Will REDD+ work? The need for interdisciplinary research to address key challenges

In this article, we draw on the contributions to this issue to address the question ‘Will REDD+ work?’. We do so by differentiating between how, where and when REDD+ might work. The article shows how issues of scope, scale and pace of REDD+ are related, and how interdisciplinary research can help to distill the lessons learned from REDD+ efforts currently underway. Important research areas include the drivers of deforestation and forest degradation, monitoring, reporting and verification, co-benefits, governance capacity, linkages with related policies, and the environmental and social impacts of REDD+. In concluding, we highlight the role of interdisciplinary research in supporting the different actors involved in REDD+ to cope with the inherent heterogeneity and complexity of REDD+

Assessment of free energy predictors for ligand binding to a methyllysine histone code reader

Methyllysine histone code readers constitute a new promising group of potential drug targets. For instance, L3MBTL1, a Malignant Brain Tumor (MBT) protein, selectively binds mono- and di-methyllysine epigenetic marks (KMe, KMe2) that eventually results in the negative regulation of multiple genes through the E2F/Rb oncogenic pathway. There is a pressing need in potent and selective small-molecule probes that would enable further target validation and might become therapeutic leads. Such an endeavor would require efficient tools to assess the free energy of protein-ligand binding. However, due to an unparalleled function of the MBT binding pocket (i.e. selective binding to KMe/KMe2) and because of its distinctive structure representing a small aromatic “cage”, an accurate assessment of its binding affinity to a ligand appears to be a challenging task. Here, we report a comparative analysis of computationally affordable affinity predictors applied to a set of seven small-molecule ligands interacting with L3MBTL1. The analysis deals with novel ligands and targets, but applies widespread computational approaches and intuitive comparison metrics that makes this study compatible with and incremental to earlier large scale accounts on the efficiency of affinity predictors. Ultimately, this study has revealed three top performers, far ahead of the other techniques, including two scoring functions, PMF04 and PLP, along with a simulation-based method Molecular Mechanics Poisson-Boltzmann/Surface Area (MM-PB/SA). We discuss why some methods may perform better than others on this target class, the limits of their application, as well as how the efficiency of the most CPU-demanding techniques could be optimized

Research priorities in land use and land-cover change for the Earth system and integrated assessment modelling

Copyright © 2010 Royal Meteorological Society and Crown Copyright.This special issue has highlighted recent and innovative methods and results that integrate observations and modelling analyses of regional to global aspect of biophysical and biogeochemical interactions of land-cover change with the climate system. Both the Earth System and the Integrated Assessment modeling communities recognize the importance of an accurate representation of land use and land-cover change to understand and quantify the interactions and feedbacks with the climate and socio-economic systems, respectively. To date, cooperation between these communities has been limited. Based on common interests, this work discusses research priorities in representing land use and land-cover change for improved collaboration across modelling, observing and measurement communities. Major research topics in land use and land-cover change are those that help us better understand (1) the interaction of land use and land cover with the climate system (e.g. carbon cycle feedbacks), (2) the provision of goods and ecosystem services by terrestrial (natural and anthropogenic) land-cover types (e.g. food production), (3) land use and management decisions and (4) opportunities and limitations for managing climate change (for both mitigation and adaptation strategies)

Biophysical Probes Reveal a “Compromise” Nature of the Methyl-lysine Binding Pocket in L3MBTL1

Histone lysine methylation (Kme) encodes essential information modulating many biological processes including gene expression and transcriptional regulation. However, the atomic-level recognition mechanisms of methylated histones by their respective adaptor proteins are still elusive. For instance, it is unclear how L3MBTL1, a methyl-lysine histone code reader, recognizes equally well both mono- and di-methyl marks, but ignores unmodified and trimethylated lysine residues. We made use of Molecular Dynamics (MD) and Free Energy Perturbation (FEP) techniques in order to investigate the energetics and dynamics of the methyllysine recognition. Isothermal Titration Calorimetry (ITC) was employed to experimentally validate the computational findings. Both computational and experimental methods were applied to a set of designed “biophysical” probes that mimic the shape of a single lysine residue and reproduce the binding affinities of cognate histone peptides. Our results suggest that, besides forming favorable interactions, the L3MBTL1 binding pocket energetically penalizes both methylation states and has most probably evolved as a “compromise” that non-optimally fit to both mono- and di-methyl-lysine marks

