Although chemical phenomena are primarily associated with electrons in atoms, ions, and molecules, the masses, charges, spins, and other properties of the nuclei in these species contribute significantly as well. Isotopes, for instance, have proven invaluable in chemistry, in particular the elucidation of reaction mechanisms. Elements with unstable nuclei, for example carbon-14 undergoing beta decay, have enriched chemistry and many other scientific disciplines. The nuclei of all elements have a much more subtle and largely unknown effect on chemical phenomena. (...) All nuclei are innately chiral and, because electrons can penetrate nuclei, all atoms and molecules are likewise chiral. This article describes in considerable detail the discovery of chiral nuclei, how this unusual chirality may influence the chemical behavior of atoms and molecules, and how atomic chirality may have been responsible for the synthesis of optically active molecules in the pre-biotic world. (shrink)

From its genesis in the 1960s, the focus of inquiry in neuroscience has been on the cellular and molecular processes underlying neural activity. In this pursuit neuroscience has been enormously successful. Like any successful scientific inquiry, initial successes have raised new questions that inspire ongoing research. While there is still much that is not known about the molecular processes in brains, a great deal of very important knowledge has been secured, especially in the last 50 years. It has also attracted (...) the attention of a number of philosophers, some of whom have viewed it as evidence for a ruthlessly reductionistic program that will eventually explain how mental processes are performed in the brain in purely molecular terms. As neuroscience developed, however, there emerged a smaller group of researchers who focused on systems, behavioral, and cognitive neuroscience. These investigators have also made impressive advances in the last 50 years and they have been the focus of an even larger group of philosophers, who have appealed to systems level understanding of the brain as providing the appropriate point of connection to the information processing accounts advanced in psychology. (shrink)

Ever since it was discovered in hydra, regeneration has remained a stimulating question for developmental biologists. Cellular approaches have revealed that, within the first few hours of apical or basal hydra regeneration, differentiation and determination of nerve cells are the primary cellular events detectable. The head and foot activators (HA, FA), neuropeptides that are released upon injury, are signaling molecules involved in these processes. In conditions where it induces cellular differentiation or determination, HA behaves as an agonist of the (...) cyclic AMP (cAMP) pathway involving the modulation of CREB nuclear transcription factor activity. This cascade would be required for proper regeneration, regardless of whether the polarity involved is apical or basal. Modulations of the protein kinase C pathway, which have been shown to affect apical or basal positional values, might signal to bring about this polarity; however, endogenous ligands responsible for this modulation are as yet unknown. (shrink)

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 (...) is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy. (shrink)

Thy‐1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain1, are anchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail(2,3) (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development (4). These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy‐1 to the status of a favourite molecule. Indeed, few scientists (...) readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works.Thy‐1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology(5); it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs(1–3); it has been pivotal in studies demonstrating that GPI‐anchored molecules are able to signal across the membrane they do not span(6, 7). Thy‐1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged.Our current work on Thy‐1 in the nervous system is, we believe, finally prizing this last secret into the open. It suggests that Thy‐1 on the neuronal surface interacts with one of the main glial types of adult brain, the astrocyte, to restrict axonal growth(8). There is no current consensus that astrocytes do regulate such growth, and this is the wider question we are addressing from the perspective of Thy‐1. At issue also is how to progress from knowing the nature of a molecule to defining its function. This task has already been achieved with molecules which were harder to characterise than Thy‐1. The problem is a classic Catch 22 situation: Thy‐1 has been readily characterised because it is small and abundant it is ten times more abundant than any other surface glycoprotein on rat thymocytes(9); but since there is so much of it, whatever it does it must do rather badly (or there would be no need to have so much of it!). Defining a function based on low activity or affinity is not trivial.Here I describe two aspects of work on Thy‐1. One is long completed ‐ the research which led to Thy‐1 being isolated and characterised ‐ and included because it demonstrates features which are still applicable to much research using a antibodies today. The other is our ongoing work on the nervous system, which is at that exciting early stage where hypotheses are formed, but the answers are still coming in. (shrink)

The regulatory NodD proteins of Rhizobium bacteria mediate the activation of a gene set responsible for symbiotic nodule formation by plant signal molecules. Here we discuss the signal recognition and gene activation properties of NodD and present a model summarizing the current knowledge on NodD action.

