Mechanisms of Kaposi's Sarcoma-Associated Herpesvirus Latency and Reactivation

The life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases. During latent infection, only a limited number of KSHV genes are expressed. However, this phase of replication is essential for persistent infection, evasion of host immune response, and induction of KSHV-related malignancies. KSHV reactivation from latency produces a wide range of viral products and infectious virions. The resulting de novo infection and viral lytic products modulate diverse cellular pathways and stromal microenvironment, which promote the development of Kaposi's sarcoma (KS). The mechanisms controlling KSHV latency and reactivation are complex, involving both viral and host factors, and are modulated by diverse environmental factors. Here, we review the cellular and molecular basis of KSHV latency and reactivation with a focus on the most recent advancements in the field

Development of gas sensor based on fractal substrate structures

Gas sensor plays a key role in many applications with sensitivity being a critical performance characteristic. Increasing the surface area of gas sensing material is one approach that can increase sensitivity. Fractal geometries, which have the large specific surface area and special fractal dimension, have previously been successfully used in the design of macrostructure and microstructure of gas sensors to improve their performance. In this article, the influence of geometrical structure of the substrate on the gas sensor performance has been investigated. Two fractal structures (Koch snowflake and Menger sponge) and one traditional structure (Cylinder) were fabricated by 3-D printing and coated in Ag-doped multiwalled carbon nanotube (Ag:MWCNT)-based sensing materials. The fabricated sensors were tested with nitrogen dioxide at different temperatures and humidity. Experimental results show that the sensitivity of gas sensors with fractal structures is increased more than twice that of those with traditional geometrical structures

High Glucose Induces Reactivation of Latent Kaposi’s Sarcoma-Associated Herpesvirus

High prevalence of Kaposi’s sarcoma (KS) is seen in diabetic patients. It is unknown if the physiological condition of diabetes contributes to KS development. We found elevated levels of viral lytic gene expression when Kaposi’s sarcoma-associated herpesvirus (KSHV) infected cells were cultured in high glucose medium. To demonstrate the association between high glucose and KSHV replication, we xeno29 grafted telomerase-immortalized human umbilical vein endothelial cells that are infected with KSHV (TIVE-KSHV) into hyperglycemic and normal nude mice. The injected cells expressed significantly higher levels of KSHV lytic genes in hyperglycemic mice than in normal mice. We further demonstrated that high glucose induced production of hydrogen peroxide (H2O2), which down regulated silent information regulator 1 (SIRT1), a class-III histone deacetylase (HDAC), resulting in epigenetic transactivation of KSHV lytic genes.These results suggest that high blood glucose in diabetic patients contributes to development of KS by promoting KSHV lytic replication and infection

Self doping effect and successive magnetic transitions in superconducting Sr2_2VFeAsO3_3

We have studied a quinary Fe-based superconductor Sr$_2$VFeAsO$_3$ by the measurements of x-ray diffraction, x-ray absorption, M\"{o}ssbauer spectrum, resistivity, magnetization and specific heat. This apparently undoped oxyarsenide is shown to be self doped via electron transfer from the V$^{3+}$ ions. We observed successive magnetic transitions within the VO$_2$ layers: an antiferromagnetic transition at 150 K followed by a weak ferromagnetic transition at 55 K. The spin orderings within the VO$_2$ planes are discussed based on mixed valence of V$^{3+}$ and V$^{4+}$.Comment: One Table and more references are adde

VLBI astrometry on the white dwarf pulsar AR Scorpii

AR Scorpii (AR Sco), the only-known radio-pulsing white dwarf binary, shows unusual pulsating emission at the radio, infrared, optical, and ultraviolet bands. To determine its astrometric parameters at the radio band independently, we conducted multi-epoch Very Long Baseline Interferometry (VLBI) phase-referencing observations with the European VLBI Network at 5 GHz and the Chinese VLBI Network plus the Warkworth 30-m telescope (New Zealand) at 8.6 GHz. By using the differential VLBI astrometry, we provide high-precision astrometric measurements on the parallax (pi = 8.52(-0.07)(+0.04) mas) and proper motion (mu(alpha) = 9.48(-0.07)(+0.04) mas yr(-1), mu(delta) = -51.32(-0.38)(+0.22) mas yr (-1)). The new VLBI results agree with the optical Gaia astrometry. Our kinematic analysis reveals that the Galactic space velocities of AR Sco are quite consistent with that of both intermediate polars and polars. Combined with the previous tightest VLBI constraint on the size, our parallax distance suggests that the radio emission of AR Sco should be located within the light cylinder of its white dwarf

