Current Opinion in Chemical Biology

Molecular imaging of live cells by Raman microscopy.

Publication Date: 2013 Jun 14 PMID: 23773582
Authors: Palonpon, A. F. - Sodeoka, M. - Fujita, K.
Journal: Curr Opin Chem Biol

Raman microscopy represents an emerging class of tools for molecular imaging of live cells because of the rich information obtained by detecting molecular vibrations. Recently, several Raman imaging techniques based on the parallel detection of Raman spectra have been developed, which can achieve high spatial and temporal resolution suitable for live cell imaging. When combined with tiny Raman tags in the cellular silent region, Raman microscopy has capability to map the distribution of specific target small molecules with minimum perturbation from the tag. Here we review these recent advances in cell imaging techniques based on spontaneous Raman scattering and highlight its potential for the observation and analysis of biological functions.

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Synthetic fluorescent probes for monovalent copper.

Publication Date: 2013 Jun 13 PMID: 23769869
Authors: Fahrni, C. J.
Journal: Curr Opin Chem Biol

Fluorescent probes are powerful and cost-effective tools for the detection of metal ions in biological systems. Compared to non-redox-active metal ions, the design of fluorescent probes for biological copper is challenging. Within the reducing cellular environment, copper is predominantly present in its monovalent oxidation state; therefore, the design of fluorescent probes for biological copper must take into account the rich redox and coordination chemistry of Cu(I). Recent progress in understanding the underlying solution chemistry and photophysical pathways led to the development of new probes that offer high fluorescence contrast and excellent selectivity towards monovalent copper.

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Making connections-strategies for single molecule fluorescence biophysics.

Publication Date: 2013 Jun 13 PMID: 23769868
Authors: Grohmann, D. - Werner, F. - Tinnefeld, P.
Journal: Curr Opin Chem Biol

Fluorescence spectroscopy and fluorescence microscopy carried out on the single molecule level are elegant methods to decipher complex biological systems; it can provide a wealth of information that frequently is obscured in the averaging of ensemble measurements. Fluorescence can be used to localise a molecule, study its binding with interaction partners and ligands, or to follow conformational changes in large multicomponent systems. Efficient labelling of proteins and nucleic acids is very important for any fluorescence method, and equally the development of novel fluorophores has been crucial in making biomolecules amenable to single molecule fluorescence methods. In this paper we review novel coupling strategies that permit site-specific and efficient labelling of proteins. Furthermore, we will discuss progressive single molecule approaches that allow the detection of individual molecules and biomolecular complexes even directly isolated from cellular extracts at much higher and much lower concentrations than has been possible so far.

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Chemical tags: inspiration for advanced imaging techniques.

Publication Date: 2013 Jun 12 PMID: 23769339
Authors: Chen, Z. - Cornish, V. W. - Min, W.
Journal: Curr Opin Chem Biol

This review summarizes recent applications of chemical tags in conjunction with advanced bio-imaging techniques including single-molecule fluorescence, spatiotemporally resolved ensemble microscopy techniques, and imaging modalities beyond fluorescence. We aim to illustrate the unique advantages of chemical tags in facilitating contemporary microscopy to address biological problems that are difficult or near impossible to approach otherwise. We hope our review will inspire more innovative applications enabled by the mingling of these two growing fields.

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New approaches for sensing metabolites and proteins in live cells using RNA.

Publication Date: 2013 Jun 6 PMID: 23746618
Authors: Strack, R. L. - Jaffrey, S. R.
Journal: Curr Opin Chem Biol

Tools to study the abundance, distribution, and flux of intracellular molecules are crucial for understanding cellular signaling and physiology. Although powerful, the current FRET-based technology for imaging cellular metabolites is not easily generalizable. Thus, new platforms for generating genetically encoded sensors are needed. We recently developed a new class of biosensors on the basis of Spinach, an RNA mimic of GFP. In this case, RNA aptamers against a target ligand are modularly fused to Spinach that substantially induce Spinach fluorescence in the presence of ligand. We have used this approach to detect metabolites and proteins both in vitro and in living bacteria, thus providing an alternative to FRET-based sensors and a generalizable approach for generating fluorescent sensors to any ligand of interest.

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Protein labeling with fluorogenic probes for no-wash live-cell imaging of proteins.

