The hypothalamus is a specialized area in the brain that integrates the control of energy homeostasis. More than 70 years ago, it was proposed that the central nervous system sensed circulating levels of metabolites such as glucose, lipids and amino acids and modified feeding according to the levels of those molecules. This led to the formulation of the Glucostatic, Lipostatic and Aminostatic Hypotheses. It has taken almost that much time to demonstrate that circulating long‐chain fatty acids act as signals (...) of nutrient surplus in the hypothalamus. Moreover, pharmacological and/or genetic inhibition of fatty acid synthase, AMP‐activated protein kinase and carnitine palmitoyltransferase 1 results in profound decrease in feeding and body weight in rodents. The molecular mechanism behind these actions depends on changes in the cellular pool of malonyl‐CoA and fatty acyl‐CoAs. Current evidence also suggests that this pathway may play a major role in the physiological regulation of feeding, by integrating hormonal and nutrient‐derived signals in the hypothalamus. Here, we summarize what is known about hypothalamic fatty acid metabolism and feeding control and provide future directions for research. Understanding these molecular mechanisms could provide new targets for the treatment of obesity and related disorders. BioEssays 29: 248–261, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The Arf family proteins are best known for their roles in the vesicle biogenesis. However, they also play fundamental roles in a wide range of cellular regulation besides vesicular trafficking, such as modulation of lipid metabolic enzymes, cytoskeleton remodeling, ciliogenesis, lysosomal, and mitochondrial morphology and functions. Growing studies continue to expand the downstream effector landscape of Arf proteins, especially for the less‐studied members, revealing new biological functions, such as amino acid sensing. Experiments with cutting‐edge technologies and in (...) vivo functional studies in the last decade help to provide a more comprehensive view of Arf family functions. In this review, we summarize the cellular functions that are regulated by at least two different Arf members with an emphasis on those beyond vesicle biogenesis. (shrink)

Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three‐decade‐old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now (...) independently reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTOR‐governed synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl (...) glycerol; R59022, DAG kinase inhibitor; AA, arachidonic acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

Correspondence analysis of 28 proteomes selected to span the entire realm of prokaryotes revealed universal biases in the proteins’ amino acid distribution. Integral Inner Membrane Proteins always form an individual cluster, which can then be used to predict protein localisation in unknown proteomes, independently of the organism’s biotope or kingdom. Orphan proteins are consistently rich in aromatic residues. Another bias is also ubiquitous: the amino acid composition is driven by the GþC content of the first codon (...) position. An unexpected bias is driven, in many proteomes, by the AANbox of the genetic code, suggesting some functional biochemical relationship between asparagine and lysine. Less-significant biases are driven by the rare amino acids, cysteine and tryptophan. Some allow identification of species-specific functions or localisation such as surface or exported proteins. Errors in genome annotations are also revealed by correspondence analysis, making it useful for quality control and correction. (shrink)

Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram negative bacilli to control and treat. One of the major challenges that the pathogenic bacteria face in their host is the scarcity of freely available iron. To survive under such conditions, bacteria express new proteins on their outer membrane and also secrete iron chelators called siderophores. Antibodies directed against these proteins associated with iron uptake exert a bacteriostatic or bactericidal effect against A. baumanii in vitro, by blocking (...) siderophore mediated iron uptake pathways. Attempts should be made to discover peptides that could mimic protein epitopes and possess the same immunogenicity as the whole protein. Subsequently, theoretical methods for epitope prediction have been developed leading to synthesis of such peptides that are important for development of immunodiagnostic tests and vaccines. The present study was designed to in silico resolving the major obstacles in the control or in prevention of the diseases caused by A. baumannii. We exploited bioinformatic tools to better understand and characterize the Baumannii acinetobactin utilization structure of A. baumannii and select appropriate regions as effective B cell epitopes. In conclusion, amino acids 26–191 of cork domain and 321–635 of part of the barrel domain including L4–L9, were selected as vaccine candidates. These two regions contain functional exposed amino acids with higher score of B cell epitopes properties. Majority of amino acids are hydrophilic, flexible, accessible, and favorable for B cells from secondary structure point of view. (shrink)

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle‐mediated transport, peroxisome assembly, 26S protease (...) function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non‐exclusive) such possibilities are: (1) ATP‐dependent proteasome function and (2) ATP‐dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP‐dependent protein clamp. (shrink)

