently document key management-relevant findings, including mesorectal fascia and circumferential resection margin status, depth of extramural spread, extramural vascular invasion, lateral pelvic lymph nodes, and low rectal sphincter complex involvement. This retrospective audit assessed whether use of a structured MRI reporting template was associated with improved completeness of primary rectal cancer staging reports. This retrospective audit included 60 pelvic MRI reports performed for suspected or biopsy-proven primary rectal carcinoma at a tertiary care radiology department. Thirty consecutive reports prepared before template implementation were assigned to the free-text reporting group, and 30 reports prepared after template implementation were assigned to the structured reporting group. Reports were assessed using a predefined checklist of essential MRI staging elements, including tumor location, distance from the anal verge, craniocaudal tumor length, circumferential tumor position, relationship to the anorectal junction and anterior peritoneal reflection, MRI T category, depth of extramural spread, mesorectal fascia/circumferential resection margin status, extramural vascular invasion, mesorectal nodes, tumor deposits, lateral pelvic lymph nodes, sphincter complex involvement, levator ani involvement, adjacent organ invasion, and final MRI-based risk summary. The primary and only measured outcome was report completeness. The mean completeness score was higher in the structured reporting group than in the free-text group, with mean scores of 91.3% and 58.6%, respectively. Structured reports showed more complete documentation of several clinically important staging domains that were inconsistently recorded in free-text reports, including mesorectal fascia/circumferential resection margin relationship, depth of extramural spread, extramural vascular invasion, lateral pelvic nodal assessment, and low rectal sphincter complex assessment. Structured reports also more frequently included a concise MRI-based risk summary integrating tumor level, T stage, nodal status, margin risk, extramural vascular invasion, and anticipated surgical relevance. No formal statistical hypothesis testing was performed; therefore, these findings should be interpreted descriptively rather than inferentially. Implementation of a structured MRI reporting template was associated with higher report completeness in this descriptive retrospective audit of primary rectal cancer staging reports. The structured template was associated with more complete documentation of clinically relevant reporting elements, particularly margin status, extramural spread, extramural vascular invasion, lateral pelvic nodes, and low rectal sphincter complex involvement. However, report completeness was the only measured outcome, and no formal statistical testing was performed. Further studies with statistical testing, reviewer blinding, and assessment of diagnostic accuracy or clinical outcomes are needed.

ID: 42564688
Title: Three-dimensional photoacoustic tomography with ultrasound localization priors.
Abstract: Three-dimensional photoacoustic tomography (3D-PAT) enables noninvasive structural and functional imaging with optical absorption contrast and ultrasonic detection depth. However, its spatial resolution is limited by acoustic diffraction, and incomplete detection geometry can substantially degrade image fidelity and quantitative accuracy. Here, we present a ULM-guided model-based reconstruction framework, termed 3D-PAULMprior that incorporates sub-diffraction vascular priors from concurrent ultrasound localization microscopy (ULM) into 3D photoacoustic reconstruction. The method uses weighted regional Laplacian regularization to integrate high-resolution vascular information into the inverse problem, thereby enhancing vascular sharpness, suppressing limited-view artifacts, and improving blood oxygen saturation estimation. We validated 3D-PAULMprior using numerical simulations, tissue-mimicking phantoms, and in vivo mouse brain imaging. Compared with conventional reconstruction, 3D-PAULMprior reduced the system blurring, increased contrast-to-noise ratio, and enhanced structural similarity. In vivo, 3D-PAULMprior enhanced the delineation of the vascular structures that were poorly resolved in conventional reconstructions and produced more spatially confined sO₂ maps. These results establish 3D-PAULMprior as a robust multimodal reconstruction strategy for high-resolution structural and functional photoacoustic imaging.