The Hippo Kinase Pathway: a master regulator of proliferation, development and differentiation

Hippo signaling transduction pathway is widely conserved through evolution and controls cell growth, homeostasis, apoptosis, commitment, differentiation and senescence. It consists of a conserved kinase cascade whose final targets are the transcriptional coactivator Yorkie (Yki) in Drosophila and the homologues YAP and TAZ in mammals. These transcriptional coactivators are unable to bind DNA per se, and can regulate the activity of their target genes only in association with transcription factors. In Drosophila, Yki associates with the transcription factors Sd and Hth regulating pro-proliferative and anti-apoptotic genes. In mammals instead, YAP/TAZ can associate with several distinct transcription factors. This depends from the type of signals to which cells are subjected, the cell type and the developmental stage. The transcriptional outcome resulting from this association can be either pro-apoptotic or pro-proliferative. Hippo pathway dysregulation has been associated with several pathologic conditions (tissue overgrowth, developmental defects and cancer). In particular, solid tumors show an upregulation or hyperactivation of YAP/TAZ, while several hematologic tumors are associated with YAP downregulation. This might suggest that the Hippo pathway holds the potential to be an attractive target for novel therapeutic approaches for cancer

Network sensitivity of systemic risk

A growing body of studies on systemic risk in financial markets has emphasized the key importance of taking into consideration the complex interconnections among financial institutions. Much effort has been put into modeling the contagion dynamics of financial shocks and into assessing the resilience of specific financial markets, either using real network data, reconstruction techniques or simple toy networks. Here, we address the more general problem of how shock propagation dynamics depend on the topological details of the underlying network. To this end, we consider different realistic network topologies, all consistent with balance sheet information obtained from real data on financial institutions. In particular, we consider networks of varying density and with different block structures. In addition, we diversify in the details of the shock propagation dynamics. We confirm that the systemic risk properties of a financial network are extremely sensitive to its network features. Our results can aid in the design of regulatory policies to improve the robustness of financial markets

Aberrant transcriptional and post-transcriptional regulation of SPAG5, a YAP-TAZ-TEAD downstream effector, fuels breast cancer cell proliferation

Sperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer

Folic Acid Exposure Rescues Spina Bifida Aperta Phenotypes in Human Induced Pluripotent Stem Cell Model

Neural tube defects (NTDs) are severe congenital abnormalities, caused by failed closure of neural tube during early embryonic development. Periconceptional folic acid (FA) supplementation greatly reduces the risk of NTDs. However, the molecular mechanisms behind NTDs and the preventive role of FA remain unclear. Here, we use human induced pluripotent stem cells (iPSCs) derived from fetuses with spina bifida aperta (SBA) to study the pathophysiology of NTDs and explore the effects of FA exposure. We report that FA exposure in SBA model is necessary for the proper formation and maturation of neural tube structures and robust differentiation of mesodermal derivatives. Additionally, we show that the folate antagonist methotrexate dramatically affects the formation of neural tube structures and FA partially reverts this aberrant phenotype. In conclusion, we present a novel model for human NTDs and provide evidence that it is a powerful tool to investigate the molecular mechanisms underlying NTDs, test drugs for therapeutic approaches

In the rat maximal dentate activation model of partial complex epilepsy, the anticonvulsant activity of levetiracetam is modulated by nitric oxide-active drugs

In the rat maximal dentate activation model of partial complex epilepsy, the anticonvulsant activity of levetiracetam is modulated by nitric oxide-active drug

Ancient settlements in central Italy and capable faults: consequences for urban planning in the L'Aquila region.

Active and capable faults (FAC) represent one of the most important risk for human activities in seismically active areas. The scientific and civil communities are constantly increasing their attention about this matter. In the Italian context, the post seismic reconstruction after the 2009 April 6th L'Aquila earthquake clearly highlighted the need of criteria for the old settlement rebuilding and/or the choice of new sites suitable for new villages. We focused our study on the identification of FACs in a sector of the central Apennines characterized by a high density of Quaternary faults and by a high density distribution of ancient urban settlements. Using classical geological, geomorphological and paleoseismological approaches, together with a temporal criteria and bibliographic analysis, we evaluate the activity and capability of the recognized faults. Then, we propose some analysis and reflections about the regulation concerning the FAC in Italy, taking into account the huge number and high density of FACs that involves the Italian urban settlements.Published263-2662T. Tettonica attivaN/A or not JCRrestricte

Ancient settlements in central Italy and capable faults: consequences for urban planning in the L'Aquila region.

Active and capable faults (FAC) represent one of the most important risk for human activities in seismically active areas. The scientific and civil communities are constantly increasing their attention about this matter. In the Italian context, the post seismic reconstruction after the 2009 April 6th L'Aquila earthquake clearly highlighted the need of criteria for the old settlement rebuilding and/or the choice of new sites suitable for new villages. We focused our study on the identification of FACs in a sector of the central Apennines characterized by a high density of Quaternary faults and by a high density distribution of ancient urban settlements. Using classical geological, geomorphological and paleoseismological approaches, together with a temporal criteria and bibliographic analysis, we evaluate the activity and capability of the recognized faults. Then, we propose some analysis and reflections about the regulation concerning the FAC in Italy, taking into account the huge number and high density of FACs that involves the Italian urban settlements