The HMMER website, available at http://www.ebi.ac.uk/Tools/hmmer/, provides access to the protein homology search algorithms found in the HMMER software suite. Since the first release of the website in 2011, the search repertoire has been expanded to include the iterative search algorithm, jackhmmer. The continued growth of the target sequence databases means that traditional tabular representations of significant sequence hits can be overwhelming to the user. Consequently, additional ways of presenting homology search results have been developed, allowing them to be summarised according to taxonomic distribution or domain architecture. The taxonomy and domain architecture representations can be used in combination to filter the results according to the needs of a user. Searches can also be restricted prior to submission using a new taxonomic filter, which not only ensures that the results are specific to the requested taxonomic group, but also improves search performance. The repertoire of profile hidden Markov model libraries, which are used for annotation of query sequences with protein families and domains, has been expanded to include the libraries from CATH-Gene3D, PIRSF, Superfamily and TIGRFAMs. Finally, we discuss the relocation of the HMMER webserver to the European Bioinformatics Institute and the potential impact that this will have.

In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40-and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APP sw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APP sw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

Driven by remarkable advances in the understanding of structure and reaction mechanisms, organic synthesis will be increasingly directed to producing bioinspired and newly designed molecules. Molecular evolution on Earth over the past 3.8 billion years has produced an extraordinary library of chemical structures, unsurpassed in number, diversity and function. Each structure is a treasure-trove of information and inspiration, a molecular textbook encoded in the language of chemistry. Collectively, these molecules comprise the chemical genome of our planet, and represent a universe ripe for exploration. With modern analytical tools, each of these structural tomes can now be read, enabling an understanding of how structure relates to function. More significantly, we can now use organic synthesis not only to make copies of these molecules, but also to prepare bioinspired or designed compounds, some with functions unheard of in the natural world -compounds that will influence, if not shape, every facet of our existence.Our emerging molecular literacy is creating a revolution that will transform our world. The ability to design, create and control molecules has opened a vast frontier of research and an age of unprecedented opportunity. Scientists from every background are being drawn to this molecular frontier, creating a melting pot of disciplinary fusions and the resultant ability to address problems that transcend the boundaries of individual fields. From molecular biology to molecular computing, molecular medicine, molecular (nano) technology and even molecular gastronomy, science is becoming increasingly integrated and 'molecularized'.Chemists have been laying the foundations for this molecular revolution for the past two centuries. Before that, nature's archive was the sole or primary source of chemicals used by humans. This has now changed. Through extraordinarily innovative advances in tools, theories and methods, synthesis has provided a reliable supply of many natural compounds as well as others created by design. Indeed the question of whether a molecule from nature could be made is increasingly giving way to whether it could be made in a way that impacts on supply and science. Of increasing importance now is the question of what molecules to make. Naturally occurring molecules are produced in their ecosystems for uses other than what we seek or need. Their activities in humans are thus serendipitous and unoptimized but provide a rich source of information and inspiration. We are now on the cusp of a period in which we can use this inspiration to design molecules with superior or new functions and make them in increasingly efficient, practical and environmentally friendly ways [1][2][3][4][5][6][7][8][9][10][11] .

The separate developments of microarray patterning of DNA oligonucleotides, and of DNA hairpins as sensitive probes for oligonucleotide identification in solution, have had a tremendous impact on basic biological research and clinical applications. We have combined these two approaches to develop arrayable and label-free biological sensors based on fluorescence unquenching of DNA hairpins immobilized on metal surfaces. The thermodynamic and kinetic response of these sensors, and the factors important in hybridization efficiency, were investigated. Hybridization efficiency was found to be sensitive to hairpin secondary structure, as well as to the surface distribution of DNA hairpins on the substrate. The identity of the bases used in the hairpin stem as well as the overall loop length significantly affected sensitivity and selectivity. Surface-immobilized hairpins discriminated between two sequences with a single base-pair mismatch with high sensitivity (over an order of magnitude difference in signal) under identical assay conditions (no change in stringency). This represents a significant improvement over other microarray-based techniques.

There is a keen interest in developing techniques for rapid genetic analysis that do not require labeling of an analyte. Here we demonstrate that fluorophore-tagged DNA hairpins attached to gold films can function as immobilized "molecular beacons". Two DNA hairpins incorporating portions of the Staphlococcus aureus FemA and mecR methicillin-resistance genes were attached to a gold substrate. Upon exposure to the complement, a approximately 26-fold increase in fluorescence intensity was measured corresponding to a 96 +/- 5% quenching efficiency. Studies with nonspecific DNA indicate that DNA hairpins immobilized on a gold surface retain their ability to bind complementary DNA sequences selectively.

Macroporous silicon microcavities for detection of large biological molecules have been fabricated from highly doped n‐type silicon. Well‐defined controllable pore sizes up to 120 nm have been obtained by systematically optimizing the etching parameters. The dependence of the sensor sensitivity on pore size is discussed. Excellent infiltration inside these macroporous silicon microcavities is demonstrated using 60 nm diameter latex spheres and rabbit IgG (150 kDa; 1Da = 1 g mol–1). The sensing performance of the device is tested using a biotin/streptavidin couple, and protein concentration down to 1–2 μM (equivalent to 0.3 ng mm–2) could be detected. Simulations show that the sensitivity of the technique is currently approximately 1–2 % of a protein monolayer.

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Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is an RNA-mediated disease. Dramatically expanded (CUG) repeats accumulate in nuclei, and sequester RNA-binding proteins such as the splicing regulator MBNL1. We have employed resin-bound dynamic combinatorial chemistry (RBDCC) to identify the first examples of compounds able to inhibit MBNL1 binding to (CUG) repeat RNA. Screening an RBDCL with a theoretical diversity of 11,325 members yielded several molecules with significant selectivity for binding to (CUG) repeat RNA over other sequences. These compounds were also able to inhibit the interaction of GGG-(CUG)109-GGG RNA with MBNL1 in vitro, with Ki values in the low micromolar range.