A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in (...) every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states. (shrink)

Apoptosis proteins play an essential role in regulating a balance between cell proliferation and death. The successful prediction of subcellular localization of apoptosis proteins directly from primary sequence is much benefited to understand programmed cell death and drug discovery. In this paper, by use of Chou’s pseudo amino acid composition , a total of 317 apoptosis proteins are predicted by support vector machine . The jackknife cross-validation is applied to test predictive capability of proposed method. The predictive results (...) show that overall prediction accuracy is 91.1% which is higher than previous methods. Furthermore, another dataset containing 98 apoptosis proteins is examined by proposed method. The overall predicted successful rate is 92.9%. (shrink)

In the yeast Saccharomyces cerevisiae, the regulation of expression of many of the enzymes for amino acid biosynthesis involves an interlinked general control system. Molecular and genetic analyses of this system reveal an underlying set of hierarchical transcriptional controls and a novel translational regulatory mechanism for governing expression of a key activator gene.

Glutamate is the major excitatory neurotransmitter in the mammalian brain, with receptors on every neuron in the central nervous system; it has major roles in fast synaptic transmission and in the establishment of certain forms of memory. More than 20 years ago Olney and his colleagues(1) described the [Excitotoxic Hypothesis] which postulates that, in addition to its normal function in the healthy brain, glutamate can kill neurons by prolonged, receptorsmediated depolarization resulting in irreversible disturbances in ion homeostasis. Therefore, glutamate is (...) a two‐edged sword; in certain undefined, adverse conditions it undergoes a transition from neurotransmitter to neurotoxin. Its toxicity has been implicated in the death of neurons in ischemia, epilepsy, and the neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's diseases(2–5). Recent advances in the molecular cloning of the genes for the glutamate family of receptors has revealed a plethora of receptor subtypes and an unexpected level of complexity in the mechanisms of receptor expression and function. (shrink)

The concept of information has acquired a strikingly prominent role in contemporary biology. This trend is especially marked within genetics, but it has also become important in other areas, such as evolutionary theory and developmental biology, particularly where these fields border on genetics. The most distinctive biological role for informational concepts, and the one that has generated the most discussion, is in the description of the relations between genes and the various structures and processes that genes play a role in (...) causing. For many biologists, the causal role of genes should be understood in terms of their carrying information about their various products. That information might require the cooperation of various environmental factors before it can be "expressed," but the same can be said of other kinds of message. An initial response might be to think that this mode of description is entirely anchored in a set of well-established facts about the role of DNA and RNA within protein synthesis, summarized in the familiar chart representing the "genetic code," mapping DNA base triplets to amino acids. However, informational enthusiasm in biology predates even a rudimentary understanding of these mechanisms (Schrodinger 1944). And more importantly, current applications of informational concepts extend far beyond anything that can receive an obvious justification in terms of the familiar facts about the specification of protein molecules by DNA. This includes: 1 (i) The description of whole-organism phenotypic traits (including complex behavioral traits) as specified or coded for by information contained in the genes, (ii) The treatment of many causal processes within cells, and perhaps of the wholeorganism developmental sequence, in terms of the execution of a program stored in the genes, (iii) The idea that genes themselves, for the purpose of evolutionary theorizing, should be seen as, in some sense, "made" of information.. (shrink)

The genetic code has been regarded as arbitrary in the sense that the codon-amino acid assignments could be different than they actually are. This general idea has been spelled out differently by previous, often rather implicit accounts of arbitrariness. They have drawn on the frozen accident theory, on evolutionary contingency, on alternative causal pathways, and on the absence of direct stereochemical interactions between codons and amino acids. It has also been suggested that the arbitrariness of the genetic (...) code justifies attributing semantic information to macromolecules, notably to DNA. I argue that these accounts of arbitrariness are unsatisfactory. I propose that the code is arbitrary in the sense of Jacques Monod's concept of chemical arbitrariness: the genetic code is arbitrary in that any codon requires certain chemical and structural properties to specify a particular amino acid, but these properties are not required in virtue of a principle of chemistry. This notion of arbitrariness is compatible with several recent hypotheses about code evolution. I maintain that the code's chemical arbitrariness is neither sufficient nor necessary for attributing semantic information to nucleic acids. (shrink)