Publication Date: 2013 Jun 3 PMID: 23743124
Authors: Hori, Y. - Kikuchi, K.
Journal: Curr Opin Chem Biol

Protein labeling by using a protein tag and its specific fluorescent probe is increasingly becoming a useful technique for the real-time imaging of proteins in living cells. Recently, fluorogenic probes for protein labeling were developed. When using these probes, a washing step is not required for the removal of free probes from the cells, thus, allowing rapid detection of proteins in living cells with high signal-to-noise ratio. Various chemical principles have been applied in the designing of probes to include a turn-on fluorescence switch that is activated by the protein labeling reaction. In this review, we describe about the design strategy of the probes and the advances in fluorogenic protein labeling systems.

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Visualizing molecular diffusion through passive permeability barriers in cells: conventional and novel approaches.

Publication Date: 2013 May 31 PMID: 23731778
Authors: Lin, Y. C. - Phua, S. C. - Lin, B. - Inoue, T.
Journal: Curr Opin Chem Biol

Diffusion barriers are universal solutions for cells to achieve distinct organizations, compositions, and activities within a limited space. The influence of diffusion barriers on the spatiotemporal dynamics of signaling molecules often determines cellular physiology and functions. Over the years, the passive permeability barriers in various subcellular locales have been characterized using elaborate analytical techniques. In this review, we will summarize the current state of knowledge on the various passive permeability barriers present in mammalian cells. We will conclude with a description of several conventional techniques and one new approach based on chemically inducible diffusion trap (CIDT) for probing permeable barriers.

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Biofuels for the 21st century.

Publication Date: 2013 Jun PMID: 23722079
Authors: Burkart, M. D. - Mayfield, S. P.
Journal: Curr Opin Chem Biol

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Fluorescent probes for monitoring regulated secretion.

Publication Date: 2013 May 24 PMID: 23711436
Authors: Li, W. H. - Li, D.
Journal: Curr Opin Chem Biol

Numerous secretory cells use the regulated secretory pathway to release signaling molecules. Regulated secretion is an essential component of the intercellular communication network of a multicellular organism and serves diverse functions in neurobiology, endocrinology, and many other aspects of animal physiology. Probes that can monitor a specific exocytotic event with high temporal and spatial resolution would be invaluable tools for studying the molecular and cellular mechanisms underlying stimulus-secretion coupling, and for characterizing secretion defects that are found in different human diseases. This review summarizes different strategies and recent progress in developing fluorescent sensors for imaging regulated cell secretion.

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Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis.

Publication Date: 2013 Jun PMID: 23711435
Authors: Birault, V. - Solari, R. - Hanrahan, J. - Thomas, D. Y.
Journal: Curr Opin Chem Biol

Cystic fibrosis (CF) is the most frequent lethal genetic disease and the most frequent mutation is F508del-cystic fibrosis transmembrane regulator (CFTR). In common with some other protein trafficking diseases the mutant protein is functional but recognized by the cellular quality control system retained in the endoplasmic reticulum (ER) and degraded. There have been some recent impressive advances in developing corrector compounds that restore the trafficking of the mutant protein to the plasma membrane. The targets of these correctors and possible mechanisms of action are discussed.

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Hydrothermal conversion of biomass to fuels and energetic materials.

Publication Date: 2013 Jun PMID: 23707262
Authors: Kruse, A. - Funke, A. - Titirici, M. M.
Journal: Curr Opin Chem Biol

Available biomass, preferentially residues, can be divided in two groups: biomass with a high or natural water content ('wet' or 'green' biomass) and biomass with low water content such as wood and straw. In 'dry' biomass gasification processes, originating in most coal processing technologies, biomass of low water content is necessary to avoid the energy loss by water evaporation. In contrast, hydrothermal processes need water as reaction medium; therefore, these processes are preferentially used for wet or 'green' biomass. In this review paper we will describe the main research directions in the hydrothermal conversion of biomass into fuels and carbon throughout gasification to produce H2 or CH4, liquefaction to produce crude oils and phenols from lignin as well as carbonization to produce carbonaceous materials which can be either used as fuels (carbon negative chars) or interesting energetic materials (hydrothermal carbons).

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Advances in microalgae engineering and synthetic biology applications for biofuel production.

