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Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar type II cells act as epithelial stem cells, being able to transdifferentiate into alveolar type I cells, which mediate gas exchange, thus contributing to lung homeostasis and repair after damage. Impaired epithelial transdifferentiation is emerging as a major pathogenetic mechanism driving both onset and progression of fibrosis in the lung. Here, we show that lung endothelial cells secrete angiocrine factors that regulate alveolar cell differentiation. Specifically, we build on our previous data on the anti-fibrotic microRNA-200c and identify the Vascular Endothelial Growth Factor receptor 1, also named Flt1 , as its main functional target in endothelial cells. Endothelial-specific knockout of Flt1 reproduces the anti-fibrotic effect of microRNA-200c against pulmonary fibrosis and results in the secretion of a pool of soluble factors and matrix components able to promote epithelial transdifferentiation in a paracrine manner. Collectively, these data indicate the existence of a complex endothelial-epithelial paracrine crosstalk in vitro and in vivo and position lung endothelial cells as a relevant therapeutic target in the fight against pulmonary fibrosis.

Deep learning is widely applied in bioinformatics and biomedical imaging, due to its ability to perform various clinical tasks automatically and accurately. In particular, the application of deep learning techniques for the automatic identification of glomeruli in histopathological kidney images can play a fundamental role, offering a valid decision support system tool for the automatic evaluation of the Karpinski metric. This will help clinicians in detecting the presence of sclerotic glomeruli in order to decide whether the kidney is transplantable or not. In this work, we implemented a deep learning framework to identify and segment sclerotic and non-sclerotic glomeruli from scanned Whole Slide Images (WSIs) of human kidney biopsies. The experiments were conducted on a new dataset collected by both the Siena and Trieste hospitals. The images were segmented using the DeepLab V2 model, with a pre-trained ResNet101 encoder, applied to 512 × 512 patches extracted from the original WSIs. The results obtained are promising and show a good performance in the segmentation task and a good generalization capacity, despite the different coloring and typology of the histopathological images. Moreover, we present a novel use of the CD10 staining procedure, which gives promising results when applied to the segmentation of sclerotic glomeruli in kidney tissues.

Summary Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis.

Freezing-cryosurgery, and electrolysis-electrochemical therapy (EChT), are two important minimally invasive surgery tissue ablation technologies. Despite major advantages they also have some disadvantages. Cryosurgery cannot induce cell death at high subzero freezing temperatures and requires multiple freeze thaw cycles, while EChT requires high concentrations of electrolytic products-which makes it a lengthy procedure. Based on the observation that freezing increases the concentration of solutes (including products of electrolysis) in the frozen region and permeabilizes the cell membrane to these products, this study examines the hypothesis that there could be a synergistic effect between freezing and electrolysis in their use together for tissue ablation. Using an animal model we refer to as vivens ex vivo, which may be of value in reducing the use of animals for experiments, combined with a Hematoxylin stain of the nucleus, we show that there are clinically relevant protocols in which the cell nucleus appears intact when electrolysis and freezing are used separately but is affected by certain combinations of electrolysis and freezing.

Background Histopathological analysis represents the gold standard in clinical practice for diagnosing skin neoplasms. While the current diagnostic workflow has specialized in producing robust and accurate results, interpreting tissue architecture and malignant cellular morphology correctly remains one of the greatest challenges for pathologists. This paper aims to explore the prospect of applying x‐ray virtual histology to human skin tumor excisions and correlating it with the histological validation. Materials and Methods Seven skin biopsies containing intriguing melanoma types and pigmented skin lesions were scanned using x‐ray Computed micro‐Tomography (μCT) and then sectioned for conventional histology assessment. Results The tissue microarchitecture reconstructed by μCT offers detailed insights into diagnosing the malignancy or benignity of the skin lesions. Three‐dimensional reconstruction via x‐ray virtual histology reveals infiltrative patterns in basal cell carcinoma and evaluated invasiveness in melanoma. The technology enables the identification of pagetoid distributions of neoplastic cells and the assessment of melanoma depth in three dimensions. Conclusion Although the proposed approach is not intended to replace conventional histology, the non‐destructive nature of the sample and the clarity provided by virtual inspection demonstrate the promising impact of μCT as a valid support method prior to conventional histological sectioning. Indeed, μCT images can suggest the optimal sectioning position before using a microtome, as is commonly performed in histological practice. Moreover, the three‐dimensional nature of the proposed approach paves the way for a more accurate assessment of significant prognostic factors in melanoma, such as Breslow thickness, by considering the whole micro‐volume rather than a two‐dimensional observation.

