To use sensory information efficiently to make judgments and guide action in the world, the brain must represent and use information about uncertainty in its computations for perception and action. Bayesian methods have proven successful in building computational theories for perception and sensorimotor control, and psychophysics is providing a growing body of evidence that human perceptual computations are ‘Bayes' optimal’. This leads to the ‘Bayesian coding hypothesis’: that the brain represents sensory information probabilistically, in the form of probability distributions. Several computational schemes have recently been proposed for how this might be achieved in populations of neurons. Neurophysiological data on the hypothesis, however, is almost non-existent. A major challenge for neuroscientists is to test these ideas experimentally, and so determine whether and how neurons code information about sensory uncertainty.
Theories of developmental dyslexia differ on how to best interpret the great variety of symptoms (linguistic, sensory and motor) observed in dyslexic individuals. One approach views dyslexia as a specific phonological deficit, which sometimes co-occurs with a more general sensorimotor syndrome. This article on the neurobiology of dyslexia shows that neurobiological data are indeed consistent with this view, explaining both how a specific phonological deficit might arise, and why a sensorimotor syndrome should be significantly associated with it. This new conceptualisation of the aetiology of dyslexia could generalize to other neurodevelopmental disorders, and might further explain heterogeneity within each disorder and comorbidity between disorders.
Pharmacologists have studied receptors for more than a century but a molecular understanding of their properties has emerged only during the past 30-35 years. In this article, I provide a personal retrospective of how developments and discoveries primarily during the 1970s and 1980s led to current concepts about the largest group of receptors, the superfamily of seven-transmembrane (7TM) receptors [also known as G-protein-coupled receptors (GPCRs)]. Significant technical advances such as the development of methods for radioligand binding, solubilization and purification of the β - adrenoceptor and other adrenoceptors led to the cloning of receptor genes and the discovery of their 7TM architecture and homology with rhodopsin. A universal mechanism of receptor regulation by G-protein-coupled receptor kinases (GRKs) and arrestins, originally discovered as a means of 'desensitizing' G-protein-mediated second-messenger generation, was subsequently found to mediate both receptor endocytosis and activation of a growing list of signaling pathways such as those involving mitogen-activated protein kinases. Numerous opportunities for novel therapeutics should emerge from current and future research on 7TM receptor biology.
Endothelin (ET) is a potent vasoconstrictive peptide that was isolated initially from the conditioned medium of cultured endothelial cells. In 1988, details of the isolation and identification, amino acid sequence, cDNA sequence and pharmacology of ET were published. Subsequently, ET isoforms, ET receptors and endothelin-converting enzyme (ECE) were cloned. Because ET was thought to be important in cardiovascular homeostasis, many investigators focused on the physiological and pathophysiological significance of ET. Accordingly, ET receptor antagonists and ECE inhibitors have been developed rapidly, mostly for the treatment of cardiovascular diseases. The field of molecular biology has provided valuable information about ET, including evidence that the ET system plays important roles in the early development of the neural crest and, thus, in the formation of organs. These results now present new avenues of ET research.
Archaea possess unique membrane phospholipids that generally comprise isoprenoid ethers built on -glycerol-1-phosphate (G1P). By contrast, bacterial and eukaryal membrane phospholipids are fatty acid esters linked to -glycerol-3-phosphate (G3P). The two key dehydrogenase enzymes that produce G1P and G3P, G1PDH and G3PDH, respectively, are not homologous. Various models propose that these enzymes originated during the speciation of the two prokaryotic domains, and the nature (and even the very existence) of lipid membranes in the last universal common ancestor (cenancestor) is subject to debate. G1PDH and G3PDH belong to two separate superfamilies that are universally distributed, suggesting that members of both superfamilies existed in the cenancestor. Furthermore, archaea possess homologues to known bacterial genes involved in fatty acid metabolism and synthesize fatty acid phospholipids. The cenancestor seems likely to have been endowed with membrane lipids whose synthesis was enzymatic but probably non-stereospecific.
Actin participates in more protein–protein interactions than any other known protein, including the interaction of actin with itself to form the helical polymer F-actin. The vast majority of actin-binding proteins (ABPs) can be grouped into conserved families. Only a handful of structures of complexes of actin with ABPs have been determined so far. These structures are starting to reveal how certain ABPs, including gelsolin, vitamin D-binding protein and Wiskott–Aldrich syndrome protein (WASP)-homology domain-2-related proteins, share a common actin-binding motif. It is proposed here that other ABPs, including actin itself, might share this motif, providing a mechanism whereby ABPs and actin compete for a common binding site. Of particular interest is a hydrophobic pocket that mediates important interactions in five of the existing structures of actin complexes. As the pocket remains accessible in F-actin, it is proposed that this pocket represents a primary target for F-actin-binding proteins, such as calponin-homology-related proteins and myosin.
There is general agreement that midbrain dopamine neurons play key roles in reward processing. What is more controversial is the role they play in processing salient stimuli that are not rewarding. This controversy has arisen for three main reasons. First, salient sensory stimuli such as tones and lights, which are assumed not to be rewarding, increase dopamine neuron activity. Second, aversive stimuli increase firing in a minority of putative dopamine neurons. Third, dopamine release is increased following aversive stimuli. Consequently, it has been suggested that these midbrain dopamine neurons are activated by all salient stimuli, rather than specifically by rewards. However, reconsideration of these issues, in light of new findings, suggests this controversy can be resolved in favour of reward theories.
Vitamin K epoxide reductase (VKOR) recycles reduced vitamin K, which is used subsequently as a co-factor in the γ-carboxylation of glutamic acid residues in blood coagulation enzymes. VKORC1, a subunit of the VKOR complex, has recently been shown to possess this activity. Here, we show that VKORC1 is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea. Four cysteine residues and one residue, which is either serine or threonine, are identified as likely active-site residues. In some plant and bacterial homologues the VKORC1 homologous domain is fused with domains of the thioredoxin family of oxidoreductases. These might reduce disulfide bonds of VKORC1-like enzymes as a prerequisite for their catalytic activities.
Models of protein folding have historically focused on a subset of ‘well-behaved’ proteins that can be successfully refolded from denaturants . Energy landscapes, including folding funnel ‘cartoons’, describe the largely uncomplicated folding of these isolated chains at infinite dilution. However, the frequent failure of many polypeptides to fold to their native state requires more comprehensive models of folding to accommodate the crucial role of interactions between partially folded intermediates. By incorporating additional deep minima, which reflect off-pathway interchain interactions, the folding funnel concept can be extended to describe the behavior of a more diverse set of proteins under more physiologically relevant conditions. In particular, the effects of ribosomes (translation), molecular chaperones and other aspects of the cellular environment on early chain conformations can be included to account for the folding behavior of polypeptide chains in cells.
Cytokine research has spawned the introduction of new therapies that have revolutionized the treatment of many important diseases. These therapeutic advances have resulted from two very different strategies. The first therapeutic strategy embodies the administration of purified, recombinant cytokines. The second relies on the administration of therapeutics that inhibit the harmful effects of upregulated, endogenous cytokines. Examples of successful cytokine therapeutics include hematopoietic growth factors (colony stimulating factors) and interferons. Prime examples of cytokine antagonists that have profoundly altered the treatment of some inflammatory disorders are agents that inhibit the effects of tumor necrosis factor (TNF). In this article, we highlight some of the studies that have been responsible for the introduction of cytokine and anti-cytokine therapies, with emphasis on the development of interferons and anti-TNF agents.