Publication Date: 2013 Jun PMID: 23684717
Authors: Gimpel, J. A. - Specht, E. A. - Georgianna, D. R. - Mayfield, S. P.
Journal: Curr Opin Chem Biol

Among the technologies being examined to produce renewable fuels, microalgae are viewed by many in the scientific community as having the greatest potential to become economically viable. Algae are capable of producing greater than 50,000kg/acre/year of biomass [1]. Additionally, most algae naturally accumulate energy-dense oils that can easily be converted into transportation fuels. To reach economic parity with fossil fuels there are still several challenges. These include identifying crop protection strategies, improving harvesting and oil extraction processes, and increasing biomass productivity and oil content. All of these challenges can be impacted by genetic, molecular, and ultimately synthetic biology techniques, and all of these technologies are being deployed to enable algal biofuels to become economically competitive with fossil fuels.

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Next generation therapeutics.

Publication Date: 2013 Jun PMID: 23683350
Authors: Carter, P. J. - Hazuda, D. - Wells, J. A.
Journal: Curr Opin Chem Biol

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Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story.

Publication Date: 2013 Jun PMID: 23683349
Authors: Stamford, A. - Strickland, C.
Journal: Curr Opin Chem Biol

Several fragment-based methods have been applied to the discovery of new lead sources for inhibitors of BACE1, an important therapeutic target for Alzheimer's disease. Among the most common fragment hits were various amidine-containing molecules in which the amidine engaged in discrete H-bond donor-acceptor interaction with the BACE1 catalytic dyad. Structure and medicinal chemistry knowledge-based optimization with emphasis on ligand efficiency resulted in identification of a key pharmacophore comprising a non-planar cyclic amidine scaffold directly attached to a phenyl group projecting into S1. This key pharmacophore is a common feature of known clinical candidates and has dominated the recent patent literature. A structural comparison of the non-planar cyclic amidine motif with other BACE1 pharmacophores highlights its uniqueness and distinct advantages.

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Engineering fatty acid biosynthesis in microalgae for sustainable biodiesel.

Publication Date: 2013 Jun PMID: 23683348
Authors: Blatti, J. L. - Michaud, J. - Burkart, M. D.
Journal: Curr Opin Chem Biol

Microalgae are a promising feedstock for biodiesel and other liquid fuels due to their fast growth rate, high lipid yields, and ability to grow in a broad range of environments. However, many microalgae achieve maximal lipid yields only under stress conditions hindering growth and providing compositions not ideal for biofuel applications. Metabolic engineering of algal fatty acid biosynthesis promises to create strains capable of economically producing fungible and sustainable biofuels. The algal fatty acid biosynthetic pathway has been deduced by homology to bacterial and plant systems, and much of our understanding is gleaned from basic studies in these systems. However, successful engineering of lipid metabolism in algae will necessitate a thorough characterization of the algal fatty acid synthase (FAS) including protein-protein interactions and regulation. This review describes recent efforts to engineer fatty acid biosynthesis toward optimizing microalgae as a biodiesel feedstock.

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Two-in-One antibodies with dual action Fabs.

Publication Date: 2013 Jun PMID: 23683347
Authors: Eigenbrot, C. - Fuh, G.
Journal: Curr Opin Chem Biol

Mechanisms and biological roles of antibody multi-specificity are topics of high interest. Evidence of conformational flexibility in antigen-combining sites and their utility in the recognition of different antigens appeared two decades ago. In the last three years an appreciation has emerged that recognition of very much more diverse protein antigens is within the scope of multi-specificity and also that this is sometimes, but not always, associated with structural plasticity. The ability to invent non-promiscuous, high affinity antibodies which are 'specific' for more than one antigen such as the recently described dual-specific Two-in-One DAF antibodies, provides not only insights into the evolution of antibody specificity but also a promise of powerful medicines fully within the paradigm of targeted therapies.

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Innovation in academic chemical screening: filling the gaps in chemical biology.

Publication Date: 2013 Jun PMID: 23683346
Authors: Hasson, S. A. - Inglese, J.
Journal: Curr Opin Chem Biol

Academic screening centers across the world have endeavored to discover small molecules that can modulate biological systems. To increase the reach of functional-genomic and chemical screening programs, universities, research institutes, and governments have followed their industrial counterparts in adopting high-throughput paradigms. As academic screening efforts have steadily grown in scope and complexity, so have the ideas of what is possible with the union of technology and biology. This review addresses the recent conceptual and technological innovation that has been propelling academic screening into its own unique niche. In particular, high-content and whole-organism screening are changing how academics search for novel bioactive compounds. Importantly, we recognize examples of successful chemical probe development that have punctuated the changing technology landscape.

