Vps27-Hse1 and ESCRT-I complexes cooperate to increase efficiency of sorting ubiquitinated proteins at the endosome

Ubiquitin (Ub) attachment to cell surface proteins causes their lysosomal degradation by incorporating them into lumenal membranes of multivesicular bodies (MVBs). Two yeast endosomal protein complexes have been proposed as Ub-sorting “receptors,” the Vps27-Hse1 complex and the ESCRT-I complex. We used NMR spectroscopy and mutagenesis studies to map the Ub-binding surface for Vps27 and Vps23. Mutations in Ub that ablate only Vps27 binding or Vps23 binding blocked the ability of Ub to serve as an MVB sorting signal, supporting the idea that both the Vps27-Hse1 and ESCRT-I complexes interact with ubiquitinated cargo. Vps27 also bound Vps23 directly via two PSDP motifs present within the Vps27 COOH terminus. Loss of Vps27-Vps23 association led to less efficient sorting into the endosomal lumen. However, sorting of vacuolar proteases or the overall biogenesis of the MVB were not grossly affected. In contrast, disrupting interaction between Vps27 and Hse1 caused severe defects in carboxy peptidase Y sorting and MVB formation. These results indicate that both Ub-sorting complexes are coupled for efficient recognition of ubiquitinated cargo

Astronomical X-Ray Optics Using Mono-Crystalline Silicon: High Resolution, Light Weight, and Low Cost

X-ray astronomy critically depends on X-ray optics. The capability of an X-ray telescope is largelydetermined by the point-spread function (PSF) and the photon-collection area of its mirrors, the same astelescopes in other wavelength bands. Since an X-ray telescope must be operated above the atmosphere inspace and that X-rays reflect only at grazing incidence, X-ray mirrors must be both lightweight and thin, bothof which add significant technical and engineering challenge to making an X-ray telescope. In this paper wereport our effort at NASA Goddard Space Flight Center (GSFC) of developing an approach to making an Xraymirror assembly that can be significantly better than the mirror assembly currently flying on the ChandraX-ray Observatory in each of the three aspects: PSF, effective area per unit mass, and production cost per uniteffective area. Our approach is based on the precision polishing of mono-crystalline silicon to fabricate thinand lightweight X-ray mirrors of the highest figure quality and micro-roughness, therefore, having thepotential of achieving diffraction-limited X-ray optics. When successfully developed, this approach will makeimplementable in the 2020s and 2030s many X-ray astronomical missions that are currently on the drawingboard, including sounding rocket flights such as OGRE, Explorer class missions such as STAR-X andFORCE, Probe class missions such as AXIS, TAP, and HEX-P, as well as large missions such as Lynx

Kinematic Alignment and Bonding of Silicon Mirrors for High-Resolution Astronomical X-Ray Optics

Optics for the next generation's high-resolution, high throughput x-ray telescope requires fabrication of well-formed lightweight mirror segments and their integration at arc-second precision. Recent advances in the fabrication of silicon mirrors developed at NASA/Goddard prompted us to develop a new method of mirror alignment and integration. In this method, stiff silicon mirrors are aligned quasi-kinematically and are bonded in an interlocking fashion to produce a "meta-shell" with large collective area. We address issues of aligning and bonding mirrors with this method and show a recent result of 4 seconds-of-arc for a single pair of mirrors tested at soft x-rays

Optical design of the Off-plane Grating Rocket Experiment

The Off-plane Grating Rocket Experiment (OGRE) is a soft X-ray spectroscopy suborbital rocket payload scheduled for launch in Q3 2020 from Wallops Flight Facility. The payload will serve as a testbed for several key technologies which can help achieve the desired performance increases for the next generation of X-ray spectrographs and other space-based missions: monocrystalline silicon X-ray mirrors developed at NASA Goddard Space Flight Center, reflection gratings manufactured at The Pennsylvania State University, and electron-multiplying CCDs developed by the Open University and XCAM Ltd. With these three technologies, OGRE hopes to obtain the highest-resolution on-sky soft X-ray spectrum to date. We discuss the optical design of the OGRE payload