Electronic music is advancing not only in the way it is being used in performance but also in the technological sense, due to software developers advancing the ability of the synthesizer to enable the composer to create newer sounds. The introduction of the amino acid and protein synthesizers from MIT is one such example, along with sampling sounds from interstellar bodies through the process of sonification in order to create presets as additional source material for the composer’s palette. (...) The creative process used in creating electronic music on a tablet computer introduces a new musical instrument to be used in live music performances. The fluidity and immediacy of how electronic sounds can be created with tablet computer synthesizers affords the composer to have a new behavioural sense of using them as a musical instrument that can be played intuitively. Exploring this new interface of musical composition is a subject this article will address as well as the psychological aspects pertaining to how an audience can relate to electronic music as an emerging art form removed from the classical music tradition. It will also discuss how the composer of electronic music can affect the listener’s ability to envision new conceptual landscapes, leading to experiencing new ideas and subjective fields of visionary understandings. The composer’s ability to use conceptual models, which influence the way sounds are made and how those sounds influence the listener’s experience, is an important focus of this article. (shrink)

Love, fear, hope, calculus, and game shows-how do all these spring from a few delicate pounds of meat? Neurophysiologist Ian Glynn lays the foundation for answering this question in his expansive An Anatomy of Thought, but stops short of committing to one particular theory. The book is a pleasant challenge, presenting the reader with the latest research and thinking about neuroscience and how it relates to various models of consciousness. Combining the aim of a textbook with the style of a (...) popularization, it provides all the lay reader needs to know to participate in the philosophical debate that is redefining our attitudes about our minds. Drawing on the rich history of neurological case studies, Glynn picks through the building blocks of our nervous system, examines our visual and linguistic systems, and probes deeply into our higher thought processes. The stories of great scientists, like Ramon y Cajal, and famous patients, like Sperry's split-brained epileptics, illuminate the scientific issues Glynn selects as essential for understanding consciousness. Some might argue that his lengthy explorations of natural selection overemphasize evolutionary explanations of psychological phenomena, but they must also agree that evolutionary psychology has distanced itself mightily from social Darwinism in recent years and merits a reappraisal. The great consciousness debate may form the core of the 21st-century Zeitgeist; get ready for it with An Anatomy of Thought. -Rob Lightner From Publishers Weekly How do we know? What do we think? How could a philosophical problem-'the mind-body problem,' say-induce a headache? What can evolutionary theory, molecular biology, the history of medicine and experimental psychology tell us about the features of human consciousness, and (once again) how do we know? Glynn, a physician and Cambridge University professor, meticulously attempts to answer these questions and more, setting forth the results of all sorts of research relevant to our brains-from 19th-century dissections to Oliver Sacks-like case studies, work with monkeys and supercomputers, and the enduring puzzles of philosophy, which he rightly saves for near the end. After explaining evolution by natural selection and 'clearing away much dross,' Glynn lays out the experiments and theories that have shown 'how nerve cells can carry information about the body, how they can interact' and how sense organs work; demonstrates the 'mixture of parallel and hierarchical organization' in our brains and 'the striking localization of function within it'; considers where neuroscience is likely to go; and admits that, among the many fields of exciting research just ahead, 'we can be least confident of progress toward a complete, scientific explanation of our sensations and thoughts and feelings.' Other recent explaining-the-brain books have sometimes advanced simplistic, or implausibly grand, claims about the nature and features of consciousness in general. Instead, Glynn offers a patient, informative, well-laid-out researcher's-eye view of what we have learned, how we figured it out and what we still don't know about neurons, senses, feelings, brains and minds. (Apr.) Copyright 2000 Reed Business Information, Inc. From Library Journal The nature of consciousness, which perennially troubles the minds of scientists and philosophers, is the subject of an ever-growing body of literature. Two of the latest entries approach the topic from different perspectives. Glynn, a professor of physiology and head of the Physiological Laboratory at Cambridge, offers a comprehensive summary of what we know about the brain-both its evolution and its mechanisms. Among the topics he covers are natural selection, molecular evolution, nerves and the nervous system, sensory perception, and the specific structures responsible for our intellect. Using the mechanisms involved in vision and speech as models, Glynn skillfully describes various neurological deficiencies that can lead to 'disordered seeing' and problems with the use of language. He carefully distinguishes what we know through experimental evidence from what we know through the observation of patients with neurological damage. He also describes some of the major theories that attempt to explain why these structures arose. While his book concentrates on the structures that make up the mind, Glynn is well aware that some physical events appear explicable only in terms of conscious mental events-a situation that conflicts with the laws of modern physics. Only briefly, however, does he consider the various approaches that have been taken to deal with the issues of mind/body and free will. In contrast, this is the primary focus of The Physics of Consciousness. After reviewing the fundamentals of classic physics, Walker (who has a Ph.D. in physics) summarizes elements of the new physics in which our knowledge of space, time, matter, and energy are all dependent on the moment of observation. Walker explores the meaning of consciousness as a characteristic of the observer. In this context both the observer and the act of measurement are critical. In essence, Walker leads his reader on a journey through his concept of a 'quantum mind,' which can both affect matter (including other minds) and can be affected by other distant matter/minds. To break up what would otherwise be an extremely dense text, Walker also relates the very touching story of the loss of his high-school sweetheart to leukemia. Indeed, it is his memory of their relationship that drives Walker to seek an understanding of ultimate reality. At times, he has a tendency to be dogmatic-as when he concludes, 'our consciousness, our mind, and the will of God are the same mind.' While An Anatomy of Thought is appropriate for most academic libraries, the Physics of Consciousness will be most accessible to readers with some knowledge of advanced physics. -Laurie Bartolini, Illinois State Lib., Springfield Copyright 2000 Reed Business Information, Inc. From Booklist The codiscoverers of natural selection-Charles Darwin and Alfred Wallace-disagreed over the possibility of finding an evolutionary explanation for the human mind. Glynn here argues Darwin's side of the debate, tracing an eons-long path of development starting from simple amino acids floating in primal seas and extending through the erect hominids in which the powers of a massive brain first manifest themselves. Patiently adducing evidence of an evolutionary origin for the underlying molecular machinery, Glynn dissects the nerve centers that make possible speech and hearing, sight, and reading. Pressing deeper, he lays bare the cortical foundations of personality. But those who deal with the mind must attend also to the arguments advanced by philosophers. And it is when he turns from dendrites to syllogisms (especially the vexing mind-body paradox) that Glynn's empirical reasoning fails him. In the end, he concedes his perplexity in trying to conceive of an evolutionary origin for human consciousness. This concession may set the shade of Alfred Wallace to chortling, but it will draw readers into an honest confrontation with a profound enigma. Bryce Christensen. (shrink)