Increased Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Expression in Adolescent Brain Development: A Longitudinal Micro-PET/CT Study in Rodent

Background: Brain development and maturation in adolescence is a complex process with active changes of metabolic and neurotransmission pathways. Positron emission tomography (PET) is a useful imaging modality for tracking metabolic and functional changes in adolescent brain. In this study, changes of glucose metabolism, expression of vesicular monoamine transporter 2 and dopamine transporter during adolescent brain development in rats were investigated with PET/CT.Methods: A longitudinal PET/CT study of age-dependent changes of VMAT2, DAT and glucose metabolism in adolescent brain was conducted in a group of Wistar rats (n = 6) post sequential intravenous injection of 18F-PF-(+)-DTBZ, 11C-CFT, and 18F-FDG, respectively. PET acquisition was performed at 2, 4, 9, and 12 months of age. Radiotracer uptake in different brain regions, including the striatum, cerebellum, and hippocampus, were quantified and recorded as Standardized uptake value (SUV) and striatal specific uptake ratio (SUVR: SUV in brain regions/SUV in cerebellum).Results: Variable uptake of 18F-PF-(+)-DTBZ and 11C-CFT were detected, with highest level uptake in the striatum and accumbens. There was significant age-dependent increase of 18F-PF-(+)-DTBZ and 11C-CFT uptake in the striatum from 2 months of age (SUV: 1.36 ± 0.22, 1.37 ± 0.39, respectively), to 4 months (SUV: 2.22 ± 0.29, 2.04 ± 0.33), 9 months (1.98 ± 0.34, 2.09 ± 0.18), 12 months (SUV: 1.93 ± 0.19, 2.00 ± 0.17) of age, SUV of 18F-FDG also increased from 2 months of age to older ages (SUV in the striatum: 3.71 ± 0.78 at 2 month, 5.28 ± 0.81, 5.14 ± 0.73, 4.94 ± 0.50 at 4, 9, 12 month, respectively).Conclusion: Age-dependent increases of striatal of 18F-FDG, 18F-PF-(+)-DTBZ, and 11C-CFT uptake were detected in rats from 2 to 4 month of age, demonstrating striatal development presents over the first 4 months of age. Four months of age can be considered a safe threshold to launch brain disease studies for exclusion of confusion of continuing tissue development. These findings support further investigation of age-dependent changes in expression of DAT, VMAT2, and glucose metabolism for their potential use as a new imaging biomarker for study of brain development and functional maturation

The Ubiquitin/Proteasome System Mediates Entry and Endosomal Trafficking of Kaposi's Sarcoma-Associated Herpesvirus in Endothelial Cells

Ubiquitination, a post-translational modification, mediates diverse cellular functions including endocytic transport of molecules. Kaposi's sarcoma-associated herpesvirus (KSHV), an enveloped herpesvirus, enters endothelial cells primarily through clathrin-mediated endocytosis. Whether ubiquitination and proteasome activity regulates KSHV entry and endocytosis remains unknown. We showed that inhibition of proteasome activity reduced KSHV entry into endothelial cells and intracellular trafficking to nuclei, thus preventing KSHV infection of the cells. Three-dimensional (3-D) analyses revealed accumulation of KSHV particles in a cytoplasmic compartment identified as EEA1+ endosomal vesicles upon proteasome inhibition. KSHV particles are colocalized with ubiquitin-binding proteins epsin and eps15. Furthermore, ubiquitination mediates internalization of both KSHV and one of its receptors integrin β1. KSHV particles are colocalized with activated forms of the E3 ligase c-Cbl. Knock-down of c-Cbl or inhibition of its phosphorylation reduced viral entry and intracellular trafficking, resulting in decreased KSHV infectivity. These results demonstrate that ubiquitination mediates internalization of both KSHV and one of its cognate receptors integrin β1, and identify c-Cbl as a potential E3 ligase that facilitates this process

Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi's Sarcoma-Associated Herpesvirus Reactivation from Latency

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies