Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3−/− animals. Smad3−/− animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3−/− aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3−/− VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibil

Skills for Growing Up-Epilepsy: An exploratory mixed methods study into a communication tool to promote autonomy and empowerment of youth with epilepsy

Introduction: The consequences of having epilepsy seriously hamper the development of autonomy for youth with epilepsy (YWE) and limit their social participation. This study was designed to provide insight into the impact of epilepsy on autonomy and empowerment and to evaluate the use of the Skills for Growing Up (SGU-Epilepsy) communication tool in pediatric epileptic care. Methods: A mixed methods designwas used to examine the impact of epilepsy on autonomy and empowerment and to evaluate the feasibility and use of the SGU-Epilepsy. Six focus groups with YWE and their parents were organized (N=27), and the benefits of the SGU-Epilepsy were evaluated (N=72). Results: Youth with epilepsy struggled with social participation. Beliefs of YWE and their parents on managing daily life and taking medication were not always similar. Parents worried about the passive attitude of YWE, but autonomy ofYWE seemed to be constrained by parents. The SGU-Epilepsy seemed to be feasible. It facilitated the communication on development and empowerment although it was sometimes confronting for parents. Not all YWE were motivated to use and discuss the tool. In the evaluation, no differences in perceived autonomy and empowerment between YWE who used SGU-Epilepsy and received usual care appeared. Conclusion: On the short-term, a beneficial effect of using the SGU-Epilepsy on autonomy and empowerment for YWE and their parents was not shown. The SGU-Epilepsy seemed to be a feasible instrument, however, to address nonmedical issues during pediatric consultations

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3−/− animals. Smad3−/− animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3−/− aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3−/− VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-β signaling, immune suppression may be more beneficial

ETpathfinder: a cryogenic testbed for interferometric gravitational-wave detectors

The third-generation (3G) of gravitational wave observatories, such as the Einstein Telescope (ET) and Cosmic Explorer, aim for an improvement in sensitivity of at least a factor of ten over a wide frequency range compared to the current advanced detectors. In order to inform the design of the 3G detectors and to develop and qualify their subsystems, dedicated test facilities are required. ETpathfinder prototype uses full interferometer configurations and aims to provide a high sensitivity facility in a similar environment as ET. Along with the interferometry at 1550 nm and silicon test masses, ETpathfinder will focus on cryogenic technologies, lasers and optics at 2090 nm and advanced quantum-noise reduction schemes. This paper analyses the underpinning noise contributions and combines them into full noise budgets of the two initially targeted configurations: (1) operating with 1550 nm laser light and at a temperature of 18 K and (2) operating at 2090 nm wavelength and a temperature of 123 K

ETpathfinder: a cryogenic testbed for interferometric gravitational-wave detectors

The third-generation of gravitational wave observatories, such as the Einstein Telescope (ET) and Cosmic Explorer (CE), aim for an improvement in sensitivity of at least a factor of ten over a wide frequency range compared to the current advanced detectors. In order to inform the design of the third-generation detectors and to develop and qualify their subsystems, dedicated test facilities are required. ETpathfinder prototype uses full interferometer configurations and aims to provide a high sensitivity facility in a similar environment as ET. Along with the interferometry at 1550 nm and silicon test masses, ETpathfinder will focus on cryogenic technologies, lasers and optics at 2090 nm and advanced quantum-noise reduction schemes. This paper analyses the underpinning noise contributions and combines them into full noise budgets of the two initially targeted configurations: 1) operating with 1550 nm laser light and at a temperature of 18 K and 2) operating at 2090 nm wavelength and a temperature of 123 K

ETpathfinder: a cryogenic testbed for interferometric gravitational-wave detectors

The third-generation of gravitational wave observatories, such as the Einstein Telescope (ET) and Cosmic Explorer (CE), aim for an improvement in sensitivity of at least a factor of ten over a wide frequency range compared to the current advanced detectors. In order to inform the design of the third-generation detectors and to develop and qualify their subsystems, dedicated test facilities are required. ETpathfinder prototype uses full interferometer configurations and aims to provide a high sensitivity facility in a similar environment as ET. Along with the interferometry at 1550 nm and silicon test masses, ETpathfinder will focus on cryogenic technologies, lasers and optics at 2090 nm and advanced quantum-noise reduction schemes. This paper analyses the underpinning noise contributions and combines them into full noise budgets of the two initially targeted configurations: 1) operating with 1550 nm laser light and at a temperature of 18 K and 2) operating at 2090 nm wavelength and a temperature of 123 K

ETpathfinder: a cryogenic testbed for interferometric gravitational-wave detectors

The third-generation of gravitational wave observatories, such as the Einstein Telescope (ET) and Cosmic Explorer (CE), aim for an improvement in sensitivity of at least a factor of ten over a wide frequency range compared to the current advanced detectors. In order to inform the design of the third-generation detectors and to develop and qualify their subsystems, dedicated test facilities are required. ETpathfinder prototype uses full interferometer configurations and aims to provide a high sensitivity facility in a similar environment as ET. Along with the interferometry at 1550 nm and silicon test masses, ETpathfinder will focus on cryogenic technologies, lasers and optics at 2090 nm and advanced quantum-noise reduction schemes. This paper analyses the underpinning noise contributions and combines them into full noise budgets of the two initially targeted configurations: 1) operating with 1550 nm laser light and at a temperature of 18 K and 2) operating at 2090 nm wavelength and a temperature of 123 K

ETpathfinder: a cryogenic testbed for interferometric gravitational-wave detectors

The third-generation of gravitational wave observatories, such as the Einstein Telescope (ET) and Cosmic Explorer (CE), aim for an improvement in sensitivity of at least a factor of ten over a wide frequency range compared to the current advanced detectors. In order to inform the design of the third-generation detectors and to develop and qualify their subsystems, dedicated test facilities are required. ETpathfinder prototype uses full interferometer configurations and aims to provide a high sensitivity facility in a similar environment as ET. Along with the interferometry at 1550 nm and silicon test masses, ETpathfinder will focus on cryogenic technologies, lasers and optics at 2090 nm and advanced quantum-noise reduction schemes. This paper analyses the underpinning noise contributions and combines them into full noise budgets of the two initially targeted configurations: 1) operating with 1550 nm laser light and at a temperature of 18 K and 2) operating at 2090 nm wavelength and a temperature of 123 K