AbstractIRF4, a transcription factor in the interferon regulatory factor family, is a key regulator in immune cell differentiation indicated to have an essential role in the development of lymphoid malignancies. Genome-wide association studies previously identified a set of overlapping mutations within the IRF4 DNA-binding domain in T-cell lymphoma and multiple myeloma, several of which appeared to be associated with better prognosis. Mapping these mutations to the known crystal structure of the IRF4:PU.1:DNA ternary complex and a new structure of the IRF4 DNA-binding domain in the apo state suggested they might interfere with DNA-binding, directly or via destabilisation of domain structure. We characterised these cancer-associated IRF4 mutants experimentally using the recombinant IRF4 DNA-binding domain (DBD)in vitroand examined the clinically relevant mutant K123Rin cellulo. Using fluorescence polarisation, surface plasmon resonance, differential scanning fluorimetry and molecular dynamics, we find that mutation may give rise to significant differences in DNA-binding kinetics and thermal stability without compromising the affinity of IRF4 DNA-binding. The K123R IRF4 mutant showed increased transcriptional activity via a luciferase reporter assay and increased nuclear partitioning, which may be preferentially selected for in multiple myeloma. We discuss our observations in relation to the improved prognosis conferred by this mutation.

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• Pub. Date : 2025
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With the significant advancements in nuclear technology, countries have invested considerable research into radiation shielding and protection materials. Neutrons and gamma photons have strong penetrating abilities, which can directly jeopardize human health or lead to the failure of electronic components. Therefore, developing high-performance materials for neutron and gamma photon radiation shielding has become a critical priority. Gadolinium (Gd), a rare earth element with the largest neutron absorption cross-section among natural elements, performs excellently as a neutron absorber. Gd-containing radiation composite shielding materials are typically classified into four main categories based on their matrix: metal-based, glass-based, ceramic-based, and polymer-based. This paper reviews the current research status of these four types of radiation shielding materials. It provides a comprehensive summary and evaluation of each material’s preparation processes, microstructures, mechanical properties, and shielding performance. Additionally, the paper discusses the role of Gd in each type of matrix material and addresses the current challenges in the field.

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• Pub. Date : 2025
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ABSTRACTIncomplete mapping of gene expression within human (epiphyseal) growth plates contributes to the challenges of diagnosing and treating patients with skeletal growth disorders. To address this issue, we applied spatially resolved transcriptomics to rare growth plate biopsies obtained from healthy adolescents. In addition to identifying novel markers of each zone of the human growth plate, spatial profiling revealed that the expression of genes associated with poorly understood growth disorders, including NKX3-2, SGMS2 and WNK4, is restricted to specific human growth plate zones. By elaborating on the low transcriptional activity of resting zone chondrocytes, we found that a subset of these cells exists in a functionally quiescent statein vivo, as determined by their predominantly nuclear mRNA, abundant heterochromatin, and ability to exit the G0 phase under specific conditions - features shared with skeletal stem cells in mouse growth plates. Additionally, we identified distinct and overlapping sub-populations of human resting zone chondrocytes; an exploration of their hierarchy determined that CHRDL2 and/or SFRP5-positive sub-populations are among the least quiescent resting zone cells. In summary, we generated the most comprehensive gene expression characterization of the human growth plate, which revealed novel zone-specific markers, new primary growth disorders, candidate pharmacological targets, and led us to uncover sub-populations of resting zone chondrocytes with features of quiescent stem cells. These results contribute to a better understanding of the cellular and molecular mechanisms governing human height and can facilitate improved diagnosis and treatment strategies of patients with skeletal growth disorders.

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• Pub. Date : 2025
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AbstractAimsIt was recently demonstrated that the intracellular signalling phosphatase calcineurin is subject to cleavage by the protease calpain, resulting in a truncated calcineurin fragment that is a strong inductor of myocardial hypertrophy. We now address the question of whether inhibition of calpain function in cardiomyocytes, and thereby prevention of calcineurin truncation, attenuates development of myocardial hypertrophy.Methods and resultsWe generated a transgenic mouse model with conditional cardiac calpastatin overexpression (CAST OE) and compared their cardiac hypertrophic response to angiotensin‐II (AngII) with that of non‐induced control animals. Angiotensin‐II osmotic mini‐pumps were removed 3 weeks after implantation and cardiac hypertrophy was re‐evaluated 3 weeks after pump removal. Induction of calpastatin overexpression resulted in 88% inhibition of calpain activity and suppressed calcineurin truncation. In CAST OE mice, basal phenotype and AngII‐induced myocardial hypertrophy were comparable with non‐induced controls (mean heart to body weight ratios ± SD in milligrams per gram: CAST OE, 4.8 ± 0.4; CAST OE + AngII, 7.1 ± 0.5; non‐induced, 4.9 ± 0.4; non‐induced + AngII, 7.2 ± 0.4). However, CAST OE mice demonstrated a complete reversal of hypertrophy when angiotensin‐II was removed, whereas hypertrophy persisted in non‐induced controls (CAST OE 5.0 ± 0.5; non‐induced 7.0 ± 0.4; P < 0.0001). Persistent hypertrophy in controls was accompanied by nuclear accumulation of truncated calcineurin and elevated activity of the Nuclear Factor of Activated T‐cells pathway. Moreover, we found that truncated calcineurin was insufficiently ubiquitinylated compared with its full‐length form and thus escaped degradation over several weeks in our in vivo experiments.ConclusionsOur data demonstrate that calpain‐mediated cleavage results in nuclear accumulation of a truncated, constitutively active and degradation‐resistant calcineurin isoform that sustains a long‐term myocardial hypertrophic response to angiotensin‐II beyond withdrawal of the stimulus. Cardiomyocyte specific calpain inhibition by transgenic calpastatin overexpression prevented the post‐stimulus myocardial hypertrophic response.

