Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications

Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK-ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK-ligand/OPG pathway, and the clinical development of anti-RANK-ligand therapy.     

Recruitment of a double bond isomerase to serve as a reductive dehalogenase during biodegradation of pentachlorophenol

Tetrachlorohydroquinone dehalogenase catalyzes the replacement of chlorine atoms on tetrachlorohydroquinone and trichlorohydroquinone with hydrogen atoms during the biodegradation of pentachlorophenol by Sphingomonas chlorophenolica. The sequence of the active site region of tetrachlorohydroquinone dehalogenase is very similar to those of the corresponding regions of maleylacetoacetate isomerases, enzymes that catalyze the glutathione-dependent isomerization of a cis double bond in maleylacetoacetate to the trans configuration during the catabolism of phenylalanine and tyrosine. Furthermore, tetrachlorohydroquinone dehalogenase catalyzes the isomerization of maleylacetone (an analogue of maleylacetoacetate) at a rate nearly comparable to that of a bona fide bacterial maleylacetoacetate isomerase. Since maleylacetoacetate isomerase is involved in a common and presumably ancient pathway for catabolism of tyrosine, while tetrachlorohydroquinone dehalogenase catalyzes a more specialized reaction, it is likely that tetrachlorohydroquinone dehalogenase arose from a maleylacetoacetate isomerase. The substrates and overall transformations involved in the dehalogenation and isomerization reactions are strikingly different. This enzyme provides a remarkable example of Nature's ability to recruit an enzyme with a useful structural scaffold and elaborate upon its basic catalytic capabilities to generate a catalyst for a newly needed reaction.     

Land suitability for energy crops under scenarios of climate change and land‐use

Bioenergy is expected to play a critical role in climate change mitigation. Most integrated assessment models assume an expansion of agricultural land for cultivation of energy crops. This study examines the suitability of land for growing a range of energy crops on areas that are not required for food production, accounting for climate change impacts and conservation requirements. A global fuzzy logic model is employed to ascertain the suitable cropping areas for a number of sugar, starch and oil crops, energy grasses and short rotation tree species that could be grown specifically for energy. Two climate change scenarios are modelled (RCP2.6 and RCP8.5), along with two scenarios representing the land which cannot be used for energy crops due to forest and biodiversity conservation, food agriculture and urban areas. Results indicate that 40% of the global area currently suitable for energy crops overlaps with food land and 31% overlaps with forested or protected areas, highlighting hotspots of potential land competition risks. Approximately 18.8 million km² is suitable for energy crops, to some degree, and does not overlap with protected, forested, urban or food agricultural land. Under the climate change scenario RCP8.5, this increases to 19.6 million km² by the end of the century. Broadly, climate change is projected to decrease suitable areas in southern regions and increase them in northern regions, most notably for grass crops in Russia and China, indicating that potential production areas will shift northwards which could potentially affect domestic use and trade of biomass significantly. The majority of the land which becomes suitable is in current grasslands and is just marginally or moderately suitable. This study therefore highlights the vital importance of further studies examining the carbon and ecosystem balance of this potential land‐use change, energy crop yields in sub‐optimal soil and climatic conditions and potential impacts on livelihoods.     

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor

Introduction

As a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy.

Methods

Peripheral blood samples were obtained from RA patients, including a subset treated with anti-TNF, and from healthy controls to examine influenza-specific responses following seasonal influenza vaccination. Serum antibody was measured by hemagglutination inhibition assay. The frequency of influenza vaccine-specific antibody secreting cells and memory B cells was measured by EliSpot. Plasmablast (CD19+IgD-CD27hiCD38hi) induction was measured by flow cytometry.

Results

Compared with healthy controls, RA patients treated with anti-TNF exhibited significantly decreased influenza-specific serum antibody and memory B cell responses throughout multiple years of the study. The short-term influenza-specific effector B cell response was also significantly decreased in RA patients treated with anti-TNF as compared with healthy controls, and correlated with decreased influenza-specific memory B cells and serum antibody present at one month following vaccination.

Conclusions

RA patients treated with anti-TNF exhibit a compromised immune response to influenza vaccine, consisting of impaired effector and consequently memory B cell and antibody responses. The results suggest that the increased incidence and severity of infection observed in this patient population could be a consequence of diminished antigen-responsiveness. Therefore, this patient population would likely benefit from repeat vaccination and from vaccines with enhanced immunogenicity.     

Manipulating the desiccation tolerance and vigor of dry somatic embryos of Medicago sativa L. with sucrose,heat shock and abscisic acid

Summary The effects of sucrose concentration in the maturation medium in combination with a heat shock treatment at 36°C were investigated in an attempt to improve the vigor of seedlings grown from dry somatic embryos of alfalfa (Medicago sativa L.). Callus was formed from petiole expiants and dispersed in liquid suspension medium in the presence of 5 M 2,4-D. The cell suspension was sieved to synchronize embryo development. The 200 – 500 m fraction was plated on embryo development medium without 2,4-D, grown for 14 days, and transferred to maturation medium. With 3% sucrose in the maturation medium, the somatic embryos germinated precociously and were unable to survive desiccation. At higher sucrose concentrations, germination was delayed and the embryos continued to accumulate dry matter. After 13 days on 6% sucrose medium (27 days after sieving), the somatic embryos were tolerant of drying to 12% moisture without exposure to exogenous ABA. Heat shock, which presumably stimulates endogenous ABA synthesis, improved the desiccation tolerance of somatic embryos if applied prior to day 27 after sieving, but its effects were minimal after day 27. High sucrose concentrations up to 9% in the maturation medium were optimal during the first 8 days on maturation medium (days 14 to 22 after sieving), but a lower concentration (6%) was optimal during the later stages of embryo maturation (days 22 to 30 after sieving). The inclusion of 10^–5 M ABA in the maturation medium with 6% sucrose further improved embryo quality if applied approximately 20 days after sieving.     

How can accelerated development of bioenergy contribute to the future UK energy mix? Insights from a MARKAL modelling exercise

Background  

This work explores the potential contribution of bioenergy technologies to 60% and 80% carbon reductions in the UK energy system by 2050, by outlining the potential for accelerated technological development of bioenergy chains. The investigation was based on insights from MARKAL modelling, detailed literature reviews and expert consultations. Due to the number and complexity of bioenergy pathways and technologies in the model, three chains and two underpinning technologies were selected for detailed investigation: (1) lignocellulosic hydrolysis for the production of bioethanol, (2) gasification technologies for heat and power, (3) fast pyrolysis of biomass for bio-oil production, (4) biotechnological advances for second generation bioenergy crops, and (5) the development of agro-machinery for growing and harvesting bioenergy crops. Detailed literature searches and expert consultations (looking inter alia at research and development needs and economic projections) led to the development of an 'accelerated' dataset of modelling parameters for each of the selected bioenergy pathways, which were included in five different scenario runs with UK-MARKAL (MED). The results of the 'accelerated runs' were compared with a low-carbon (LC-Core) scenario, which assesses the cheapest way to decarbonise the energy sector.