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Cerebral cavernous malformations associated with loss of function of Ccm1 are shown to be formed by endothelial cells undergoing endothelial-to-mesenchymal transition (EndMT) induced by TGF-β and BMP signalling; inhibition of TGF-β and BMP signalling prevents EndMT and the appearance of CCM lesions. CCM disease pathology Cerebral cavernous malformation (CCM) is a genetic disease causing lesions of the brain vasculature that can lead to seizures and stroke. Neurosurgery is the only treatment offered today. CCM lesions are caused by loss-of-function mutations in one of three genes: CCM1 , CCM2 and CCM3 . Elisabetta Dejana and colleagues show that lesions associated with loss of function of CCM1 are formed by endothelial cells undergoing endothelial-to-mesenchymal transition (EndMT), induced by activation of transforming growth factor-β (TGF-β) signalling. They show that inhibition of TGF-β signalling prevents EndMT and the appearance of CCM lesions in vivo . Inhibitors of various steps of the TGF-β and bone morphogenetic protein signalling pathways might therefore be candidates to reduce or reverse the development of CCM lesions. Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1 ), CCM2 ( OSM ) and CCM3 ( PDCD10 ), and occurs in both sporadic and familial forms 1 . Recent studies 2 , 3 , 4 , 5 , 6 , 7 have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear 8 . Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions 9 . Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium 10 , 11 , 12 . Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.

Accurate and automated detection and tracking of cells in microscopy images is a persistent challenge in biotechnology and biomedical research. Effective detection and tracking are crucial for understanding biological processes and extracting meaningful data for subsequent simulations. In this study, we present an integrated pipeline that leverages a fine-tuned YOLOv8x model for detecting cells and cell divisions across microscopy image series. While YOLOv8x exhibits strong detection capabilities, it occasionally misses certain cells, leading to gaps in data. To mitigate this, we incorporate the DeepSORT tracking algorithm, which enhances data association and reduces the cells’ identity (ID) switches by utilizing a pre-trained convolutional network for robust multi-object tracking. This combination ensures continuous detection and compensates for missed detections, thereby improving overall recall. Our approach achieves a recall of 93.21% with the enhanced DeepSORT algorithm, compared to the 53.47% recall obtained by the original YOLOv8x model. The proposed pipeline effectively extracts detailed information from structured image datasets, providing a reliable approximation of cellular processes in culture environments.

This paper presents a network-based bibliometric analysis of digital transformation in the shipping industry, a sector undergoing rapid change due to advancements in automation, artificial intelligence, blockchain, and Internet of Things. The study synthesizes existing knowledge to identify trends, challenges, and opportunities for industry stakeholders and researchers. Unlike previous literature reviews, this work adopts a graph theory approach applied to a large dataset of scientific publications, without predefined technological or industrial sub-domains. Data were collected from EBSCO, ProQuest, and IEEE eXplore, then refined using OpenAlex to comprise 2293 scientific publications. The analysis includes descriptive statistics, co-authorship network analysis, co-citation network analysis, and thematic analysis. The findings reveal a significant increase in publications since 2005, with exponential growth after 2015. They also suggest a potential inflection point after 2024. A small percentage of authors and institutions account for a disproportionate share of publications, suggesting a skewed distribution of research efforts and encouraging funding agencies to broaden maritime research worldwide. The co-authorship network exhibits a heavy-tail distribution and interconnected communities, indicating extensive national and international collaborations. The co-citation analysis identifies key research areas such as fuel consumption optimization, safety and risk management, and smart port development. Thematic analysis highlights the growing importance of artificial intelligence and cybersecurity.

Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell–selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor–independent stimulation of β-catenin transcription activity in CCM3 -deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin–driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3 -deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

Reproducing the characteristics and the functional responses of the blood-brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.

The reconstruction in MRI assumes a uniform radio-frequency field. However, this is violated due to coil field nonuniformity and sensitivity variations. In whole-body MRI, the nonuniformities are more complex due to the imaging with multiple coils that typically have different overall sensitivities that result in sharp sensitivity changes at the junctions between adjacent coils. These lead to images with anatomically inconsequential intensity nonuniformities that include jump discontinuities of the intensity nonuniformities at the junctions corresponding to adjacent coils. The body is also imaged with multiple contrasts that result in images with different nonuniformities. A method is presented for the joint intensity uniformity restoration of two such images to achieve intensity homogenization. The effect of the spatial intensity distortion on the auto-co-occurrence statistics of each image as well as on the joint-co-occurrence statistics of the two images is modeled in terms of Point Spread Function (PSF). The PSFs and the non-stationary deconvolution of these PSFs from the statistics offer posterior Bayesian expectation estimates of the nonuniformity with Bayesian coring. Subsequently, a piecewise smoothness constraint is imposed for nonuniformity. This uses non-isotropic smoothing of the restoration field to allow the modeling of junction discontinuities. The implementation of the restoration method is iterative and imposes stability and validity constraints of the nonuniformity estimates. The effectiveness and accuracy of the method is demonstrated extensively with whole-body MRI image pairs of thirty-one cancer patients.

In Mathematical Music theory, the Aperiodic Tiling Complements Problem consists in finding all the possible aperiodic complements of a given rhythm A. The complexity of this problem depends on the size of the period n of the canon and on the cardinality of the given rhythm A. The current state-of-the-art algorithms can solve instances with n smaller than 180. In this paper, we propose an ILP formulation and a SAT Encoding to solve this mathemusical problem, and we use the Maplesat solver to enumerate all the aperiodic complements. We then enhance the SAT model in two different ways. First, we enforce the SAT model with a set of clauses that retrieves the solutions up to translation. Second, we propose a decomposition of the solution space that allows to parallelize the resolution of the problem. We validate our different models using several different periods and rhythms and we compute for the first time the complete list of aperiodic tiling complements of standard Vuza rhythms for canons with period n=180,420,900.

Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte-induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.

Many deadlock prevention approaches have been suggested in the literature for Petri net models of flexible manufacturing systems, based on siphon enumeration and control. With medium and large problem dimensions, such methods often require both an excessive computational load and extremely large control sub-nets, making them unfeasible or impractical. In this work, a simple approach is proposed for the design of sub-optimal but compact controllers. The approach is based on the anticipated allocation of a sub-set of resources that decouples the deadlock prevention problem in two much smaller and simpler problems, each devoted to the deadlock prevention for a sub-set of resources only. The application of the two designed control sub-nets to the original Petri net together with resource anticipation ensures deadlock prevention. A heuristic algorithm is also provided for the selection of a suitable resource partition, in order to maximize the control quality and performance. Several illustrative benchmark examples are provided.

Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell–selective ablation of theCCM3gene. We report an early, cell-autonomous, Wnt-receptor–independent stimulation of β-catenin transcription activity inCCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin–driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelialCCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.