Unless one embraces activities as foundational, understanding activities in mechanisms requires an account of the means by which entities in biological mechanisms engage in their activities—an account that does not merely explain activities in terms of more basic entities and activities. Recent biological research on molecular motors exemplifies such an account, one that explains activities in terms of free energy and constraints. After describing the characteristic “stepping” activities of these molecules and mapping the stages of those steps onto the (...) stages of the motors’ hydrolytic cycles, researchers pieced together from images of the molecules in different hydrolyzation states accounts of how the chemical energy in ATP is transformed in the constrained environments of the motors into the characteristic activities of the motors. We argue that New Mechanism’s standard set of analytic categories—entities, activities, and organization—should be expanded to include constraints and energetics. Not only is such an expansion required descriptively to capture research on molecular motors but, more importantly from a philosophical point of view, it enables a non-regressive account of activities in mechanisms. In other words, this expansion enables a philosophical account of mechanistic explanation that avoids a regress of entities and activities “all the way down.” Rather, mechanistic explanation bottoms out in constraints and energetics. (shrink)

Recent debates about the biological and evolutionary conditions for sentience have generated a renewed interest in fine-grained functionalism. According to one such account advanced by Peter Godfrey-Smith, sentience depends on the fine-grained activities characteristic of living organisms. Specifically, the scale, context and stochasticity of these fine-grained activities. One implication of this view is that contemporary artificial intelligence is a poor candidate for sentience. Insofar as current AI lacks the ability to engage in such living activities it will lack sentience, no (...) matter what its coarse-grained functions. In this paper, we review the case for fine-grained functionalism and show that there are contemporary machines that fulfil the fine-grained functional criteria identified by Godfrey-Smith, and thus are candidates for sentience. Molecular machines such as Brownian computers are analogous to metabolic activity in their scale, context and stochasticity, and can serve as the basis of AI. Molecular computation is a promising candidate for artificial sentience according to contemporary philosophical accounts of sentience. (shrink)

Ethylene (C2H4) is a gaseous plant hormone produced by higher and lower (green) plants and, when grown on appropriate substrates, also by fungi, yeasts and bacteria. Ethylene is involved in many developmental processes in plants and is biologically active in trace amounts (10 – 100 nl/I of air) that may be present in the outside air due to industrial air pollution(1). Fruit ripening and flower senescence especially, in a variety of commercially important crops, are dramatically stimulated by ethylene. Following (...) characterization of the genes coding for the key enzymes in ethylene biosynthesis, i.e. ACC synthase and ACC oxidase, it has become clear that their expression is regulated in a complex manner involving developmental, hormonal and tissue‐specific factors. This was recently very elegantly demonstrated for the expression of ACC oxidase genes in developing petunia flowers by Tang et al.(2). The spatial and temporal expression patterns, especially in the reproductive organs, suggest a hitherto unknown role for ethylene in reproductive processes such as the self‐incompatible response and the secretion of cellular exudate by the stigma and nectary. (shrink)

The recent development of single molecule detection techniques has opened new horizons for the study of individual macromolecules under physiological conditions. Conformational subpopulations, internal dynamics and activity of single biomolecules, parameters that have so far been hidden in large ensemble averages, are now being unveiled. Herein, we review a particular attractive solution‐based single molecule technique, fluorescence correlation spectroscopy (FCS). This time‐averaging fluctuation analysis which is usually performed in Confocal setups combines maximum sensitivity with high statistical confidence. FCS has proven to (...) be a very versatile and powerful tool for detection and temporal investigation of biomolecules at ultralow concentrations on surfaces, in solution, and in living cells. The introduction of dual‐color cross‐correlation and two‐photon excitation in FCS experiments is currently increasing the number of promising applications of FCS to biological research. BioEssays 24:758–764, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Two types of interleukin 1 (IL‐1α and IL‐1β) have been defined by purifying the molecules from activated human peripheral blood cells, followed by cloning and expressing the molecules in Escherichia coli. Both types of IL‐1 stimulate proliferation and differentiation of T‐ and B‐lymphocytes and induce cartilage proteoglycan degradation but differ in other properties. For example, demineralization and appears to be a major mediator in the pathogenesis of joint erosion in rheumatoid arthritis. Synthetic adjuvants elicit the production of IL‐1 (...) separate from endogenous pyrogen, and this property is required for the new generation of vaccines based on antigens produced by recombinant DNA technology. (shrink)