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The human microbiome is a source of therapeutic drug targets.

Publication Date: 2013 Jun PMID: 23680493
Authors: Wallace, B. D. - Redinbo, M. R.
Journal: Curr Opin Chem Biol

It was appreciated early in drug discovery that the microbiota play an important role in the efficacy of therapeutic compounds. Indeed, the first antibiotic sulfa drugs were shown in the 1940s to be transformed by the bacteria that encode what we now call the intestinal microbiome. Here we briefly review the roles symbiotic bacteria play in the chemistry of human health, and we focus on the emerging appreciation that specific enzyme targets expressed by microbial symbiotes can be selectively disrupted to achieve clinical outcomes. We conclude that components of the microbiome should be considered 'druggable targets,' and we suggest that our rapidly evolving understanding of the chemical biology of mammalian-microbial symbiosis will translate into improved human health.

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Protein conjugation with genetically encoded unnatural amino acids.

Publication Date: 2013 Jun PMID: 23664497
Authors: Kim, C. H. - Axup, J. Y. - Schultz, P. G.
Journal: Curr Opin Chem Biol

The site-specific incorporation of unnatural amino acids with orthogonal chemical reactivity into proteins enables the synthesis of structurally defined protein conjugates. Amino acids containing ketone, azide, alkyne, alkene, and tetrazine side chains can be genetically encoded in response to nonsense and frameshift codons. These bio-orthogonal chemical handles allow precise control over the site and stoichiometry of conjugation, and have enabled medicinal chemistry-like optimization of the physical and biological properties of protein conjugates, especially the next-generation protein therapeutics.

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Chemistry and combustion of fit-for-purpose biofuels.

Publication Date: 2013 Jun PMID: 23664492
Authors: Rothamer, D. A. - Donohue, T. J.
Journal: Curr Opin Chem Biol

From the inception of internal combustion engines, biologically derived fuels (biofuels) have played a role. Nicolaus Otto ran a predecessor to today's spark-ignition engine with an ethanol fuel blend in 1860. At the 1900 Paris world's fair, Rudolf Diesel ran his engine on peanut oil. Over 100 years of petroleum production has led to consistency and reliability of engines that demand standardized fuels. New biofuels can displace petroleum-based fuels and produce positive impacts on the environment, the economy, and the use of local energy sources. This review discusses the combustion, performance and other requirements of biofuels that will impact their near-term and long-term ability to replace petroleum fuels in transportation applications.

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Production of advanced biofuels in engineered E. coli.

Publication Date: 2013 Jun PMID: 23659832
Authors: Wen, M. - Bond-Watts, B. B. - Chang, M. C.
Journal: Curr Opin Chem Biol

Commercial fermentation processes have long taken advantage of the synthetic power of living systems to rapidly and efficiently transform simple carbon sources into complex molecules. In this regard, the ability of yeasts to produce ethanol from glucose at exceptionally high yields has served as a key feature in its use as a fuel, but is also limited by the poor molecular properties of ethanol as a fuel such as high water miscibility and low energy density. Advances in metabolic engineering and synthetic biology allow us to begin constructing new high-flux pathways for production of next generation biofuels that are key to building a sustainable pipeline for liquid transportation fuels.

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Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases.

Publication Date: 2013 Jun PMID: 23647985
Authors: Ryno, L. M. - Wiseman, R. L. - Kelly, J. W.
Journal: Curr Opin Chem Biol

Protein homeostasis (or proteostasis) within the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR consists of three integrated signaling pathways activated by the accumulation of misfolded proteins within the ER lumen. Activation of the UPR alters ER proteostasis through translational attenuation of new protein synthesis and transcriptional remodeling of ER proteostasis pathways, providing a mechanism to adapt ER proteostasis in response to cellular stress. The capacity of the UPR to alter ER proteostasis suggests that exogenous manipulation of UPR signaling pathways offers therapeutic promise to alter the fate of pathologic proteins associated with human protein misfolding diseases. Here, we discuss the therapeutic potential of exogenous UPR activation to treat human disease and highlight specific small molecule approaches for regulating UPR signaling that could be beneficial to treat protein misfolding diseases.

