Lyngekofoed6665

Cleavage of amyloid precursor protein (APP) by BACE-1 (β-site APP cleaving enzyme 1) is the rate-limiting step in amyloid-β (Aβ) production and a neuropathological hallmark of Alzheimer's disease (AD). Despite decades of research, mechanisms of amyloidogenic APP processing remain highly controversial. Here, we show that in neurons, APP processing and Aβ production are controlled by the protein complex-2 (AP-2), an endocytic adaptor known to be required for APP endocytosis. Now, we find that AP-2 prevents amyloidogenesis by additionally functioning downstream of BACE1 endocytosis, regulating BACE1 endosomal trafficking and its delivery to lysosomes. AP-2 is decreased in iPSC-derived neurons from patients with late-onset AD, while conditional AP-2 knockout (KO) mice exhibit increased Aβ production, resulting from accumulation of BACE1 within late endosomes and autophagosomes. Deletion of BACE1 decreases amyloidogenesis and mitigates synapse loss in neurons lacking AP-2. Taken together, these data suggest a mechanism for BACE1 intracellular trafficking and degradation via an endocytosis-independent function of AP-2 and reveal a novel role for endocytic proteins in AD. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.PURPOSE To identify nonpharmacological clinically effective interventions for constipation in adults. METHODS A systematic review of experimental studies of nonpharmacological interventions addressing participants' management of constipation using samples of adults over 18 years of age was conducted. In evaluating the methodological quality of the eligible studies, we used the assumptions of the Cochrane Collaboration, and for the reporting of items in the systematic review we used the Model of Preferential Reporting Items for Systematic Reviews and Meta-Analyses. The protocol of this review was recorded in the International Prospective Register of Systematic Reviews of the University of York under number 43693. RESULTS This review included 12 randomized controlled trials. Nonpharmacological effective interventions for the resolution of constipation were identified individualized intervention based on the participant's modifiable risk factors of constipation promoting literacy in health; educational measures in dietary modification and lifestyle; and abdominal massage. CONCLUSIONS Specific nonpharmacological interventions are crucial for nurses' clinical practice and of major importance for clients and families. Evidence on these interventions in resolving constipation is still scarce and fails to provide evidence-based data to support nursing clinical practice. CLINICAL RELEVANCE Personal lifestyles, comorbidities, medication, and sedentary habits are likely to be risk factors in constipation. Thus, it is important to invest in nonpharmacological interventions that promote changes in behavior regarding prevention or resolution of constipation. Moreover, nursing researchers worldwide should conduct research for clinical practice regarding the fundamentals of care. © 2020 Sigma Theta Tau International.Extrusion-based 3D bioprinting is hampered by the inability to print materials of low-viscosity. In this study, a single initiating system based on ruthenium (Ru) and sodium persulfate (SPS) is utilized for a sequential dual-step crosslinking approach 1) primary (partial) crosslinking in absence of light to alter the bioink's rheological profile for print fidelity, and 2) subsequent secondary post-printing crosslinking for shape maintenance. Allyl-functionalized gelatin (Gel-AGE) is used as a bioink, allowing thiol-ene click reaction between allyl moieties and thiolated crosslinkers. A systematic investigation of primary crosslinking reveals that a thiol-persulfate redox reaction facilitates thiol-ene crosslinking, mediating an increase in bioink viscosity that is controllable by tailoring the Ru/SPS, crosslinker, and/or Gel-AGE concentrations. Thereafter, subsequent photoinitiated secondary crosslinking then facilitates maximum conversion of thiol-ene bonds between AGE and thiol groups. The dual-step crosslinking method is applicable to a wide biofabrication window (3-10 wt% Gel-AGE) and is demonstrated to allow printing of low-density (3 wt%) Gel-AGE, normally exhibiting low viscosity (4 mPa s), with high shape fidelity and high cell viability (>80%) over 7 days of culture. The presented approach can therefore be used as a one-pot system for printing low-viscous bioinks without the need for multiple initiating systems, viscosity enhancers, or complex chemical modifications. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.This study evaluated the effect of thermosensitive hydroxybutyl chitosan (HBC) hydrogel loaded with human platelet lysate (hPL) on skin wound healing in rats. hPLs were generated by freeze-thaw method of platelet-rich plasma from healthy donors. mTOR inhibitor Successful grafting of hydroxybutyl group to chitosan molecular chain to obtain HBC hydrogel was confirmed by Fourier-transform infrared spectroscopy. HBC/hPL was prepared by combining 10% (vol/vol) hPL with HBC solution. Surface morphologies were determined by Scanning Electron Microscopy, rheological properties were measured by rheometer, and sustained release of factors from HBC/hPL was measured by enzyme-linked immunoassay. We evaluated the in vitro effect of HBC/hPL on human umbilical cord vein endothelial cell (HUVEC) proliferation, migration, and tube formation. The effect of growth factors released from HBC/hPL in promoting skin wound healing was evaluated by gross observation, histology, immunohistochemistry, and immunofluorescence in vivo. Rheological analyses indicated the gelation temperatures of HBC and HBC/hPL were 17 and 14°C, respectively. ELISA showed sustained release of human platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-β1 from HBC/hPL hydrogel. In vitro studies revealed HBC/hPL promoted greater levels of HUVECs proliferation, migration, and tube formation than the HBC and control groups. In vivo studies showed better wound healing, greater amounts of newly formed collagen, as well as neovascular and neo-epidermis markers in the wound site of HBC/hPL-treated group compared to the HBC and control groups. HBC/hPL is a promising potential therapeutic agent for promoting skin wound healing via the sustained release of growth factors. © 2020 Wiley Periodicals, Inc.