Combined effect of elevated UVB,elevated temperature and fertilization on growth,needle structure and phytochemistry of young Norway spruce (Picea abies) seedlings

Simultaneously with warming climate, other climatic and environmental factors are also changing. Here, we investigated for the first time the effects of elevated temperature, increased ultraviolet‐B (UVB) radiation, fertilization and all combinations of these on the growth, secondary chemistry and needle structure of 1‐year‐old Norway spruce (Picea abies (L.) Karst.) seedlings in an outdoor experiment. After one growing season, elevated temperature increased root : shoot ratio and concentrations of needle piperidine alkaloids, while concentrations of needle catechins and acetophenones and bark flavonoids decreased compared with ambient temperature seedlings. UVB‐radiation increased concentrations of bark condensed tannins, while fertilization increased total biomass and concentrations of needle catechins. In addition to the main effects, concentrations of some individual phenolic compounds showed UV × temperature or UV × temperature × fertilization interactions, and fertilization modified temperature response on root : shoot ratio. All the treatments described here affected the defence chemistry profiles of the seedlings, which may imply some changes in plant‐herbivore interactions in connection with changing climate. The interactions between treatments indicate a need for further experiments involving several simultaneously affecting environmental changes.     

Collagen Network of Articular Cartilage Modulates Fluid Flow and Mechanical Stresses in Chondrocyte

The extracellular matrix of articular cartilage modulates the mechanical signals sensed by the chondrocytes. In the present study, a finite element model (FEM) of the chondrocyte and its microenvironment was reconstructed using the information from fourier transform infrared imaging spectroscopy. This environment consisted of pericellular, territorial (mainly proteoglycans), and inter-territorial (mainly collagen) matrices. The chondrocyte, pericellular, and territorial matrix were assumedto be mechanically isotropic and poroelastic, whereas the inter-territorial matrix, due to its high collagen content, was assumed to be transversely isotropic and poroelastic. Under instantaneous strain-controlled compression, the FEM indicated that the fluid pressure within the chondrocyte increased nonlinearly as a function of the in-plane Young’s modulus of the collagen network. Under instantaneous force-controlled compression, the chondrocyte experienced the highest fluid pressure when the in-plane Young’s modulus of the collagen network was ~4 MPa. Based on the present results, the mechanical characteristics of the collagen network of articular cartilage can modify fluid flow and stresses in chondrocytes. Therefore, the integrity of the collagen network may be an important determinant in cell stimulation and in the control of the matrix maintenance.     

Virus-Infection or 5′ppp-RNA Activates Antiviral Signal through Redistribution of IPS-1 Mediated by MFN1

In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-β promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5′ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.     

Knockdown of endogenous RNF4 exacerbates ischaemia‐induced cardiomyocyte apoptosis in mice

RNF4, a poly‐SUMO‐specific E3 ubiquitin ligase, is associated with protein degradation, DNA damage repair and tumour progression. However, the effect of RNF4 in cardiomyocytes remains to be explored. Here, we identified the alteration of RNF4 from ischaemic hearts and oxidative stress‐induced apoptotic cardiomyocytes. Upon myocardial infarction (MI) or H₂O₂/ATO treatment, RNF4 increased rapidly and then decreased gradually. PML SUMOylation and PML nuclear body (PML‐NB) formation first enhanced and then degraded upon oxidative stress. Reactive oxygen species (ROS) inhibitor was able to attenuate the elevation of RNF4 expression and PML SUMOylation. PML overexpression and RNF4 knockdown by small interfering RNA (siRNA) enhanced PML SUMOylation, promoted p53 recruitment and activation and exacerbated H₂O₂/ATO‐induced cardiomyocyte apoptosis which could be partially reversed by knockdown of p53. In vivo, knockdown of endogenous RNF4 via in vivo adeno‐associated virus infection deteriorated post‐MI structure remodelling including more extensive interstitial fibrosis and severely fractured and disordered structure. Furthermore, knockdown of RNF4 worsened ischaemia‐induced cardiac dysfunction of MI models. Our results reveal a novel myocardial apoptosis regulation model that is composed of RNF4, PML and p53. The modulation of these proteins may provide a new approach to tackling cardiac ischaemia.     

Screening of benzenesulfonamide in combination with chemically diverse fragments against carbonic anhydrase by differential scanning fluorimetry

Abstract

The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (bCA) delivered >100 hits that either caused, on their own, a significant thermal shift (ΔT_m , °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of hCA II, IX and XII which were efficacious in vivo. Such a re-discovery of suitable BSA periphery essentially validates the new fragment-based approach to the discovery of future CAIs. Structures of other validated fragment hits are reported.     

IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass

The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4(+) T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23-induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19(-/-) mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19(-/-) mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides.     

Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment.     

Temporal variation in abundance, return rate and life histories of previously spawned Atlantic salmon in a large subarctic river

The 30 year time series analyses revealed large temporal variation in the return rates and a recent increase in abundance of previous spawning Atlantic salmon Salmo salar in the River Teno, northern Scandinavia. The mean proportion of repeat spawners was 7 and 4% in the total Atlantic salmon catch and 9 and 22% in multi‐sea‐winter (MSW) catch component for females and males, respectively. Previous spawners constituted on the average 7% of the catch in mass but up to 20%(31 t) and 30%(19 t) in 2003 and in 2004, respectively. In 1975–2000, the proportion of previous spawners varied between 1 and 6%(3–12% of MSW Atlantic salmon), whereas in 2001–2004, they accounted for 8–21%(16–35% of MSW Atlantic salmon) of the total Atlantic salmon catch. The number of previous spawners in the catch correlated significantly with the preceding numbers of respective 1–3 sea‐winter (SW) maiden Atlantic salmon 2 years earlier. The recent increase in the numbers of 1S1 and 2S1 (1 or 2 years at sea followed by first spawning and 1 year reconditioning period at sea) alternate spawning Atlantic salmon was a consequence of higher numbers of maiden 1SW and 2SW Atlantic salmon in the catches and increased sea temperatures. Similarly, the return rate of 1SW Atlantic salmon to second spawning has improved in recent years. Most previous spawners ascended and were captured early in the fishing season. The smolt and sea‐age combinations of repeat spawners comprised 68 age groups contributing with the annual mean of 15 age groups to the great diversity of the River Teno Atlantic salmon population complex.