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Targeting the untargetable: recent advances in the selective chemical modulation of protein phosphatase-1 activity.

Publication Date: 2013 Jun PMID: 23647984
Authors: Chatterjee, J. - Kohn, M.
Journal: Curr Opin Chem Biol

Protein phosphatase-1 (PP1) has long been neglected as a potential drug target owing to its misinterpreted unselective nature. However, growing evidence demonstrates that PP1 is highly selective in complex with regulatory proteins at the holoenzyme level, each of which is involved in different essential cellular signaling events. Here we summarize promising approaches to specifically activate or inhibit PP1 activity, and discuss remaining challenges and potential solutions. The summarized chemical tools pave the way for a better understanding of PP1's role in signaling networks, and the effects resulting from their application suggest their potential as future therapeutic candidates.

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Allosteric inhibition of HIV-1 integrase activity.

Publication Date: 2013 Jun PMID: 23647983
Authors: Engelman, A. - Kessl, J. J. - Kvaratskhelia, M.
Journal: Curr Opin Chem Biol

HIV-1 integrase is an important therapeutic target in the fight against HIV/AIDS. Integrase strand transfer inhibitors (INSTIs), which target the enzyme active site, have witnessed clinical success over the past 5 years, but the generation of drug resistance poses challenges to INSTI-based therapies moving forward. Integrase is a dynamic protein, and its ordered multimerization is critical to enzyme activity. The integrase tetramer, bound to viral DNA, interacts with host LEDGF/p75 protein to tether integration to active genes. Allosteric integrase inhibitors (ALLINIs) that compete with LEDGF/p75 for binding to integrase disrupt integrase assembly with viral DNA and allosterically inhibit enzyme function. ALLINIs display steep dose response curves and synergize with INSTIs ex vivo, highlighting this novel inhibitor class for clinical development.

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Stabilizing membrane proteins through protein engineering.

Publication Date: 2013 Jun PMID: 23639904
Authors: Scott, D. J. - Kummer, L. - Tremmel, D. - Pluckthun, A.
Journal: Curr Opin Chem Biol

Integral membrane proteins (IMPs) are crucial components of all cells but are difficult to study in vitro because they are generally unstable when removed from their native membranes using detergents. Despite the major biomedical relevance of IMPs, less than 1% of Protein Data Bank (PDB) entries are IMP structures, reflecting the technical gap between studies of soluble proteins compared to IMPs. Stability can be engineered into IMPs by inserting stabilizing mutations, thereby generating proteins that can be successfully applied to biochemical and structural studies when solubilized in detergent micelles. The identification of stabilizing mutations is not trivial, and this review will focus on the methods that have been used to identify stabilized membrane proteins, including alanine scanning and screening, directed evolution and computational design.

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Advanced biofuel production by the yeast Saccharomyces cerevisiae.

Publication Date: 2013 Jun PMID: 23628723
Authors: Buijs, N. A. - Siewers, V. - Nielsen, J.
Journal: Curr Opin Chem Biol

Replacement of conventional transportation fuels with biofuels will require production of compounds that can cover the complete fuel spectrum, ranging from gasoline to kerosene. Advanced biofuels are expected to play an important role in replacing fossil fuels because they have improved properties compared with ethanol and some of these may have the energy density required for use in heavy duty vehicles, ships, and aviation. Moreover, advanced biofuels can be used as drop-in fuels in existing internal combustion engines. The yeast cell factory Saccharomyces cerevisiae can be turned into a producer of higher alcohols (1-butanol and isobutanol), sesquiterpenes (farnesene and bisabolene), and fatty acid ethyl esters (biodiesel), and here we discusses progress in metabolic engineering of S. cerevisiae for production of these advanced biofuels.

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Targeting T cells to tumor cells using bispecific antibodies.

Publication Date: 2013 Jun PMID: 23623807
Authors: Frankel, S. R. - Baeuerle, P. A.
Journal: Curr Opin Chem Biol

The immune system, and in particular T cells, can be harnessed to treat cancer. Several bispecific T cell engaging antibodies of the BiTE((R)) format are in early or late-stage clinical development. These small recombinant antibody constructs effectively trigger killing of cancer cells by temporarily attached, polyclonal T cells. Blinatumomab, a CD19/CD3-bispecific BiTE((R)) antibody, has demonstrated high clinical activity in B cell leukemia and lymphoma patients. Three additional BiTE antibodies directed against surface target antigen expressed on solid tumors are being evaluated in phase I clinical trials. Alternative approaches to direct polyclonal T cells to kill cancer cells are under intense investigation.

