Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Blockchain-Enabled iWellChain Framework Integration With the National Medical Referral System: Development and Usability Study.

BACKGROUND: Medical referral is the transfer of a patient's care from one physician to another upon request. This process involves multiple steps that require provider-to-provider and provider-to-patient communication. In Taiwan, the National Health Insurance Administration (NHIA) has implemented a national medical referral (NMR) system, which encourages physicians to refer their patients to different health care facilities to reduce unnecessary hospital visits and the financial stress on the national health insurance. However, the NHIA's NMR system is a government-based electronic medical referral service, and its referral data access and exchange are limited to authorized clinical professionals using their national health smart cards over the NHIA virtual private network. Therefore, this system lacks scalability and flexibility and cannot establish trusting relationships among patients, family doctors, and specialists. OBJECTIVE: To eliminate the existing restrictions of the NHIA's NMR system, this study developed a scalable, flexible, and blockchain-enabled framework that leverages the NHIA's NMR referral data to build an alliance-based medical referral service connecting health care facilities. METHODS: We developed a blockchain-enabled framework that can integrate patient referral data from the NHIA's NMR system with electronic medical record (EMR) and electronic health record (EHR) data of hospitals and community-based clinics to establish an alliance-based medical referral service serving patients, clinics, and hospitals and improve the trust in relationships and transaction security. We also developed a blockchain-enabled personal health record decentralized app (DApp) based on our blockchain-enabled framework for patients to acquire their EMR and EHR data; DApp access logs were collected to assess patients' behavior and investigate the acceptance of our personal authorization-controlled framework. RESULTS: The constructed iWellChain Framework was installed in an affiliated teaching hospital and four collaborative clinics. The framework renders all medical referral processes automatic and paperless and facilitates efficient NHIA reimbursements. In addition, the blockchain-enabled iWellChain DApp was distributed for patients to access and control their EMR and EHR data. Analysis of 3 months (September to December 2018) of access logs revealed that patients were highly interested in acquiring health data, especially those of laboratory test reports. CONCLUSIONS: This study is a pioneer of blockchain applications for medical referral services, and the constructed framework and DApp have been applied practically in clinical settings. The iWellChain Framework has the scalability to deploy a blockchain environment effectively for health care facilities; the iWellChain DApp has potential for use with more patient-centered applications to collaborate with the industry and facilitate its adoption.

Correction: Src and SHP2 coordinately regulate the dynamics and organization of vimentin filaments during cell migration.

The original version of this article contained error in Fig. 6b, where several panels were missing from the published version. The corrected version of this Figure now appears in the article.

Src and SHP2 coordinately regulate the dynamics and organization of vimentin filaments during cell migration.

Vimentin intermediate filaments (VIFs), expressed in most mesenchymal and cancer cells, undergo dramatic reorganization during cell migration; however, the mechanism remains obscure. This study demonstrates that upon growth-factor stimulation, Src directly phosphorylates vimentin at Tyr117, leading to VIF disassembly into squiggles and particles at the cell edge during lamellipodia formation. The protein tyrosine phosphatase SHP2 counteracted the Src effects on VIF tyrosine phosphorylation and organization. VIFs formed by vimentin Y117D mutant were more soluble and dynamic than those formed by the wild-type and Y117F mutant. Increased expression of vimentin promoted growth-factor induced lamellipodia formation and cell migration, whereas the mutants suppressed both. The vimentin-induced increase in lamellipodia formation correlated with the activation of Rac and Vav2, with the latter associated with VIFs and recruited to the plasma membrane upon growth-factor stimulation. These results reveal a novel mechanism for regulating VIF dynamics through Src and SHP2 and demonstrate that proper VIF dynamics are important for Rac activation and cell migration.