The question of whether “genetic information” is a merely causal factor in development or can be made sense of semantically, in a way analogous to a language or other type of representation, has generated a long debate in the philosophy of biology. It is intimately connected with another intense debate, concerning the limits of genetic determinism. In this paper I argue that widespread attempts to draw analogies between genetic information and information contained in books, blueprints or computer programs, are fundamentally (...) inadequate. In development, gene exons are the central part of an intricate and densely ramified semantic Genetic Informational Network. DNA in the entire genome is in a state of continuous positive and negative feedback with itself and with its ‘environment’, and is ‘read’ and acted upon by the cell in various alternative and complementary ways. The linear combinatorial coding relation between codons and amino acids is but one aspect of semantic genetic information, which is, when considered in its entirety, a far wider and richer concept. (shrink)

The notion of the value of information is discussed. The value one attributes to information is determined by the result of its reception by an open nonequilibrium system. Qualitative reasoning shows that the concept of value of information makes sense only in nonequilibrium situations, and is directly connected with the nonredundancy of information. In biology it is the value and not the amount of information that is important. The value of information is especially high if there are instabilities in the (...) system; these are connected with the notions of purpose and of freedom of will. The notion of selective value, introduced by Eigen in the theory of the prebiological evolution of macromolecules, is discussed. The amount of information in various codons is calculated and the conventional definition of its value is given based on the determination of the danger of the replacement of one amino acid by another with a different value of hydrophobicity. It is shown that the relative probability of transversion is considerably lower than that of transition. As most nonsense mutations are transversions, the genetic code provides decreased probability for the most dangerous mutations. It is shown that the information of the codonUGG(Trp) is highest in both amount and value. (shrink)

