A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor

AbstractHuman immunodeficiency virus 1 (HIV-1) Nef downregulates surface expression of CD4, an integral component of the functional HIV receptor complex, through accelerated endocytosis of surface receptors and diminished transport of CD4 from the Golgi network to the plasma membrane [1–3]. HIV-1 Nef also diminishes surface expression of major histocompatibility complex (MHC) class I antigens [4]. In the case of HIV-2 and simian immunodeficiency virus 1 (SIV-1) Nef, aminoterminal tyrosine-based motifs mediate the binding of Nef to the AP-1 and AP-2 adaptors and this interaction appears to be required for CD4 downregulation [5,6]. As these tyrosine motifs are not present in the HIV-1 Nef protein, the molecular basis for the presumed interaction of Nef with components of the endocytic machinery is unknown. Here, we identify a highly conserved dileucine motif in HIV-1 Nef that is required for downregulation of CD4. This motif acts as an internalization signal in the context of a CD8-Nef chimera or in a fusion of the interleukin-2 receptor α with an 11-amino-acid region from Nef containing the dileucine motif. Finally, HIV-1 Nef binds to the AP-1 adaptor, both in vitro and in vivo, in a dileucine-dependent manner. We conclude that this conserved dileucine motif in HIV-1 Nef serves as a key interface for interaction with components of the host protein trafficking machinery. Our findings also reveal an evolutionary difference between HIV-1 and HIV-2/SIV in which the Nef proteins utilize structurally distinct motifs for binding cellular adaptors

Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone

Measuring the impact of cancer: a comparison of non-Hodgkin lymphoma and breast cancer survivors

Introduction Self-report instruments such as the Impact of Cancer (IOC) are designed to measure quality of life (QOL) impacts that cancer survivors attribute to their cancer experience. Generalizability of QOL findings across dis-tinct diagnostic categories of survivors is untested. W

Sensorimotor function of the cervical spine in healthy volunteers

© 2015 The Authors. Abstract Background Sensorimotor mechanisms are important for controlling head motion. However, relatively little is known about sensorimotor function in the cervical spine. This study investigated how age, gender and variations in the test conditions affect measures of position sense, movement sense and reflex activation in cervical muscles. Methods Forty healthy volunteers (19M/21F, aged 19-59 years) participated. Position sense was assessed by determining repositioning errors in upright and flexed neck postures during tests performed in 25%, 50% and 75% cervical flexion. Movement sense was assessed by detecting thresholds to passive flexion and extension at velocities between 1 and 25 s- 1. Reflexes were assessed by determining the latency and amplitude of reflex activation in trapezius and sternocleidomastoid muscles. Reliability was evaluated from intraclass correlation coefficients. Findings Mean repositioning errors ranged from 1.5 to 2.6, were greater in flexed than upright postures (P = 0.006) and in people aged over 25 years (P = 0.05). Time to detect head motion decreased with increasing velocity (P < 0.001) and was lower during flexion than extension movements (P = 0.002). Reflexes demonstrated shorter latency (P < 0.001) and greater amplitude (P = 0.009) in trapezius compared to sternocleidomastoid, and became slower and weaker with age. None of the measures were influenced by gender. Reliability was good for movement sense measures, but was influenced by the test conditions when assessing position sense. Interpretation Increased repositioning errors and slower reflexes in older subjects suggest that sensorimotor function in the cervical spine becomes impaired with age. In position sense tests, reliability was influenced by the test conditions with mid-range flexion movements, performed in standing, providing the most reliable measurements

Role of Cell-to-Cell Variability in Activating a Positive Feedback Antiviral Response in Human Dendritic Cells

In the first few hours following Newcastle disease viral infection of human monocyte-derived dendritic cells, the induction of IFNB1 is extremely low and the secreted type I interferon response is below the limits of ELISA assay. However, many interferon-induced genes are activated at this time, for example DDX58 (RIGI), which in response to viral RNA induces IFNB1. We investigated whether the early induction of IFNBI in only a small percentage of infected cells leads to low level IFN secretion that then induces IFN-responsive genes in all cells. We developed an agent-based mathematical model to explore the IFNBI and DDX58 temporal dynamics. Simulations showed that a small number of early responder cells provide a mechanism for efficient and controlled activation of the DDX58-IFNBI positive feedback loop. The model predicted distributions of single cell responses that were confirmed by single cell mRNA measurements. The results suggest that large cell-to-cell variation plays an important role in the early innate immune response, and that the variability is essential for the efficient activation of the IFNB1 based feedback loop