This review will discuss how STAT (Signal Transducers and Activators of Transcription) proteins, a group of transcription factors that transmit signals from the extracellular surface of cells to the nucleus, are involved in growth control. I will discuss the anatomy of a STAT protein, how it works as a transcription factor, the molecules that regulate its “activity”, the phenotypes of mice that lack individual STAT proteins and their involvement in growth, differentiation, apoptosis, and transformation. Finally, a number of examples (...) will be presented of how dysregulated STAT signaling may be involved in the pathogenesis of cancer. BioEssays 23:161–169, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The Periodic Table has the column of the noble gas atoms (He, Ne, Ar, Kr, Xe, Rn) as one of its main pillars. Indeed the inert chemical nature of their closed shell structure is so striking that it is sometimes extended to all such structures. Is it true however that any closed shell, say a closed d-subshell will denote a lack of chemical activity? Take the noble metals for instance, so renowned for their catalytic capacity. Platinum has 10 electrons in (...) its valence shell which makes one of its excited states to be a closed 5d10–6s0 state. Surely this state would not be expected to be crucial to the catalytic activity of platinum, or would it? Or take palladium whose ground state is precisely the 4d10–5s0 state, should we expect that an isolated Pd atom at near zero-point temperature would attack a closed-shell hydrogen molecule efficiently? We shall here show that this is precisely the case; the closed-shell excited states of nickel and platinum are indeed crucial, through symmetry avoided crossings, for their reactivity. Other valuable catalysts as ruthenium depend on their excited states with maximal d-shell occupancy for their activity. The most notable confirmation of this new finding; that closed d-shells are vital to the catalytic activity of noble metals however, is the case of palladium whose closed-shell ground state is indeed capable of attacking hydrogen and hydrocarbon molecules even at temperatures well below 10 K as was predicted theoretically and immediately confirmed experimentally. (shrink)

Oxygenated derivatives of cholesterol (oxysterols) are widely distributed in nature, being found in the blood and tissues of animals and man as well as in foodstuff. They exhibit many biological activities which are of potential physiological, pathological or pharmacological importance. Many oxysterols have been found to be potent inhibitors of cholesterol biosynthesis and one or more oxysterols may play a role as the physiologic feedback regulator of cholesterol synthesis. Oxysterols also inhibit cell replication and have cytotoxic properties effects which suggest (...) that these sterols may participate in the regulation of cell proliferation and may be potentially useful as therapeutic agents for cancer. Furthermore, there is considerable evidence that oxysterols may be involved in the pathogenesis of atherosclerosis. Although the mechanism of action of oxysterols in all these instances is not well understood, the existence of cytosolic and microsomal proteins which bind oxysterols with high affinity and specificity suggests that this group of compounds may represent a family of intracellular regulatory molecules. (shrink)

We have been using feather development as a model for understanding the molecular basis of pattern formation and to explore the roles of homeoproteins, retinoids and adhesion molecules in this process. Two kinds of homeobox (Hox) protein gradients in the skin have been identified: a ‘microgradient’ within a single feather bud and a ‘macrogradient’ across the feather tract. The asynchronous alignment of different Hox macrogradients establishes a unique repertoire of Hox expression patterns in skin appendages within the integument, designated (...) here as the ‘Hox codes of skin appendages’. It is hypothesized that these Hox codes contribute to the phenotypic determination of skin appendages. High doses of retinoic acid cause a morphological transformation between feather and scale, while low doses of retinoic acid cause an alteration of the axial orientation of skin appendages. We have tested the ability of molecules directly involved in the feather formation process to mediate the action of the Hox codes, and surmise that adhesion molecules are potential candidates. Using specific Fabs to suppress the activity of adhesion molecules, we have found that L‐CAM is involved in the formation of the hexagonal pattern, N‐CAM is involved in mediating dermal condensations, tenascin is involved in feather bud growth and elongation, and integrin β‐1 is essential for epithelial‐mesenchymal interactions. More work is in progress to fully understand the molecular pathways regulating the feather formation process. (shrink)