Identification of Non-Peptide Malignant Brain Tumor (MBT) Repeat Antagonists by Virtual Screening of Commercially Available Compounds

The Malignant Brain Tumor (MBT) repeat is an important epigenetic-code “reader” and is functionally associated with differentiation, gene silencing and tumor suppression1–3. Small molecule probes of MBT domains should enable a systematic study of MBT-containing proteins, and potentially reveal novel druggable targets. We designed and applied a virtual screening strategy, which identified potential MBT antagonists in a large database of commercially available compounds. A small set of virtual hits was purchased and submitted to experimental testing. Nineteen of the purchased compounds showed a specific dose-dependent protein binding and will provide critical structure-activity information for subsequent lead generation and optimization

Oxidoreductases on their way to industrial biotransformations

Fungi produce heme-containing peroxidases and peroxygenases, flavin-containing oxidases and dehydrogenases, and different copper-containing oxidoreductases involved in the biodegradation of lignin and other recalcitrant compounds. Heme peroxidases comprise the classical ligninolytic peroxidases and the new dye-decolorizing peroxidases, while heme peroxygenases belong to a still largely unexplored superfamily of heme-thiolate proteins. Nevertheless, basidiomycete unspecific peroxygenases have the highest biotechnological interest due to their ability to catalyze a variety of regio- and stereo-selective monooxygenation reactions with H2O2 as the source of oxygen and final electron acceptor. Flavo-oxidases are involved in both lignin and cellulose decay generating H2O2 that activates peroxidases and generates hydroxyl radical. The group of copper oxidoreductases also includes other H2O2 generating enzymes - copper-radical oxidases - together with classical laccases that are the oxidoreductases with the largest number of reported applications to date. However, the recently described lytic polysaccharide monooxygenases have attracted the highest attention among copper oxidoreductases, since they are capable of oxidatively breaking down crystalline cellulose, the disintegration of which is still a major bottleneck in lignocellulose biorefineries, along with lignin degradation. Interestingly, some flavin-containing dehydrogenases also play a key role in cellulose breakdown by directly/indirectly "fueling" electrons for polysaccharide monooxygenase activation. Many of the above oxidoreductases have been engineered, combining rational and computational design with directed evolution, to attain the selectivity, catalytic efficiency and stability properties required for their industrial utilization. Indeed, using ad hoc software and current computational capabilities, it is now possible to predict substrate access to the active site in biophysical simulations, and electron transfer efficiency in biochemical simulations, reducing in orders of magnitude the time of experimental work in oxidoreductase screening and engineering. What has been set out above is illustrated by a series of remarkable oxyfunctionalization and oxidation reactions developed in the frame of an intersectorial and multidisciplinary European RTD project. The optimized reactions include enzymatic synthesis of 1-naphthol, 25-hydroxyvitamin D3, drug metabolites, furandicarboxylic acid, indigo and other dyes, and conductive polyaniline, terminal oxygenation of alkanes, biomass delignification and lignin oxidation, among others. These successful case stories demonstrate the unexploited potential of oxidoreductases in medium and large-scale biotransformations