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Abstract Purpose The new high resolution positron emission tomography (PET) myocardial perfusion imaging tracer, 18F-flurpiridaz, is set to enter clinical use soon following its recent regulatory approval. We developed an approach for evaluating subendocardial analysis for stress total perfusion deficit (TPD) and ischemic TPD, assessed its performance for detection of coronary artery disease (CAD) and compared these measures to transmural analysis and expert physician assessments. Methods Myocardial perfusion image data from the 18F-flurpiridaz phase III clinical trial (NCT01347710) were used. The subendocardial layer was automatically defined on the left ventricular contours and used for the derivation of polar maps. Areas under the receiver operating characteristic curve (AUC) for quantitative and visual measures were evaluated for detecting CAD, defined as ≥ 50% stenosis by invasive coronary angiography. Results In total, 753 cases were analyzed, with a median age of 63 (interquartile range 56,69) and 69% male. AUC for detecting ≥ 50% stenosis was higher for subendocardial than transmural analysis for stress (0.795 vs. 0.762, respectively; p = 0.013) and ischemic (0.795 vs. 0.767, respectively; p = 0.049) TPD. Subendocardial and transmural TPD achieved diagnostic performance greater than or comparable to that of the readers’ assessments in the total population as well as across subgroups of interest. Conclusion Subendocardial analysis of ischemic perfusion improves the detection of CAD compared to transmural quantitative analysis or expert visual reading. These measures can be derived automatically with minimal user interaction. Integrating TPD quantitative measures could standardize the diagnostic approach for this novel tracer.

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• Pub. Date : 2025
• Page : pp.104612-104612
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Abstract SARS-CoV-2 can encode circular RNAs (circRNAs); however, the potential effects of exogenous SARS-CoV-2 circRNAs on cardiovascular sequelae remain unknown. Three circRNAs derived from the nucleocapsid (N) gene of SARS-CoV-2, namely, circSARS-CV2-Ns, were identified for functional studies. In particular, circSARS-CV2-N1368 was shown to enhance platelet adhesiveness to endothelial cells (ECs) and inhibit EC-dependent vascular relaxation. Moreover, exogenous expression of circSARS-CV2-N1368 suppressed EC proliferation and migration and decreased angiogenesis and cardiac organoid beating. Mechanistically, we elucidated that circSARS-CV2-N1368 sponged the microRNA miR-103a-3p, which could reverse circSARS-CV2-N1368-induced EC damage. Additionally, activating transcription factor 7 (ATF7) was identified as a target gene of miR-103a-3p, and Toll-like receptor 4 (TLR4) was verified as a downstream gene of ATF7 that mediates circARS-CV2-N1368-induced activation of nuclear factor kappa B (NF-κB) signaling and ROS production in ECs. Importantly, the reactive oxygen species (ROS) scavenger NAC mitigated the circSARS-CV2-N1368-promoted EC impairment. Our findings reveal that the TLR4/NF-κB/ROS signal pathway is critical for mediating circSARS-CV2-N1368-promoted oxidative damage in ECs, providing insights into the endothelial impairment caused by circSARS-CV2-Ns.

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AbstractThis review discusses the evolving role of radiotherapy (RT) in the surgical treatment of pancreatic ductal adenocarcinoma (PDAC). Despite advancements in multidisciplinary treatment, PDAC continues to present significant challenges in surgical treatment strategies. Neoadjuvant therapy, in combination with chemotherapy and RT, aims to improve patient outcomes by reducing tumor size, controlling local spread, and eradicating micrometastatic disease that cannot be detected at the time of diagnosis. Recent randomized trials have shown that both neoadjuvant chemoradiotherapy (NACRT) and neoadjuvant chemotherapy (NAC) improve surgical outcomes compared with upfront surgery. A network meta‐analysis integrating multiple trials demonstrated that NACRT significantly improves overall survival compared to NAC (HR: 0.79, 95% CI: 0.64–0.98). NACRT has also shown advantage in local tumor control. For locally advanced PDAC, the role of RT in conversion therapy is being actively investigated. The integration of RT in treatment regimens requires careful consideration of its therapeutic benefits against potential adverse effects. Although experimental studies suggest potential immunological benefits of RT, clinical validation remains incomplete. Recent advances in radiation delivery techniques have improved the therapeutic ratio, although further clinical validation is needed. The optimal sequence and combination of these treatment modalities with surgical strategies continue to be evaluated in ongoing clinical trials. This review synthesizes evidence from recent clinical trials and previous studies to evaluate the effectiveness, challenges, and potential of RT in PDAC treatment, aiming to inform both current clinical practice and future research directions.

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