It is suggested that if Cultural-Historical Activity Theory (CHAT) is to fulfil its potential as an approach to cultural and historical science in general, then an interdisciplinary concept of activity is needed. Such a concept of activity would provide a common foundation for all the human sciences, underpinning concepts of, for example, state and social movement equally as, for example, learning and personality. For this is needed a clear conception of the ‘unit of analysis’ of activity, i.e., of what constitutes (...) ‘ an activity’, and a clear distinction between the unit of analysis and the substance , i.e., ultimate reality underlying all the human sciences: artifact-mediated joint activity. It is claimed that the concept of ‘project collaboration’ – the interaction between two or more persons in pursuit of a common objective – forms such a unit of activity, the single ‘molecule’ in terms of which both sociological and psychological phenomena can be theorised. It is suggested that such a clarification of the notion of activity allows us to see how individual actions and societal activities mutually constitute one another and are each construed in the light of the other. (shrink)

Cephalopods are extraordinary molluscs equipped with vertebrate‐like intelligence and a unique buoyancy system for locomotion. A growing body of evidence from the fossil record, embryology and Bayesian molecular divergence estimations provides a comprehensive picture of their origins and evolution. Cephalopods evolved during the Cambrian (∼530 Ma) from a monoplacophoran‐like mollusc in which the conical, external shell was modified into a chambered buoyancy apparatus. During the mid‐Palaeozoic (∼416 Ma) cephalopods diverged into nautiloids and the presently dominant coleoids. Coleoids (i.e. squids, cuttlefish (...) and octopods) internalised their shells and, in the late Palaeozoic (∼276 Ma), diverged into Vampyropoda and the Decabrachia. This shell internalisation appears to be a unique evolutionary event. In contrast, the loss of a mineralised shell has occurred several times in distinct coleoid lineages. The general tendency of shell reduction reflects a trend towards active modes of life and much more complex behaviour. (shrink)

Metabolomics, including lipidomics, is emerging as a quantitative biology approach for the assessment of energy flow through metabolism and information flow through metabolic signaling; thus, providing novel insights into metabolism and its regulation, in health, healthy ageing and disease. In this forward‐looking review we provide an overview on the origins of metabolomics, on its role in this postgenomic era of biochemistry and its application to investigate metabolite role and (bio)activity, from model systems to human population studies. We present the challenges (...) inherent to this analytical science, and approaches and modes of analysis that are used to resolve, characterize and measure the infinite chemical diversity contained in the metabolome (including lipidome) of complex biological matrices. In the current outbreak of metabolic diseases such as cardiometabolic disorders, cancer and neurodegenerative diseases, metabolomics appears to be ideally situated for the investigation of disease pathophysiology from a metabolite perspective. (shrink)

Retinoic acid (RA), a derivative of vitamin A, is essential for normal mammalian development. Developmental abnormalities induced by RA excess and vitamin A deficiency are different even though they affect the same organ systems, and it is clear that there are intraembryonic tissue differences in the requirement for RA. The developmental functions of RA are mediated by its effects on gene expression. In the nucleus, two different forms of RA bind to and activate two families of nuclear receptors, which themselves (...) co‐operate in initiating the transcription of target genes. In this article I propose that the amount of RA reaching the nucleus in different embryonic tissues is modulated by a mechanism involving three cytoplasmic binding proteins for retinol (CRBP I) and retinoic acid (CRABP I and II). Abnormalities of craniofacial development resulting from exposure of early neural plate stage embryos to RA excess have been studied in some detail; their initial stages involve alteration of both morphological development and the segment‐specific pattern of gene expression in the early hindbrain and its derived neural crest. This system is ideal for studying the relationships between retinoic acid receptors, retinoid binding proteins, and the development of genetic and morphological pattern. (shrink)

Although the Ca2+‐dependent proteinase (calpain) system has been found in every vertebrate cell that has been examined for its presence and has been detected in Drosophila and parasites, the physiological function(s) of this system remains unclear. Calpain activity has been associated with cleavages that alter regulation of various enzyme activities, with remodeling or disassembly of the cell cytoskeleton, and with cleavages of hormone receptors. The mechanism regulating activity of the calpain system in vivo also is unknown. It has been proposed (...) that binding of the calpains to phospholipid in a cell membrane lowers the Ca2+ concentration, [Ca2+], required for the calpains to autolyze, and that autolysis converts an inactive proenzyme into an active protease. Recent studies, however, show that the calpains bind to specific proteins and not to phospholipids, and that binding to cell membranes does not affect the [Ca2+] required for autolysis. It seems likely that calpain activity is regulated by binding of Ca2+ to specific sites on the calpain molecule, with binding to each site eliciting a response (proteolytic activity, calpastatin binding, etc.) specific for that site. Regulation must also involve an, as yet, undiscovered mechanism that increases the affinity of the Ca2+‐binding sites for Ca2+. (shrink)