Bilirubin neurotoxicity has been studied for decades and has been shown to affect various mechanisms via significant modulation of gene expression. This suggests that vital regulatory mechanisms of gene expression, such as epigenetic mechanisms, could play a role in bilirubin neurotoxicity. Histone acetylation has recently received attention in the CNS due to its role in gene modulation for numerous biological processes, such as synaptic plasticity, learning, memory, development and differentiation. Aberrant epigenetic regulation of gene expression in psychiatric and neurodegenerative disorders has also been described. In this work, we followed the levels of histone 3 lysine 14 acetylation (H3K14Ac) in the cerebellum (Cll) of the developing (2, 9, 17 days after the birth) and adult Gunn rat, the natural model for neonatal hyperbilirubinemia and kernicterus. We observed an age-specific alteration of the H3K14Ac in the hyperbilirubinemic animals. The GeneOntology analysis of the H3K14Ac linked chromatin revealed that almost 45% of H3K14Ac ChiP-Seq TSS-promoter genes were involved in CNS development including maturation and differentiation, morphogenesis, dendritogenesis, and migration. These data suggest that the hallmark Cll hypoplasia in the Gunn rat occurs also via epigenetically controlled mechanisms during the maturation of this brain structure, unraveling a novel aspect of the bilirubin-induced neurotoxicity.

Mesothelioma is a malignant tumor mainly correlated to occupational asbestos exposure. Rare reports describe its occurrence also in animals, mainly linked to asbestos in the environment. Asbestos exposure is demonstrated by the appearance of characteristic histological hallmarks: asbestos containing ferruginous bodies that are iron-based structures forming around fibers and also other dust particles. Here we present a clinical case of a suspect of mesothelioma in the peritoneum of a dog with parallel histological observation of ferruginous bodies. To possibly correlate the dog tumor to environmental exposure, we performed X-ray fluorescence (XRF) analyses at two different synchrotrons to resolve the ferruginous bodies’ composition. While the histological examination diagnoses a tubulo-papillary mesothelioma, the XRF analyses show that ferruginous bodies contain Si particles, resembling formations of exogenous origin; however, the morphology is unlikely that of asbestos fibers. We speculate that the peritoneal mesothelioma of this dog could be related to environmental exposure to non-asbestos material.

Structural variants (SVs) correspond to different types of genomic variants larger than 50 bp. Many findings suggest the use of long-read (LR) rather than short-read (SR) sequencing to improve the accuracy of SVs detection. Here, we present the results of an in-depth analysis for detection of SVs, mainly large insertions and deletions, in 14 French bovine breeds, based on whole-genome sequence (WGS) data comprising 176 LR and 571 SR samples, with 154 individuals having both LR and SR data available. We first investigated possible biases on the performances of well-known SVs detection tools, namely CUTESV, PBSV, and SNIFFLES, using LR from different technologies, including PacBio HiFi, Oxford ONT, and PacBio CLR. We subsequently highlighted the abilities of tools for detecting SVs (DELLY, LUMPY, and MANTA) and for genotyping known SVs (GRAPHTYPER, SVTYPER, PARAGRAPH, and VG toolkit) using SR data. We then show how the incremental composition of samples in the reference panel affected the SVs genotyping for six validation individuals sequenced in SR. We then searched for the optimal parameters and created the final SVs reference panel consisting of 25,191 deletions and 30,118 insertions. Finally, we emphasized the landscape of the genotyped SVs segregating across 571 SR individuals of 14 breeds.

Although several maize genome assemblies are publicly available, those of lines important to European breeding programs are underrepresented. Using PacBio long-read sequencing, we assembled high-quality chromosome-level genomes of 29 key lines of European breeding relevance, encompassing Northern flint and European flint lines used for adaptation to Northern European climate, lines derived from European landraces of tropical origin, and American temperate dent lines adapted to European regions. Genome assembly sizes range from 2.17 to 2.35 gigabases, with scaffold N50s ranging from 219 to 254 megabases. Completeness assessment revealed BUSCO scores ranging from 97.7 to 98.5 and merqury completeness scores ranging from 96.62 to 98.30. Calling structural variants and SNPs relative to the B73 reference sequence revealed the expected separation of inbred groups. Flint lines contribute the highest number of novel variants, thus emphasizing the importance of sequencing flint material to complete the maize pangenome. These high-quality genome assemblies therefore provide new opportunities to understand the dynamics of maize structural variation, and to identify the functional variations underlying maize phenotypic diversity.

This work investigated the sorption and the diffusion properties of CO2 under high pressure and the further modificationsinduced in Poly(lactic acid) (PLA) thin layers. Poly(ethylene terephtalate) (PET) was also considered for comparativepurposes. Firstly, from thermodynamic equilibrium, the CO2 sorption isotherm (two sorption-desorption cycles, up to25 bar, at 25 °C) gave strong evidence of a physisorption mechanism and of a hysteresis phenomenon. Infrared spectroscopyanalysis confirmed that no chemical reaction occurred. Secondly, from the kinetics aspect, the CO2 diffusion coefficient wasfound around 10–13 m2·s–1 and was slightly faster for sorption compared to desorption. Additionally, when CO2 sorption occurred,the PLA structure and its functional properties were modified due to plasticization and swelling. CO2 plasticizationreduced the glass transition temperature of PLA and accelerated the physical ageing of the polymer. These results are thereforeof significant importance in industrial processing and applications which involve close contact between CO2 and PLA.