When cells are starved of their substrate, many nutrient transporters are induced. These undergo rapid endocytosis and redirection of their intracellular trafficking when their substrate becomes available again. The discovery that some of these transporters also act as receptors, or transceptors, suggests that at least part of the sophisticated controls governing the trafficking of these proteins has to do with their signaling function rather than with control of transport. In yeast, the general amino acid permease Gap1 mediates signaling (...) to the protein kinase A pathway. Its endocytic internalization and intracellular trafficking are subject to amino acid control. Other nutrient transceptors controlling this signal transduction pathway appear to be subject to similar trafficking regulation. Transporters with complex regulatory control have also been suggested to function as transceptors in other organisms. Hence, precise regulation of intracellular trafficking in nutrient transporters may be related to the need for tight control of nutrient‐induced signaling. (shrink)

Are acids natural kinds? Or are they merely relevant kinds? Although acidity has been one of the oldest and most important concepts in chemistry, surprisingly little ink has been spilled on the natural kind question. I approach the question from the perspective of microstructural essentialism. After explaining why both Brønsted acids and Lewis acids are considered functional kinds, I address the challenges of multiple realization and multiple determination. Contra Manafu and Hendry, I argue that the stereotypical properties of acids are (...) not multiply realized. Instead, given the equivalence between the proton-donating and electron-accepting mechanisms of Brønsted and Lewis, respectively, I show that acidity as a property type can be identified with a unique microstructural property, namely the presence of a LUMO or other low energy empty orbital. In doing so, I defend the view that the Lewis theory encompasses Brønsted--Lowry, and that all Brønsted acids are also Lewis acids. Contra Hacking and Chang, I thus maintain that the different concepts of acidity do not crosscut, and that the hierarchy requirement is met. Finally, by characterizing natural kinds as powerful objects and by adopting a dispositional view of functions, I illustrate how the microessentialist can make sense of the latent and relational character of most acids. In sum, I contend that acids are genuine natural kinds, even for the microstructural essentialist. (shrink)

Are acids natural kinds? Or are they merely relevant kinds? Although acidity has been one of the oldest and most important concepts in chemistry, surprisingly little ink has been spilled on the natural kind question. I approach the question from the perspective of microstructural essentialism. After explaining why both Brønsted acids and Lewis acids are considered functional kinds, I address the challenges of multiple realization and multiple determination. Contra Manafu and Hendry, I argue that the stereotypical properties of acids are (...) not multiply realized. Instead, given the equivalence between the proton-donating and electron-accepting mechanisms of Brønsted and Lewis, respectively, I show that acidity as a property type can be identified with a unique microstructural property, namely the presence of a LUMO or other low energy empty orbital. In doing so, I defend the view that the Lewis theory encompasses Brønsted–Lowry, and that all Brønsted acids are also Lewis acids. Contra Hacking and Chang, I thus maintain that the different concepts of acidity do not crosscut, and that the hierarchy requirement is met. Finally, by characterizing natural kinds as powerful objects and by adopting a dispositional view of functions, I illustrate how the microessentialist can make sense of the latent and relational character of most acids. In sum, I contend that acids are genuine natural kinds, even for the microstructural essentialist. (shrink)

The central dogma of molecular biology dictates that, with only a few exceptions, information proceeds from DNA to protein through an RNA intermediate. Examining the enigmatic steps from prebiotic to biological chemistry, we take another road suggesting that primordial peptides acted as template for the self-assembly of the first nucleic acids polymers. Arguing in favour of a sort of archaic “reverse translation” from proteins to RNA, our basic premise is a Hadean Earth where key biomolecules such as amino acids, (...) polypeptides, purines, pyrimidines, nucleosides and nucleotides were available under different prebiotically plausible conditions, including meteorites delivery, shallow ponds and hydrothermal vents scenarios. Supporting a protein-first scenario alternative to the RNA world hypothesis, we propose the primeval occurrence of short two-dimensional peptides termed “selective amino acid- and nucleotide-matching oligopeptides” (henceforward SANMAOs) that noncovalently bind at the same time the polymerized amino acids and the single nucleotides dispersed in the prebiotic milieu. In this theoretical paper, we describe the chemical features of this hypothetical oligopeptide, its biological plausibility and its virtues from an evolutionary perspective. We provide a theoretical example of SANMAO’s selective pairing between amino acids and nucleosides, simulating a poly-Glycine peptide that acts as a template to build a purinic chain corresponding to the glycine’s extant triplet codon GGG. Further, we discuss how SANMAO might have endorsed the formation of low-fidelity RNA’s polymerized strains, well before the appearance of the accurate genetic material’s transmission ensured by the current translation apparatus. (shrink)