BET proteins such as Brd3 and Brd4 are chromatin‐associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti‐inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets. Small molecules (...) that either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of targeting a Nrf2 or BET proteins individually. (shrink)

The T lymphocyte receptor for antigen, which operates in conjunction with gene products of the major histocompatibility complex (MHC), is a molecular complex comprised of five polypeptide chains. Both the 49 kDa alpha and 43 kDa beta chains are immunoglobulin‐like and thus contain variable domains responsible for ligand binding. In contrast, the 20–25 kDa T3 gamma, delta and epsilon chains are monomorphic structures presumably involved in transmembrane signalling. The alpha and beta subunits are disulfide bonded to each other and held (...) in noncovalent association with the T3 chains. T3‐Ti receptor crosslinking leads to conformational modification of a second T lineage specific molecule, termed the 50 kDa T11 structure which in turn leads to protein kinase C activation, elevation in intracytoplasmic free calcium and Na+/H+ antiport stimulation. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a (...) previously developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

Endothelial cells line the inside of all blood vessels, forming a structurally and functionally heterogenous population of cells. Their complexity and diversity has long been recognized, yet very little is known about the molecules and regulatory mechanisms that mediate the heterogeneity of different endothelial cell populations. The constitutive organ‐ and microenvironment‐specific phenotype of endothelial cells controls internal body compartmentation, regulating the trafficking of circulating cells to distinct vascular beds. In contrast, surface molecules associated with the activated cytokine‐inducible endothelial (...) phenotype play a critical role in pathological conditions including inflammation, tumor angiogenesis, and wound healing. Differentiation of the endothelial cell phenotypes appears to follow similar mechanisms to the differentiation of hematopoietic cells, with the exception that endothelial cells maintain transdifferentiating competence. The present review offers a scheme of endothelial cell differentially expressed endothelial cell molecules as targets for directed therapeutic intervention. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing (...) the 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

Quantum mechanical and molecular dynamics methods were used to analyze the structure and stability of neutral and zwitterionic configurations of the extracted active site sequence from a Burkholderia cepacia lipase, histidyl-seryl-glutamin (His86-Ser87-Gln88) and its mutated form, histidyl-cysteyl-glutamin (His86-Cys87-Gln88) in vacuum and different solvents. The effects of solvent dielectric constant, explicit and implicit water molecules and side chain mutation on the structure and stability of this sequence in both neutral and zwitterionic forms are represented. The quantum mechanics computations represent (...) that the relative stability of zwitterionic and neutral configurations depends on the solvent structure and its dielectric constant. Therefore, in vacuum and the considered non-polar solvents, the neutral form of the interested sequences is more stable than the zwitterionic form, while their zwitterionic form is more stable than the neutral form in the aqueous solution and the investigated polar solvents in most cases. However, on the potential energy surfaces calculated, there is a barrier to proton transfer from the positively charged ammonium group to the negatively charged carboxylat group or from the ammonium group to the adjacent carbonyl oxygen and or from side chain oxygen and sulfur to negatively charged carboxylat group. Molecular dynamics simulations (MD) were also performed by using periodic boundary conditions for the zwitterionic configuration of the hydrated molecules in a box of water molecules. The obtained results demonstrated that the presence of explicit water molecules provides the more compact structures of the studied molecules. These simulations also indicated that side chain mutation and replacement of sulfur with oxygen leads to reduction of molecular flexibility and packing. (shrink)

Human B cell stimulatory factor 2 (originally designated BSF2) was initially characterized and isolated as a T cell‐derived factor that caused the terminal maturation of activated B cells to immunoglobulin producing cells. Molecular cloning of the cDNA has revealed that BSF2 is identical with 26 kD protein, interferon β2, plasmacytoma growth factor and hepatocyte stimulating factor and the designation “IL‐6” has been proposed for this molecule. It is now known that BSF2/IL‐6 has a wide variety of biological functions and that (...) abnormal regulation of BSF2/IL‐6 expression may be related to the pathogenesis of certain autoimmune diseases such as rheumatoid arthritis and multiple myeloma. (shrink)