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Next generation biofuel engineering in prokaryotes.

Publication Date: 2013 Jun PMID: 23623045
Authors: Gronenberg, L. S. - Marcheschi, R. J. - Liao, J. C.
Journal: Curr Opin Chem Biol

Next-generation biofuels must be compatible with current transportation infrastructure and be derived from environmentally sustainable resources that do not compete with food crops. Many bacterial species have unique properties advantageous to the production of such next-generation fuels. However, no single species possesses all characteristics necessary to make high quantities of fuels from plant waste or CO2. Species containing a subset of the desired characteristics are used as starting points for engineering organisms with all desired attributes. Metabolic engineering of model organisms has yielded high titer production of advanced fuels, including alcohols, isoprenoids, and fatty acid derivatives. Technical developments now allow engineering of native fuel producers, as well as lignocellulolytic and autotrophic bacteria, for the production of biofuels. Continued research on multiple fronts is required to engineer organisms for truly sustainable and economical biofuel production.

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Drugging the human methylome: an emerging modality for reversible control of aberrant gene transcription.

Publication Date: 2013 Jun PMID: 23619004
Authors: Wigle, T. J. - Copeland, R. A.
Journal: Curr Opin Chem Biol

Protein and DNA methylation have emerged as critical mechanisms for the control of regulated gene transcription. In humans, the addition, recognition and removal of methyl groups are orchestrated by at least 344 proteins that we collectively refer to as the 'methylome'. The large size of the methylome likely reflects the importance of precise control over this small covalent modification. An increasing number of reports implicating the misregulation of methylation in disease make the proteins governing this modification attractive target for small molecule drug discovery. In light of the emerging opportunities for the development of therapeutics that modulate methylation-dependent pathways, this review examines the protein families that constitute the methylome, with emphasis on the methylation of arginine and lysine residues of proteins. Genetic aberrations that give rise to disease are highlighted, in addition to recent proof-of-concept successes in the development of small molecule modulators of methylome constituents.

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Spectral expansion and antenna reduction can enhance photosynthesis for energy production.

Publication Date: 2013 Jun PMID: 23602382
Authors: Blankenship, R. E. - Chen, M.
Journal: Curr Opin Chem Biol

We consider two approaches for improving the efficiency of photosynthesis: the expansion of the solar spectrum that drives oxygenic photosynthesis and the reduction of antenna systems that couple to the photochemical reaction center. The first approach can possibly result in an increase of 19% in the number of photons available per unit area if the photosynthetically active radiation spectrum is expanded to 750nm. The second approach can in principle shift the photosynthesis light response curve to significantly higher intensities, thereby reducing the amount of excess light, which is absorbed photons in excess of the number that can be utilized. The implementation of these approaches may lead to apparent improvement in photosynthetic efficiency in many but not all the cases.

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Expanding the microalgal industry - continuing controversy or compelling case?

Publication Date: 2013 Jun PMID: 23587864
Authors: Stephens, E. - Ross, I. L. - Hankamer, B.
Journal: Curr Opin Chem Biol

Herein we examine the potential role that microalgae might play in the approaching challenges of energy and fuel security, and food and water supply. Microalgal production systems remain the subject of controversy however, generally consisting of arguments about the economic and environment sustainability of these systems. We discuss these aspects and draw some parallels with other systems to highlight real advantages and obstacles to expanding the modern microalgal industry. Emerging alternative production models and the relatively early developmental state of the microalgal biofuels industry provide room for extensive innovation that has the potential to bring the technology to a highly productive maturity.

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Analytical and bioanalytical technologies for characterizing antibody-drug conjugates.

Publication Date: 2013 Jun PMID: 23570980
Authors: Alley, S. C. - Anderson, K. E.
Journal: Curr Opin Chem Biol

Antibody-drug conjugates (ADCs) require multiple assays for analytical and bioanalytical characterization due to their heterogeneous and dynamic nature. These assays can help address questions from the drug-loading distribution following conjugation to exposure-response relationships after dosing in vivo. This review describes new assay technologies that have been developed for physiochemical characterization and determination of pharmacokinetic parameters of ADCs.

