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. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. 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. 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. 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.

Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always controlled for. Therefore, the aim of the current study was to investigate whole-brain functional connectivity, unbiased by a priori definition of regions or networks of interest, in medication-free depressive patients without comorbidity. We analyzed resting-state fMRI data of 19 medication-free patients with a recent diagnosis of major depression (within 6 months before inclusion) and no comorbidity, and 19 age- and gender-matched controls. Independent component analysis was employed on the concatenated data sets of all participants. Thirteen functionally relevant networks were identified, describing the entire study sample. Next, individual representations of the networks were created using a dual regression method. Statistical inference was subsequently done on these spatial maps using voxel-wise permutation tests. Abnormal functional connectivity was found within three resting-state networks in depression: (1) decreased bilateral amygdala and left anterior insula connectivity in an affective network, (2) reduced connectivity of the left frontal pole in a network associated with attention and working memory, and (3) decreased bilateral lingual gyrus connectivity within ventromedial visual regions. None of these effects were associated with symptom severity or gray matter density. We found abnormal resting-state functional connectivity not previously associated with major depression, which might relate to abnormal affect regulation and mild cognitive deficits, both associated with the symptomatology of the disorder.

IntroductionProtective immunity against pathogens relies on the production of high-affinity antibodies by long-lived plasma cells (PCs). Moreover, the ability to respond faster and with more potent antibodies to subsequent encounters with the same infectious agent depends on the generation of long-lived memory B cells. Both, high-affinity memory B cells and PCs differentiate from antigenspecific B cells that are recruited into the GC reaction during T cell-dependent immune responses (1). In GCs, B cells undergo clonal expansion, a process during which they accumulate mutations at high frequency within the Ig heavy and light chain variable (V) region genes. The highly dynamic nature of the GC reaction is characterized by repeated cycles of cell division, Ig somatic mutation, and strict selection based on the ability of B cells to capture and present antigen to T follicular helper cells (2). These processes occur within distinct areas of the GC reached by B cells through migratory paths regulated by chemokine gradients (1). The molecular determinants enabling cyclic reentry of B cells into the proliferating and mutating compartment of centroblasts, preventing terminal differentiation and the ensuing exit from the GC, remain poorly characterized.

Functional magnetic resonance imaging (fMRI) studies have shown that anatomically distinct brain regions are functionally connected during the resting state. Basic topological properties in the brain functional connectivity (BFC) map have highlighted the BFC's small-world topology. Modularity, a more advanced topological property, has been hypothesized to be evolutionary advantageous, contributing to adaptive aspects of anatomical and functional brain connectivity. However, current definitions of modularity for complex networks focus on nonoverlapping clusters, and are seriously limited by disregarding inclusive relationships. Therefore, BFC's modularity has been mainly qualitatively investigated. Here, we introduce a new definition of modularity, based on a recently improved clustering measurement, which overcomes limitations of previous definitions, and apply it to the study of BFC in resting state fMRI of 53 healthy subjects. Results show hierarchical functional modularity in the brain.

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-tomesenchymal 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.cerebral cavernous malformation | endothelial cells | β-catenin | sulindac metabolites | vascular pathology T he vascular malformations that characterize the disease known as cerebral cavernous malformation (CCM) are concentrated in the central nervous system, and they typically show multiple lumens and vascular leakage (1). These abnormalities can result in severe neurological symptoms, including hemorrhagic stroke (2), and, to date, the only possible therapy is surgery (3). In humans, loss-of-function mutations in any one of three independent genes known as cerebral cavernous malformation 1, 2, and 3 (CCM1, CCM2, and CCM3) are the cause of the genetic form of CCM (4). Similarly, in murine models, the vascular phenotype can be reproduced by endothelium-specific loss-of-function mutations of any one of these three CCM-linked genes (5-7).We have recently reported (7) that TGF-β/BMP signaling is activated after ablation of CCM1, CCM2, or CCM3 and induces endothelial-to-mesenchymal transition (EndMT) that plays a crucial role in the development of vascular malformations. Nevertheless, the sequence of signaling responses elicited by ablation of CCM genes still remains to be defined. Inhibitors of the TGF-β/BMP-signaling pathways reduce the number and size of the malformations, but not completely (7), suggesting that other signaling pathways may be implicated.The Wnt/β-catenin pathway, in synergy with TGF-β signaling (8), is responsible for the EndMT switch of endothelial cells giving rise to the heart cushion in the embryo. In addition, the knockdown of CCM1 and CCM3 expression in cultured aortic and artery endothelial cells promotes β-catenin signaling (9, 10), although no direct link with the in vivo model of the disease has been made. Activation of canonical Wnt/β-catenin signaling is critical for brain vascularization and acquisition, by the microvasculature, of blood-brain barr...