VEGF (Vascular Endothelial Growth Factor) Induces NRP1 (Neuropilin-1) Cleavage via ADAMs (a Disintegrin and Metalloproteinase) 9 and 10 to Generate Novel Carboxy- Terminal NRP1 Fragments That Regulate Angiogenic Signaling

OBJECTIVE: NRP1(neuropilin-1) acts as a coreceptor for VEGF (vascular endothelial growth factor) with an essential role in angiogenesis. Recent findings suggest that posttranslational proteolytic cleavage of VEGF receptors may be an important mechanism for regulating angiogenesis, but the role of NRP1 proteolysis and the NRP1 species generated by cleavage in endothelial cells is not known. To characterize NRP1 proteolytic cleavage in endothelial cells, determine the mechanism, and investigate the role of NRP1 cleavage in regulation of endothelial cell function. APPROACH AND RESULTS: NRP1 species comprising the carboxy (C)-terminal and transmembrane NRP1 domains but lacking the ligand-binding A and B regions are constitutively expressed in endothelial cells. Generation of these C-terminal domain NRP1 proteins is upregulated by phorbol ester and Ca2+ ionophore, and reduced by pharmacological inhibition of metalloproteinases, by small interfering RNA-mediated knockdown of 2 members of ADAM (a disintegrin and metalloproteinase) family, ADAMs 9 and 10, and by a specific ADAM10 inhibitor. Furthermore, VEGF upregulates expression of these NRP1 species in an ADAM9/10-dependent manner. Transduction of endothelial cells with adenoviral constructs expressing NRP1 C-terminal domain fragments inhibited VEGF-induced phosphorylation of VEGFR2 (VEGF receptor tyrosine kinase)/KDR and decreased VEGF-stimulated endothelial cell motility and angiogenesis in coculture and aortic ring sprouting assays. CONCLUSIONS: These findings identify novel NRP1 species in endothelial cells and demonstrate that regulation of NRP1 proteolysis via ADAMs 9 and 10 is a new regulatory pathway able to modulate VEGF angiogenic signaling

Evaluation of a theory-informed implementation of a nursing discharge teaching intervention for older adults.

To evaluate the implementation process of a multi-site trial of a novel discharge teaching intervention. Hybrid type 3 trial. A discharge teaching intervention for older adults was implemented in medical units from August 2020 to August 2021 with 30 nurse participants. The implementation process was guided by behaviour change frameworks. Outcome data comprised determinants of nurses' behaviours related to teaching and the acceptability, appropriateness, feasibility of the intervention and frequency of teaching activities received by the participants. This study adheres to StaRI and TIDieR reporting guidelines. Twelve of 18 determinants of nurses' behaviour domains improved post-implementation. Being trained reinforced nurses' knowledge and skills in patient teaching. Practicing the intervention increased their awareness on the gaps between evidence-based teaching principles and their actual practice. The intervention was considered acceptable and moderately appropriate and feasible. A theoretically informed implementation process can influence nurses' perceptions and behaviours related to discharge teaching by targeting specific behaviour domains. Practice change to improve discharge teaching will require organizational support from nursing management. Although the conceptual foundations of the intervention tested in this study were informed by the priorities and experience of patients, this population was not directly involved in the design and conduct of the study. ClinicalTrials.gov: NCT04253665

Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury

AIMS: Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation. METHODS AND RESULTS: NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation. CONCLUSION: NRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization

Improving patient activation with a tailored nursing discharge teaching intervention for multimorbid inpatients: A quasi-experimental study.

Preliminary effectiveness test of a novel structured personalized discharge teaching intervention for multimorbid inpatients. Using a 2-group sequential pre/post-intervention design, the sample comprised 68 pre-intervention control group and 70 post- intervention group participants. The discharge teaching intervention by trained clinical nurses used structured tools to engage patients and individualize discharge teaching. Outcomes measures included Patient Activation Measure, Readiness for Hospital Discharge Scale, Discharge Care Experiences Survey, and readmission with 10 days post-discharge. The intervention had a statistically significant positive effect on improving patient activation (M=4.8; p = 0.05) from admission to post-discharge. The participation subscale of the Discharge Care Experiences Survey was higher in the intervention (M=4.1, SD=0.7) than the control group (M=3.8, SD=0.7; t (127)= -2.79, p = .01, effect size= .34). There were no significant between-group differences in Readiness for Hospital Discharge Scale and readmission. Our results suggest that a structured personalized discharge teaching intervention can improve patient activation and participation in discharge care. Further refinement of the intervention is needed to evaluate and improve specific components of the intervention. Structured personalized discharge teaching should include patient engagement strategies in the teaching-learning process