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Bispecific antibodies for delivery into the brain.

Publication Date: 2013 Jun PMID: 23570979
Authors: Watts, R. J. - Dennis, M. S.
Journal: Curr Opin Chem Biol

The blood-brain barrier (BBB) is a formidable obstacle preventing drug delivery to the brain, particularly for large protein therapeutics. The utilization of endogenous brain endothelial transport pathways, however, represents a promising approach to cross the cellular barrier through receptor-mediated transcytosis. Therapeutics designed to take advantage of this approach require at least two functionalities, one that facilitates transport and the other to provide therapeutic benefit, and bispecific antibodies are ideally suited for this task.

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Carbon partitioning in photosynthesis.

Publication Date: 2013 Jun PMID: 23542013
Authors: Melis, A.
Journal: Curr Opin Chem Biol

The work seeks to raise awareness of a fundamental problem that impacts the renewable generation of fuels and chemicals via (photo)synthetic biology. At issue is regulation of the endogenous cellular carbon partitioning between different biosynthetic pathways, over which the living cell exerts stringent control. The regulation of carbon partitioning in photosynthesis is not understood. In plants, microalgae and cyanobacteria, methods need be devised to alter photosynthetic carbon partitioning between the sugar, terpenoid, and fatty acid biosynthetic pathways, to lower the prevalence of sugar biosynthesis and correspondingly upregulate terpenoid and fatty acid hydrocarbons production in the cell. Insight from unusual but naturally occurring carbon-partitioning processes can help in the design of blueprints for improved photosynthetic fuels and chemicals production.

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Metabolic and cellular organization in evolutionarily diverse microalgae as related to biofuels production.

Publication Date: 2013 Jun PMID: 23538202
Authors: Hildebrand, M. - Abbriano, R. M. - Polle, J. E. - Traller, J. C. - Trentacoste, E. M. - Smith, S. R. - Davis, A. K.
Journal: Curr Opin Chem Biol

Microalgae are among the most diverse organisms on the planet, and as a result of symbioses and evolutionary selection, the configuration of core metabolic networks is highly varied across distinct algal classes. The differences in photosynthesis, carbon fixation and processing, carbon storage, and the compartmentation of cellular and metabolic processes are substantial and likely to transcend into the efficiency of various steps involved in biofuel molecule production. By highlighting these differences, we hope to provide a framework for comparative analyses to determine the efficiency of the different arrangements or processes. This sets the stage for optimization on the based on information derived from evolutionary selection to diverse algal classes and to synthetic systems.

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Cell-free translation of peptides and proteins:from high throughput screening to clinical production.

Publication Date: 2013 Jun PMID: 23499386
Authors: Murray, C. J. - Baliga, R.
Journal: Curr Opin Chem Biol

In the past decade, in vitro transcription/translation technologies have emerged as discovery tools for screening large protein expression libraries, for the selection of engineered polypeptide libraries, and as alternatives to conventional heterologous expression for protein production. Therapeutic proteins and peptides discovered using ribosome-based display methods that link genetic information to the encoded polypeptide generated by cell-free extracts, or purified translation components, are beginning to move forward into human clinical trials. This review details the significant progress in in vitro translation for novel protein and non-natural amino acid containing peptide discovery platforms, as well as advances in the clinical-scale production of therapeutic proteins using cell-free transcription/translation.

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Comparing life cycle assessments of different biofuel options.

Publication Date: 2013 Jun PMID: 23490811
Authors: Kendall, A. - Yuan, J.
Journal: Curr Opin Chem Biol

Life cycle assessment (LCA) has shown that first generation biofuels provide a little to no benefit for greenhouse gas (GHG) reductions compared to petroleum fuels, particularly when indirect effects are considered. Second generation fuels are intended to achieve greater GHG reductions and avoid other sustainability issues. LCAs of second generation biofuels exhibit great variability and uncertainty, leading to inconclusive results for the performance of particular pathways (combinations of feedstocks and fuels). Variability arises in part because of the prospective nature of LCAs for future fuels; however, a review of recent articles on biofuel LCA methodology indicates two additional sources of variability: real sources such as spatiotemporal heterogeneity, and methodological sources such as choices for co-product allocation methods and system boundary definition.

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