La Grange Comprehensive Plan 2018 - 2038

In the Fall of 2017, the City of La Grange and Texas Target Communities partnered to create a task force to represent the community. The task force was integral to the planning process, contributing the thoughts, desires, and opinions of community members—as well as their enthusiasm about La Grange’s future. This fifteen-month planning process ended in August 2018. The result of this collaboration is the La Grange Comprehensive Plan, which is the official policy guide for the community’s growth over the next twenty years.La Grange Comprehensive Plan 2018 - 2038 provides a guide for the future growth of the City. This document was developed by Texas Target Communities in partnership with the City of La Grange.Texas Target Communitie

Safety and Benefit of Discontinuing Statin Therapy in the Setting of Advanced, Life-Limiting Illness: A Randomized Clinical Trial

For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy

The San Pablo Dam Road Commercial District in El Sobrante, California: Baseline Study

Over the past forty years, El Sobrante, California, has changed from a small rural center in the midst of grazing land to a mostly-developed residential suburb. Both San Pablo Dam Road (the main roadway through El Sobrante) and the commercial district stretching along that roadway also have changed. San Pablo Dam Road now serves as a regional arterial as well as El Sobrante’s "Main Street." The commercial district has attracted new customers from the growing population, but faces new competition from shopping centers and super-stores located off nearby freeway interchanges.Current planning efforts for El Sobrante aim to balance local and regional traffic needs with the needs of the commercial district for economic revitalization. This study was designed to support those planning efforts. Information was assembled on the district’s development history and an inventory of its current land uses and building stock was carried out. The design and operation of San Pablo Avenue was reviewed, and an inventory of parking was carried out. Overall urban design quality was assessed, considering architectural qualities of the buildings, diversity of uses, building/street relationships, and landscape quality. Assessments of activity in the district and its popular image were carried out by means of a merchant survey, a shopper survey, and a resident survey. Finally, preliminary suggestions on alternative ways to improve the district were developed.The study found that the El Sobrante commercial district has a number of assets. Businesses provide a variety of goods and services to local residents. Customers do business in the district not only because it is convenient, but also because they enjoy good quality at good prices and appreciate the friendly, small-town atmosphere. San Pablo Dam Road is part of the commute route for many residents, making it convenient to stop in the district on the way to or from work. The steady traffic provides businesses with access to a large number of customers.Still, there are problems. A number of the district’s businesses wish they were doing better. Competition from larger, newer shopping centers wins the majority of shopping trips from the area. Some feel that the buildings and streetscape are less attractive than they should be. Traffic levels have reached the point where turning movements, biking, and walking can be uncomfortable for some.Complicating matters are the mixed reactions of business owners and customers to current and emerging conditions. Some call for significant changes to land use, urban design, street layout, and traffic management, while others are satisfied with the present situation. The lack of a united vision for San Pablo Dam Road and the commercial district presents a difficult challenge, since future design and redevelopment efforts hinge on the consistency and clarity of such a vision.The study identified a large number of possible actions, some from business leaders, some from shoppers and clients of the area, and some from the study authors

Two-dimensional mapping of scientific production of nations in the fields of physics and astronomy

The quantity and quality of scientific production in the fields of physics and astronomy over a period of 16 years (1996–2012) was studied. The level of analysis was national, with the scientific output of 108 countries being analysed. The measurement unit was the number of papers published in peer-reviewed journals, as listed on the Scopus database. Modified versions of the number of publications (Pm) and citations (Cm) were employed as indicators of quantity and quality, respectively. A two-dimensional method, the Pm-Cm diagram, was adopted to provide a coherent and simultaneous approach to study the positions, rankings, and temporal evolution of countries in the global context. A static approach to studying the Pm-Cm diagram resulted in countries being grouped into five main categories based on average positions. A dynamic approach to analysing the Pm-Cm diagram also resulted in five groups (i.e. when considering the temporal evolution patterns of the countries during the studied years). The rank and temporal-evolution group associated with each country are listed in two tables in this paper. These tables, together with the Pm-Cm diagrams (showing different scales) present a general view of the scientific activity in the field of physics and astronomy for each country. This methodology allows each country’s output to be compared with that of other countries or the world average