Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Oxidative stress is proposed as an important factor in osteoarthritis (OA). To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

Enhancing Interdisciplinary Instruction in General and Special Education: Thematic Units and Technology

This article discusses interdisciplinary thematic units in the context of special and general education curricula and focuses on ways technology can be used to enhance interdisciplinary thematic units. Examples of curriculum integration activities enhanced by technology are provided in the context of productivity tools, presentation and multimedia tools, contextual themed software, and Web-based activities.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

The Vehicle, Spring 1981

Vol. 22, No. 2 Table of Contents Old Farmers at the Arcade CafeJohn Stockmanpage 4 ConfettiCathy Georgepage 6 Ode to a Corned Beef SandwichJeff Bennettpage 6 The Ice on Kirschner\u27s CreekScott Fishelpage 7 Love Poem to LindaJohn Stockmanpage 7 Grandfather\u27s PortraitJames Marshpage 8 The MassageKathleen Alakspage 9 A Driving ForceSandy Youngpage 10 King DandelionNancy Siebenpage 12 One Afternoon - Contemplating HouseworkKelli Sanderpage 13 Tent WallsAndy Sudkamppage 14 The SentinelElise Hempelpage 16 Daddy\u27s AftershaveJeff Bennettpage 16 The WeddingChris Goerlichpage 17 UntitledCarol Hansenpage 17 Treasures in the YardScott Fishelpage 18 Hitchhiker\u27s BootsAndy Sudkamppage 20 The RaffleLaura Henrypage 21 A Walk at NightJudi Jinespage 24 Morning in the DumpJeff Bennettpage 24 In Praise of Chocolate Ice CreamJohn Stockmanpage 25 Summer on the Isle of PalmsElisabeth Cristpage 26 The WaveHerbert S. Demminpage 27 RememberingJohn Kleinsteiberpage 27 PotatoJohn Stockmanpage 28 Late ShowChris Goerlichpage 30 Love in Him - JoeDebbie Klinnertpage 31 ShoeScott Fishelpage 35 The DrinkerBob Huntpage 36 The WidowGeorge Ndu Igbudupage 37 ElectricityScott Fishelpage 37 Hatchet JackB.L. Davidsonpage 39 Walking Home LateJohn Stockmanpage 41 NovemberCindy Hubbarttpage 41 On the BusLaura Henrypage 42 HaikuJames Marshpage 43 SpillwayGloria Rhoadspage 43 Art Cover design by Linda Fraembs PhotographRobin Scholzpage 3 PhotographRobin Scholzpage 5 PhotographMichelle Glassmeyerpage 15 PhotographRobert Schinaglpage 19 PhotographTom Robertspage 38 PhotographRobert Schinaglpage 44https://thekeep.eiu.edu/vehicle/1039/thumbnail.jp

Interlaboratory comparison of methodologies for measuring the angle of incidence dependence of solar cells

The aim of this work is to compare angle of incidence (AOI) measurement setups for solar cells between laboratories with such capability. For the first time, we compare relative light transmission measurements among eight laboratories, whose measurement techniques include indoor and outdoor methods. We present the relative transmission measurements on three 156 mm x 156 mm crystalline-Si (c-Si) samples with different surface textures. The measurements are compared using the expanded uncertainties provided by each laboratory. Five of the eight labs showed an agreement better than ±2% to the weighted mean between AOIs from -75° to 70°. At AOIs of ±80° and ±85°, the same five labs showed a worst case deviation to the weighted mean of -3% to 5% and 0% to 18%, respectively. When measurement uncertainty is considered, the results show that measurements at the highest incidence angle of ±85° are problematic, as measurements from four out of the six labs reporting uncertainty were found non-comparable within their stated uncertainties. At 85° AOI a high to low range of up to 75% was observed between all eight laboratories

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development

Genome-Wide Functional Divergence after the Symbiosis of Proteobacteria with Insects Unraveled through a Novel Computational Approach

Symbiosis has been among the most important evolutionary steps to generate biological complexity. The establishment of symbiosis required an intimate metabolic link between biological systems with different complexity levels. The strict endo-cellular symbiotic bacteria of insects are beautiful examples of the metabolic coupling between organisms belonging to different kingdoms, a eukaryote and a prokaryote. The host (eukaryote) provides the endosymbiont (prokaryote) with a stable cellular environment while the endosymbiont supplements the host's diet with essential metabolites. For such communication to take place, endosymbionts' genomes have suffered dramatic modifications and reconfigurations of proteins' functions. Two of the main modifications, loss of genes redundant for endosymbiotic bacteria or the host and bacterial genome streamlining, have been extensively studied. However, no studies have accounted for possible functional shifts in the endosymbiotic proteomes. Here, we develop a simple method to screen genomes for evidence of functional divergence between two species clusters, and we apply it to identify functional shifts in the endosymbiotic proteomes. Despite the strong effects of genetic drift in the endosymbiotic systems, we unexpectedly identified genes to be under stronger selective constraints in endosymbionts of aphids and ants than in their free-living bacterial relatives. These genes are directly involved in supplementing the host's diet with essential metabolites. A test of functional divergence supports a strong relationship between the endosymbiosis and the functional shifts of proteins involved in the metabolic communication with the insect host. The correlation between functional divergence in the endosymbiotic bacterium and the ecological requirements of the host uncovers their intimate biochemical and metabolic communication and provides insights on the role of symbiosis in generating species diversity