In many cells, a nitric oxide (NO) synthase inducible by immunological stimuli produces a sustained flow of NO that lasts a long time. NO is a short‐lived molecule but it is a diffusibel ligand believed to be capable of reaching distal target sites. Further, several lines of evidence indicate that cysteine‐rich motifs of metal‐binding proteins, as well as redox‐sensitive metal clusters of metalloproteins, are natural sensors of bioradicals like NO. In metalloregulatory proteins, metals are often conveniently located at binding sites (...) and bound to cysteine residues. Accordingly, disruption of the metal‐thiolate polymetallic clusters should trigger significant remodelling of the protein structure involved in regulation. We can therefore postulate that the nitrosation reaction occurring at metal centres or cysteine‐rich motifs will preclude correct binding to regulatory sites. Several examples are given of metalloregulatory proteins whose metal is bound to thiols and may then become sensitive to NO. Recent observations indicate that in response to NO synthesis, iron regulatory protein, a eukaryotic bifunctional [Fe‐S] protein, switches from acting as aconitase to being an RNA‐binding regulator, and we suggest that the interplay between NO or a NO‐derived molecule and metal clusters at critical allosteric sites may be a crucial component of the cellular response to environmental stress. (shrink)

Structural change in the cellular prion protein, PrPC to a ProteinaseK‐resistant β‐sheet‐rich insoluble form PrPSC and its accumulation have been considered to be central to the pathogenesis of the prion diseases (TSE). In a recent paper, Deleault et al have shown that specific endogenous RNA molecules can induce in vitro structural conversion of endogenous PrPC to PrPSC.1 Small highly structured synthetic RNAs can also induce this conversion process.2 However, recent in vivo results show that PrPSC is not directly involved (...) in the prion pathogenesis.3 It is possible, however, that nucleic‐acid‐induced PrPSC associated with the inducer nucleic acid could be the components of the infectious agent. BioEssays 26:469–473, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Henry Charlton Bastian's support for spontaneous generation is shown to have developed from his commitment to the new evolutionary science of Darwin, Spencer, Huxley and Tyndall. Tracing Bastian's early career development shows that he was one of the most talented rising young stars among the Darwinians in the 1860s. His argument for a logically necessary link between evolution and spontaneous generation was widely believed among those sympathetic to Darwin's ideas. Spontaneous generation implied materialism to many, however, and it had associations (...) in Britain with radical politics and amateur science. Huxley and the X Club were trying to create a public posture of Darwinism that kept it at arm's length from those negative associations. Thus, the conflict that developed when Huxley and the X Club opposed Bastian was at least as much about factional in-fighting among the Darwinians as it was about the experiments under dispute. Huxley's strategy to defeat Bastian and define his position as "non-Darwinian" contributed significantly to the shaping of Huxley's famous address "Biogenesis and Abiogenesis." Rhetorically separating Darwinism from Bastian was thus responsible for Huxley's first clear public statement that a naturalistic origin of life was compatible with Darwin's ideas, but only in the earth's distant past. The final separation of the discourse on the meaning of Brownian movement and "active molecules" from any possible link with spontaneous generation also grew out of Huxley's strategy to defeat Bastian. Clashes between Bastian and the X Club are described at the BAAS, the Royal Society, and in the pages of "Nature" and other journals. (shrink)

The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy‐related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation complex through multiple (...) regulatory pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification. (shrink)

Pheromones play a curcial role in mate stimulation and discrimination. In the fruit fly Drosophila, the most abundant cuticular hydrocarbons act as sex pheromones during courtship behavior. There are several active molecules and they compose a sex‐ and species‐specific pheromonal bouquet. Different species from the Drosophila melanogaster subgroup have adopted alternative systems of chemical mate recognition. Recent exploration of these interspecific variations, and of intraspecific variations, has led to the characterization of genes and to the mapping of structures (...) that process the production and perception of chemical messages. (shrink)