The Y‐box proteins are the most evolutionarily conserved nucleic acid binding proteins yet defined in bacteria, plants and animals. The central nucleic acid binding domain of the vertebrate proteins is 43% identical to a 70‐amino‐acid‐long protein (CS7.4) from E. coli. The structure of this domain consists of an antiparallel fivestranded β‐barrel that recognizes both DNA and RNA. The diverse biological roles of these Y‐box proteins range from the control of the E. coli cold‐shock stress response to (...) the translational masking of messenger RNA in vertebrate gametes. This review discusses the organization of the prokaryotic and eukaryotic Y‐box proteins, how they interact with nucleic acids, and their biological roles, both proven and potential. (shrink)

Divergent evolution can explain how many proteins containing structurally similar domains, which perform a variety of related functions, have evolved from a relatively small number of modules or protein domains. However, it cannot explain how protein domains with similar, but distinguishable, functions and similar, but distinguishable, structures have evolved. Examples of this are the RNA‐binding proteins containing the RNA‐binding domain (RBD), and a newly established protein group, the cold‐shock domain (CSD) protein family. Both protein domains contain conserved RNP motifs on (...) similar single‐stranded nucleic acid‐binding surfaces. Apart from the RNP motifs, which have a similar function, the two families show little similarity in topology or amino acid sequence. This can be considered an interesting example of convergent evolution at the molecular level. Previously, a β‐sheet surface was found to interact with RNA in non‐homologous proteins from yeast, phage and man, revealing that this mode of RNA binding may be a widely recurring theme. (shrink)

D‐amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D‐cysteine in mammalian brain. D‐cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D‐cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D‐cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D‐cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D‐cysteine inhibits AKT phosphorylation at Thr 308 and (...) Ser 473 in NPCs. D‐cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D‐cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D‐cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD). (shrink)

A sensory receptor, in any organism anywhere, is sensitive through time to some distribution - energy, motion, molecular shape - indeed, anything that can produce an effect. The sensitivity is rarely direct: for example, it may track changes in relative variation rather than the absolute change of state (as when the skin responds to colder and hotter instead of to cold and hot as such); it may track differing variations under different conditions (the eyes' dark-adaptation; adaptation to sound frequencies can (...) lower the difference threshold; the kinesthetic sense will shut down if a limb is held in a stationary position too long - the limb 'going to sleep'); it may be subject to distortion of the input from overloading (dazzle producing strong-after-images); it may not be confined to one channel of sensitivity (the retina is sensitive to pressure; the hands can feel some strong sound-vibrations, the tympanum of the ear records touch). Strictly speaking there is no limit as to what intensities and what ranges receptors could be sensitive. Sharks are sensitive to electrostatic fields, homing pigeons to magnetic fields; snakes to infra-red rays; bacteria to acid concentrations; perhaps there has even been a mutant organism sensitive to the passage of cosmic rays, even though that would hardly have bestowed any conceivable survival value. What is irrefutable is that individual receptors differ markedly from organism to organism, between different members of the species (one dog being better at tracing smells than another; one person being able to sense light-waves of 375 nanometres, another not; children able to hear 20,000 Hz, older persons not), and between receptors of the same kind within one organism (one eye being sensitive to 765 nm and the other not; one ear deaf to 15,000 Hz and over, the other not). There are also just-noticeable-differences (JND's), in that one person can see two shades of a colour where another sees only one; similarly with sounds. (shrink)

ヒトと自然の交流の産物として生まれた田舎の景色には、どこか安堵する懐かしさがある。しかし、このような田舎、里山は今どれだけ残っているだろうか?21世紀にむかって、ヒトと自然環境、その産物としての文化遺 産のあり方が地球規模で問われている。本書は、21世紀にむかって文化遺産のあり方を問う。.