Magnetic-Torque Enhanced by Tunable Dipolar interactions

We use tunable dipolar-interactions between the spins of nitrogen-vacancy (NV) centers in diamond to rotate a diamond crystal. Specifically, we employ cross-relaxation between the electronic spin of pairs of NV centers in a trapped diamond to enhance the anisotropic NV paramagnetism and thus to increase the associated spin torque. Our observations open a path towards the use of mechanical oscillators to detect paramagnetic defects that lack optical transitions, to investigation of angular momentum conservation in spin relaxation processes and to novel means of cooling the motion of mechanical oscillators.Comment: 15 page

Optical Detection of Paramagnetic Defects in a CVD-grown Diamond

The electronic spins of the nitrogen-vacancy centers (NV centers) in Chemical-Vapor-Deposition (CVD) grown diamonds form ideal probes of magnetic fields and temperature, as well as promising qu-bits for quantum information processing. Studying and controlling the magnetic environment of NV centers in such high purity crystals is thus essential for these applications. We demonstrate optical detection of paramagnetic species, such as hydrogen-related complexes, in a CVD-grown diamond. The resonant transfer of the NV centers' polarized electronic spins to the electronic spins of these species generates conspicuous features in the NV photoluminescence by employing magnetic field scans along the [100] crystal direction. Our results offer prospects for more detailed studies of CVD-grown processes as well as for coherent control of the spin of novel classes of hyper-polarized paramagnetic species.Comment: 8 pages including appendi

Microporous Biodegradable Films Promote Therapeutic Angiogenesis

Peripheral arterial disease and critical limb ischemia are common symptoms of cardiovascular disease. Vascular surgery is used to create a bypass around occluded blood vessels to improve blood flow to ischemic muscle, thus avoiding the need for amputation. Attempts to vascularize tissues by therapeutic angiogenesis using delivery of exogenous angiogenic agents are underwhelming. A material-based approach that provides an endogenous stimulus capable of promoting angiogenesis and increased tissue perfusion would provide a paradigm shift in treatment options available. It is reported here that microporous biodegradable films produced using thermally induced phase separation provide a localized biophysical stimulus of proangiogenic genes in vivo that is associated with increased blood vessel density and restoration of blood flow to ischemic tissue. These findings show, for the first time, that acellular, nonfunctionalized biodegradable biomaterials can provide an innovative, material-based approach for therapeutic angiogenesis to enhance tissue reperfusion in vivo

Spectrophotometry of HII Regions, Diffuse Ionized Gas and Supernova Remnants in M31: The Transition from Photo- to Shock-Ionization

We present results of KPNO 4-m optical spectroscopy of discrete emission-line nebulae and regions of diffuse ionized gas (DIG) in M31. Long-slit spectra of 16 positions in the NE half of M31 were obtained over a 5-15 kpc range in radial distance from the center of the galaxy. The spectra have been used to confirm 16 supernova remnant candidates from the Braun & Walterbos (1993) catalog. The slits also covered 46 HII regions which show significant differences among the various morphological types (center-brightened, diffuse, rings). Radial gradients in emission-line ratios such as [OIII]/H$\beta$ and [OII]/[OIII] are observed most prominently in the center-brightened HII regions. These line ratio trends are either much weaker or completely absent in the diffuse and ring nebulae. The line ratio gradients previously seen in M31 SNRs (Blair, Kirshner, & Chevalier 1981; 1982) are well reproduced by our new data. The spectra of center-brightened HII regions and SNRs confirm previous determinations of the radial abundance gradient in M31. We use diagnostic diagrams which separate photoionized gas from shock-ionized gas to compare the spectral properties of HII regions, SNRs and DIG. This analysis strengthens earlier claims (Greenawalt, Walterbos, & Braun 1997) that the DIG in the disk of M31 is photoionized by a dilute radiation field.Comment: 45 pages, 9 figures, 7 tables, to appear in the Astronomical Journal (December 1999