Pheromones play a curcial role in mate stimulation and discrimination. In the fruit fly Drosophila, the most abundant cuticular hydrocarbons act as sex pheromones during courtship behavior. There are several active molecules and they compose a sex‐ and species‐specific pheromonal bouquet. Different species from the Drosophila melanogaster subgroup have adopted alternative systems of chemical mate recognition. Recent exploration of these interspecific variations, and of intraspecific variations, has led to the characterization of genes and to the mapping of structures (...) that process the production and perception of chemical messages. (shrink)

In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition (...) of active molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

In biological electron transport the spin, and thus the magnetic property of electrons, is neglected. Furthermore, no attention is paid to the fact that the great majority of biologically important molecules are chiral, and during excitation a magnetic moment is induced in them. It is shown, both theoretically and experimentally, that the magnetic moment of the electron and the magnetic transition moment of the optically active molecules may interact. The main consequences of such an interaction are a (...) higher probability of the occurrence of optically active molecules in triplet states, and the polarization of transported electrons. (shrink)

In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. DNA (...) in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

Since molecules are inaccessible to immediate observation, our conception of the molecule is brought about by transdiction which entails invention of various transcendental ideas. In organic chemistry we think that molecules consist of atoms, bonds, functional groups, etc. This is, however, not the unique description of the molecule as is shown by quantum mechanical calculations, for example. Then, what description represents the real molecule? Before asking this question, we have to consider what the real molecule is in the (...) first place. Constructive realism distinguishes our cognitive world and the world just given, and claims that we should accept the former as reality. Understanding our cognitive world is possible only through construction of micro-worlds. Atoms, bonds, functional groups, etc., are micro-worlds which make sense in a theoretical framework of organic chemistry. In this study we translate a micro-world to an affordance and paraphrase it as a context-relative dispositional attribute of an {agent-world} complex. Then, we can understand that it is what we take as molecular structure, not what might be out there to be found, that we should accept as reality. Excluding metaphysical fictions from scientific arguments, constructive realism makes science a meaningful activity. Constructive realism claims that, for getting knowledge of the world, we have to integrate information into our own linguistic frame, i.e., to translate it. Strangification is a technique of intentionally taking an accepted proposition out of one scientific system and putting it into a completely different context. As is the case with translation, strangification brings about deeper understanding of philosophical as well as scientific grounds on which the proposition system holds. We apply this method to molecular structure and reveal that it is an ingenious model to describe molecular behavior in multi-molecular systems with strong interactions between molecules. Information provided by strangification is essential to claim the legitimacy of a proposition system. As far as strangification is properly applied, relativism is irrelevant to constructive realism. (shrink)

Activation of resting T lymphocytes through the T cell antigen receptor complex is initiated by critical phosphorylation and dephosphorylation events that regulate the function and interaction of a number of signaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the phosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate each other at multiple sites and, as the result of (...) these interactions, they are induced to phosphorylate other cellular proteins. These phosphorylation events lead to modulation of enzymatic activities and/or serve as binding sites for other signaling molecules having phosphotyrosine‐binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinases that phosphorylate them. Some of the SH2‐domain‐containing polypeptides lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effectors, such as regulators of the Ras proteins, and further into serine/threonine‐specific protein kinase cascades. Through largely unknown steps these reactions lead to the transcription of previously silent genes, activation of lymphocyte effector functions, progression through the cell cycle and cell proliferation. (shrink)

Structure–activity relationship and quantitative SAR are modeling methods largely used in assessing biological properties of chemical substances. QSAR is based on the hypothesis that the chemical structure is responsible for the activity; it follows that similar molecules are expected to have similar properties. Similarity plays an important role in read across, which categorizes molecules primarily on the basis of similarity. Similarity, and chemical similarity too, is a property differently perceived by humans. The various proposed metrics often disagree with (...) human judgment, and no a unique metric for chemical similarity is universally adopted. Researchers argued that categorization is not only explained by similarity but depends as well on abstract knowledge and the task to accomplish. Moreover, similarity cannot be the unique explanation of a categorization, as different perceptual processes take place in category formation. Assuming that similarity judgments are deeply rooted in human knowledge and perception, cognitive sciences contributions are as important as the mathematical considerations of the classical theories. After an excursus in the many views of similarity in philosophy, mathematics, and cognitive science, the paper explores how connectionist systems, which loosely mimic the human cognitive system, could improve similarity-based choices. A case study on building SARs using connectionism and deep neural networks shows the role of similarity in building and explaining those models. A discussion about deep learning for QSAR and as a modeling tool for science concludes the presentation. (shrink)