The Off-plane Grating Rocket Experiment (OGRE) system overview

The Off-plane Grating Rocket Experiment (OGRE) is a sub-orbital rocket payload that will make the highest spectral resolution astronomical observation of the soft X-ray Universe to date. Capella, OGRE’s science target, has a well-defined line emission spectrum and is frequently used as a calibration source for X-ray observatories such as Chandra. This makes Capella an excellent target to test the technologies on OGRE, many of which have not previously flown. Through the use of state-of-the-art X-ray optics, co-aligned arrays of off-plane reflection gratings, and an X-ray camera based around four Electron Multiplying CCDs, OGRE will act as a proving ground for next generation X-ray spectrometers

Viral Endomyocardial Infection Is an Independent Predictor and Potentially Treatable Risk Factor for Graft Loss and Coronary Vasculopathy in Pediatric Cardiac Transplant Recipients

ObjectivesThis study sought to evaluate the outcome and prevalence of viral endomyocardial infection after cardiac transplantation.BackgroundViral myocardial infection causes heart failure, but its role after cardiac transplantation is unclear. We hypothesized that viral infection of the cardiac allograft reduces graft survival.MethodsBetween June 1999 and November 2004, 94 pediatric cardiac transplant patients were screened for the presence of viral genome in serial endomyocardial biopsies (EMBs) using polymerase chain reaction (PCR) assays. Graft loss, advanced transplant coronary artery disease (TCAD), and acute rejection (AR) were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan-Meier and Cox regression analyses. From November 2002 to November 2004, intravenous immunoglobulin therapy (IVIG) was administered to patients with PCR-positive EMBs. The outcomes of the IVIG-treated, PCR-positive patients (n = 20) were compared with IVIG-untreated, PCR-positive patients (n = 17).ResultsViral genomes were detected in EMBs from 37 (39%) patients; parvovirus B19, adenovirus, and Epstein-Barr virus (EBV) were the most common. The PCR-positive group (n = 37, 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57, 25% graft loss at 8.7 years) and developed advanced TCAD prematurely (p = 0.001). The number of AR episodes was similar in both groups. On multivariate analysis, presence of viral genome was an independent risk factor for graft loss (relative risk: 4.2, p = 0.015). The time to advanced TCAD after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend toward improved graft survival (p = 0.06).ConclusionsViral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients. This effect appears to be mediated through premature development of advanced TCAD. IVIG therapy in this subgroup may improve survival and merits further investigation

Management of Hypertriglyceridemia in the Diabetic Patient

The hypertriglyceridemia of diabetes can be classified into mild to moderate (triglycerides between 150–499 mg/dL) and severe hypertriglyceridemia (triglycerides ≥500 mg/dL). As in any other individuals with hypertriglyceridemia, secondary causes need to be excluded. The management of severe hypertriglyceridemia (chylomicronemia syndrome) includes aggressive reduction of triglycerides with intravenous insulin, fibrates, omega-3 fatty acids, and/or niacin therapy to avert the risk of pancreatitis. In patients with mild to moderate hypertriglyceridemia, the treatment of choice is statin therapy to achieve the low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) target goals. The evidence base would favor niacin therapy in combination with statin therapy to achieve the goals pertaining to LDL cholesterol and non-HDL cholesterol. The data about the combination of fibrate therapy with statin therapy are disappointing

A Methodological Reflection: Deconstructing Cultural Elements for Enhancing Cross-cultural Appreciation of Chinese Intangible Cultural Heritage

This paper presents a practical method of deconstructing cultural elements based on the Human Computer Interaction (HCI) perspective to enhance cross-cultural appreciation of Chinese Intangible Cultural Heritage (ICH). The author pioneered this approach during conducting two case studies as a means to enhance appreciation and engagement with Chinese ICH, such as the extraction of elements from traditional Chinese painting and puppetry with potential to support cross-cultural appreciation, as well as the establishment of an elements archive. Through integrating a series of HCI research methods, this approach provides a specific foundational framework that assists non-Chinese people to better understand the cultural significance of Chinese ICH