Browse Articles

The C/EBPα-(PU.1- <i>LOUP</i> ) regulatory circuit regulates monocyte/macrophage development and immune functions

Abstract The myeloid transcription factors PU.1 and CCAAT/enhancer-binding protein α (C/EBPα) are essential for monocyte/macrophage (Mo/MΦ) development, and their dysregulation has been linked to myeloid malignancies and immune disorders. Although their binding to enhancers for myeloid coding genes is established, their control of noncoding regulatory RNAs remains poorly understood. Using a comprehensive collection of putative and verified enhancers, we profiled the PU.1 cistrome and transcriptome, identifying a subset of noncoding genes that are both associated with PU.1-bound enhancers and regulated by PU.1. Notably, PU.1 induces expression of LOUP, an enhancer RNA transcribed from a locus containing a conserved PU.1 cis-regulatory element cluster, which is characterized by features of myeloid-specific enhancers. Disruption of a PU.1-binding motif in the LOUP promoter and the enhancer reduced LOUP promoter activity, whereas mutation of another PU.1-binding site within the LOUP gene body and the enhancer, which modulates enhancer-promoter interaction, diminished both Pu.1 and Loup levels in mice. The myeloid transcription factor C/EBPα, which binds to the enhancer, is necessary for PU.1 and LOUP expression as inducible deletion of Cebpa in mice led to their downregulation. LOUP depletion impaired Mo/MΦ marker and inflammatory cytokine expression as well as phagocytic function. Collectively, our findings reveal that PU.1 and the enhancer RNA LOUP form a previously unrecognized feed-forward loop, induced by C/EBPα, that drives their mutual expression and establishes a regulatory circuit. This circuit programs monocyte to macrophage differentiation and innate immune function, providing important implications for inflammatory diseases and myeloid malignancies.

HFpEF Explained — Prevalence, New Advances, and How to Diagnose

Correction: Enhancing fault detection in new energy vehicles via novel ensemble approach

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Toward XRF-like chemical sensitivity in the laboratory: first hyperspectral x-ray imaging demonstration using the novel CITIUS detector

Abstract X-ray spectral imaging is an advanced technique that enables material-sensitive imaging by exploiting energy-dependent interactions with matter. In this context, X-ray fluorescence (XRF) represents the benchmark technique. Despite its excellent elemental sensitivity, however, XRF is intrinsically inefficient because it relies on the detection of isotropically emitted secondary fluorescence induced by a focused beam on the sample. This requirement makes the technique difficult to implement with compact laboratory sources and, especially for tomographic applications, highly brilliant synchrotron sources are required. In a laboratory environment, spectral imaging and tomography are typically performed using photon-counting detectors. While this technology offers significant advantages, the limited number of energy thresholds and coarse energy resolution can hamper the separation of materials with similar attenuation properties. Hyperspectral detectors, featuring sub-keV energy resolution and virtually unlimited spectral binning, provide a technological solution to enable high-sensitivity, chemical-specific imaging in the laboratory. Here we present the first application of the novel CITIUS hyperspectral detector to X-ray micro-CT and radiography at the OptImaTo (Optimal Imaging and Tomography) laboratory (Trieste, Italy), based on a liquid MetalJet source (Excillum, Sweden) with a galinstan anode. Using multiple characteristic emission lines (Ga, In, Sn) and a 55 Fe source, a sharp energy resolution in the 0.5–0.8 keV range (full width at half maximum) was found, enabling fine energy binning suitable for advanced quantitative material identification. For the first demonstration, planar and tomographic datasets of two multi-material test samples were analyzed using a newly adapted version of the Minimum-Residual Basis Material Decomposition (MR-BMD) algorithm, optimized for hyperspectral detectors providing tens of energy bins with narrow bandwidths. Results show that the laboratory-based hyperspectral approach combined with MR-BMD enables element-sensitive imaging and, remarkably, separates materials with very similar attenuation, such as water and polypropylene. These results demonstrate accurate material identification and quantification, promisingly approaching XRF-like chemical sensitivity in the laboratory.

Evolocumab for Primary Prevention of Cardiovascular Disease

Lasting Lower Rhine–Meuse forager ancestry shaped Bell Beaker expansion

Antibacterial activity of pelargonium graveolens essential oil nanoemulsion evaluated by microfluidics and DESI mass spectrometry

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Radioluminescence 3D dose reconstruction for FLASH and conventional radiotherapy

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Fixed-point topology meets fractal memory: a Kutumba-stabilized framework for nonlocal fractal–fractional dynamics

<i>Vibrio vulnificus</i> Necrotizing Soft-Tissue Infection

Engineering thermoelectric performance in copper-doped graphene nanoribbons for energy-aware electronics

Case 12-2026: An 86-Year-Old Woman with Anorexia, Weight Loss, and Liver Lesions

Blood parameters and whole-blood transcriptomics associated with immune-related adverse events in metastatic renal cell carcinoma during nivolumab plus ipilimumab

Abstract Pretreatment immune profiles associated with immune-related adverse events (irAEs) may inform individualized management strategies, including enhanced monitoring and early toxicity intervention, in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab. In this cohort (n = 51), we analyzed pretreatment peripheral blood parameters and whole-blood transcriptomic profiles. Higher lymphocyte and monocyte counts (odds ratios [ORs] 14.36 and 9.90, respectively) were significantly associated with an increased risk of irAEs, whereas higher neutrophil counts and C-reactive protein levels (ORs 0.08 and 0.27, respectively) were associated with a decreased risk. To characterize immune pathways associated with irAE development, we performed whole-blood transcriptomic analyses. Gene set enrichment analysis revealed upregulation of lymphocyte- and humoral immunity-related pathways and downregulation of neutrophil- and inflammatory-related pathways in patients who developed irAEs. CIBERSORTx demonstrated reduced neutrophil fractions and increased proportions of CD8⁺ T cells and activated memory CD4⁺ T cells, indicating an adaptive immune-dominant profile. Exploratory analysis identified five candidate genes (ANAPC1, CDK4, MCM6, GRAP2, and BST2) that may contribute to the immune features associated with irAE development. Collectively, these findings suggest that irAE development is associated with a distinct systemic immune profile characterized by enhanced lymphocyte-related and reduced neutrophil-related immune activity.

RETRACTED: Bronchial Casts from Inhalation of Forest-Fire Smoke

How the butterfly got its name: Books in brief

Decoding the evolution of melodic and harmonic structure of Western music through the lens of network science

Abstract Music has always been central to human culture, reflecting and shaping traditions, emotions, and societal changes. Therefore, analysing the quantitative properties of musical compositions can provide insights into specific aspects of human cultural evolution. In this study, we conduct a large-scale analysis of approximately 20,000 musical pieces rooted in Western musical practices. The resulting dataset encompasses MIDI transcriptions of works from six major macro-genres, spanning nearly four centuries of musical history. We model musical composition as weighted directed networks, enabling a systematic investigation of melodic and harmonic properties through a network-based representation of music. Our results show that different genres have distinct topological and musical properties, providing valuable insights into the origins of their differences. Moreover, a temporal analysis reveals systematic changes in network-based measures, suggesting a trend toward increasing similarity and reduced complexity in the melodic and harmonic structures. Notably, within this analytical perspective, even long-established and structurally complex genres such as Classical and Jazz display patterns that are increasingly comparable to those of more recent genres.