Molecular dissection of the valproic acid effects on glioma cells

Many glioblastoma patients suffer from seizures why they are treated with antiepileptic agents. Valproic acid (VPA) is a histone deacetylase inhibitor that apart from its anticonvulsive effects in some retrospective studies has been suggested to lead to a superior outcome of glioblastoma patients. However, the exact molecular effects of VPA treatment on glioblastoma cells have not yet been deciphered. We treated glioblastoma cells with VPA, recorded the functional effects of this treatment and performed a global and unbiased next generation sequencing study on the chromatin (ChIP) and RNA level. 1) VPA treatment clearly sensitized glioma cells to temozolomide: A protruding VPA-induced molecular feature in this context was the transcriptional upregulation/reexpression of numerous solute carrier (SLC) transporters that was also reflected by euchromatinization on the histone level and a reexpression of SLC transporters in human biopsy samples after VPA treatment. DNA repair genes were adversely reduced. 2) VPA treatment, however, also reduced cell proliferation in temozolomide-naive cells: On the molecular level in this context we observed a transcriptional upregulation/reexpression and euchromatinization of several glioblastoma relevant tumor suppressor genes and a reduction of stemness markers, while transcriptional subtype classification (mesenchymal/proneural) remained unaltered. Taken together, these findings argue for both temozolomide-dependent and -independent effects of VPA. VPA might increase the uptake of temozolomide and simultaneously lead to a less malignant glioblastoma phenotype. From a mere molecular perspective these findings might indicate a surplus value of VPA in glioblastoma therapy and could therefore contribute an additional ratio for clinical decision making

The Role and Need for Space-Based Forest Biomass-Related Measurements in Environmental Management and Policy

The achievement of international goals and national commitments related to forest conservation and management, climate change, and sustainable development requires credible, accurate, and reliable monitoring of stocks and changes in forest biomass and carbon. Most prominently, the Paris Agreement on Climate Change and the United Nations’ Sustainable Development Goals in particular require data on biomass to monitor progress. Unprecedented opportunities to provide forest biomass data are created by a series of upcoming space-based missions, many of which provide open data targeted at large areas and better spatial resolution biomass monitoring than has previously been achieved. We assess various policy needs for biomass data and recommend a long-term collaborative effort among forest biomass data producers and users to meet these needs. A gap remains, however, between what can be achieved in the research domain and what is required to support policy making and meet reporting requirements. There is no single biomass dataset that serves all users in terms of definition and type of biomass measurement, geographic area, and uncertainty requirements, and whether there is need for the most recent up-to-date biomass estimate or a long-term biomass trend. The research and user communities should embrace the potential strength of the multitude of upcoming missions in combination to provide for these varying needs and to ensure continuity for long-term data provision which one-off research missions cannot provide. International coordination bodies such as Global Forest Observations Initiative (GFOI), Committee on Earth Observation Satellites (CEOS), and Global Observation of Forest Cover and Land Dynamics (GOFC‐GOLD) will be integral in addressing these issues in a way that fulfils these needs in a timely fashion. Further coordination work should particularly look into how space-based data can be better linked with field reference data sources such as forest plot networks, and there is also a need to ensure that reference data cover a range of forest types, management regimes, and disturbance regimes worldwide

Dealing with locally-driven degradation: A quick start option under REDD+

The paper reviews a number of challenges associated with reducing degradation and its related emissions through national approaches to REDD+ under UNFCCC policy. It proposes that in many countries, it may in the short run be easier to deal with the kinds of degradation that result from locally driven community over-exploitation of forest for livelihoods, than from selective logging or fire control. Such degradation is low-level, but chronic, and is experienced over very large forest areas. Community forest management programmes tend to result not only in reduced degradation, but also in forest enhancement; moreover they are often popular, and do not require major political shifts. In principle these approaches therefore offer a quick start option for REDD+. Developing reference emissions levels for low-level locally driven degradation is difficult however given that stock losses and gains are too small to be identified and measured using remote sensing, and that in most countries there is little or no forest inventory data available. We therefore propose that forest management initiatives at the local level, such as those promoted by community forest management programmes, should monitor, and be credited for, only the net increase in carbon stock over the implementation period, as assessed by ground level surveys at the start and end of the period. This would also resolve the problem of nesting (ensuring that all credits are accounted for against the national reference emission level), since communities and others at the local level would be rewarded only for increased sequestration, while the national reference emission level would deal only with reductions in emissions from deforestation and degradation