At extreme altitude (>5,000 – 5,500 m), sustained hypoxia threatens human function and survival, and is associated with marked involuntary weight loss (cachexia). This seems to be a coordinated response: appetite and protein synthesis are suppressed, and muscle catabolism promoted. We hypothesise that, rather than simply being pathophysiological dysregulation, this cachexia is protective. Ketone bodies, synthesised during relative starvation, protect tissues such as the brain from reduced oxygen availability by mechanisms including the reduced generation of reactive oxygen species, improved mitochondrial (...) efficiency and activation of the ATP‐sensitive potassium (KATP) channel. Amino acids released from skeletal muscle also protect cells from hypoxia, and may interact synergistically with ketones to offer added protection. We thus propose that weight loss in hypoxia is an adaptive response: the amino acids and ketone bodies made available act not only as metabolic substrates, but as metabolic modulators, protecting cells from the hypoxic challenge.Also watch the Video Abstract. (shrink)

Theoretical minimal RNA rings are candidate primordial genes evolved for non‐redundant coding of the genetic code's 22 coding signals (one codon per biogenic amino acid, a start and a stop codon) over the shortest possible length: 29520 22‐nucleotide‐long RNA rings solve this min‐max constraint. Numerous RNA ring properties are reminiscent of natural genes. Here we present analyses showing that all RNA rings lack dinucleotide CG (a mutable, chemically instable dinucleotide coding for Arginine), bearing a resemblance to known CG‐depleted (...) genomes. CG in “incomplete” RNA rings (not coding for all coding signals, with only 3–12 nucleotides) gradually decreases towards CG absence in complete, 22‐nucleotide‐long RNA rings. Presumably, feedback loops during RNA ring growth during evolution (when amino acid assignment fixed the genetic code) assigned Arg to codons lacking CG (AGR) to avoid CG. Hence, as a chemical property of base pairs, CG mutability restructured the genetic code, thereby establishing itself as genetically encoded biological information. (shrink)

Overmedication is nowadays a serious problem in health care due to influences from the pharmaceutical industry and agencies responsible for regulation. The situation has indeed become appalling in psychiatry, where both theories and treatments have deteriorated under the impact of the industry. The overmedication problem is associated with biased biology in medicine. Adequate biological approaches would indicate that drug therapies must yield to diet therapies, particularly treatments involving omega-3 fatty acids, in many cases. To the extent that philosophy of science (...) adapts to mainstream medicine in analyses of the current situation, it may reinforce the existing bias. To redress imbalances in health care, we ultimately have to rely on common sense. (shrink)

One of the goals of computerized tutoring systems is to optimize the learning of facts. Over a hundred years of declarative memory research have identified two robust effects that can improve such systems: the spacing and the testing effect. By making optimal use of both and adjusting the system to the individual learner using cognitive models based on declarative memory theories, such systems consistently outperform traditional methods. This adjustment process is driven by a continuously updated estimate of the rate of (...) forgetting for each item and learner on the basis of the learner's accuracy and response time. In this study, we investigated to what extent these estimates of individual rates of forgetting are stable over time and across different materials. We demonstrate that they are stable over time but not across materials. Even though most theories of human declarative memory assume a single underlying rate of forgetting, we show that, in practice, it makes sense to assume different materials are forgotten at different rates. If a computerized, adaptive fact-learning system allowed different rates of forgetting for different materials, it could adapt to individual learners more readily. (shrink)

One of the goals of computerized tutoring systems is to optimize the learning of facts. Over a hundred years of declarative memory research have identified two robust effects that can improve such systems: the spacing and the testing effect. By making optimal use of both and adjusting the system to the individual learner using cognitive models based on declarative memory theories, such systems consistently outperform traditional methods (Van Rijn, Van Maanen, & Van Woudenberg, 2009). This adjustment process is driven by (...) a continuously updated estimate of the rate of forgetting for each item and learner on the basis of the learner's accuracy and response time. In this study, we investigated to what extent these estimates of individual rates of forgetting are stable over time and across different materials. We demonstrate that they are stable over time but not across materials. Even though most theories of human declarative memory assume a single underlying rate of forgetting, we show that, in practice, it makes sense to assume different materials are forgotten at different rates. If a computerized, adaptive fact‐learning system allowed different rates of forgetting for different materials, it could adapt to individual learners more readily. (shrink)

Graphical AbstractPheomelanogenesis may have evolved as an excretory mechanism to remove excess cysteine, and in humans this might potentially confer a greater ability to avoid disease such as Parkinson's and Alzheimer's disease, in which excess cysteine is a contributory cause.