Adapter molecules in a variety of signal transduction systems link receptors to a limited number of commonly used downstream signaling pathways. During T‐cell development and mature T‐cell effector function, a multichain receptor (the pre‐T‐cell antigen receptor or the T‐cell antigen receptor) activates several protein tyrosine kinases. Receptor and kinase activation is linked to distal signaling pathways (PLC‐γ1 activation, Ca2+ influx, PKC activation and Ras/Erk activation) via the adapter protein LAT (Linker for Activation of T cells). Structure/function studies of LAT (...) including expression of selected LAT point mutations in vivo reveals that these multiple pathways are integrated at the level of the LAT adapter. These studies suggest that similar levels of control may be found in other systems where adapter molecules are known to have important functions. BioEssays 26:61–67, 2004. Published 2003 Wiley Periodicals, Inc. (shrink)

New imaging methodologies in quantitative fluorescence microscopy, such as Förster resonance energy transfer (FRET), have been developed in the last few years and are beginning to be extensively applied to biological problems. FRET is employed for the detection and quantification of protein interactions, and of biochemical activities. Herein, we review the different methods to measure FRET in microscopy, and more importantly, their strengths and weaknesses. In our opinion, fluorescence lifetime imaging microscopy (FLIM) is advantageous for detecting inter‐molecular interactions quantitatively, the (...) intensity ratio approach representing a valid and straightforward option for detecting intra‐molecular FRET. Promising approaches in single molecule techniques and data analysis for quantitative and fast spatio‐temporal protein‐protein interaction studies open new avenues for FRET in biological research. (shrink)

This paper discusses DNA-based stochastic optimizations under the constraint that the search starts from a given point in a search space. Generally speaking, a stochastic optimization method explores a search space and finds out the optimum or a sub-optimum after many cycles of trials and errors. This search process could be implemented efficiently by ``molecular computing'', which processes DNA molecules by the techniques of molecular biology to generate and evaluate a vast number of solution candidates at a time. We (...) assume the exploration starting from a single point, and propose a method to embody DNA-based optimization under this constraint, because this method has a promising application in the research field of protein engineering. In this application, a string of nucleotide bases encodes a protein possessing a specific activity, which could be given as a value of an objective function. Thus, a problem of obtaining a protein with the optimum or a sub-optimum about the desired activity corresponds to a combinatorial problem of obtaining a base sequence giving the optimum or a sub-optimum in the sequence space. Biologists usually modify a base sequence corresponding to a naturally occurring protein into another sequence giving a desired activity. In other words, they explore the space in the proximity of a natural protein as a start point. We first examined if the optimization methods that involve a single start point, such as simulated annealing, Gibbs sampler, and MH algorithms, can be implemented by DNA-based operations. Then, we proposed an application of genetic algorithm, and examined the performance of this application on a model fitness landscape by computer experiments. These experiments gave helpful guidelines in the embodiments of DNA-based stochastic optimization, including a better design of crossover operator. (shrink)

Hydrogen activation on the (100) surface of MoS2 structures was investigated by means of density functional theory calculations. Linear and quadratic synchronous transit methods with a conjugate gradient refinement of the saddle point were used to localize transition states. The calculations include heterolytic and homolytic dissociation of hydrogen; that is, an H2 molecule dissociates on an MoS2 catalyst surface into two hydrogen atoms, which react further with the catalyst surface under formation of either one Mo-H and one S-H (heterolytic) or (...) of two S-H surface groups (homolytic). Our results favor the heterolytic adsorption of hydrogen. Ni- and Co-promoted MoS2 have been considered to investigate the secondary promotional effect on the H2 dissociation. The authors observed a negative secondary promotional influence on the H2 dissociation in the case of Ni-promoted MoS2, whereas Co shows a positive effect. (shrink)

Debate over the nature of science has recently moved from the halls of academia into the public sphere, where it has taken shape as the "science wars." At issue is the question of whether scientific knowledge is objective and universal or socially mediated, whether scientific truths are independent of human values and beliefs. Ronald Giere is a philosopher of science who has been at the forefront of this debate from its inception, and Science without Laws offers a much-needed mediating perspective (...) on an increasingly volatile line of inquiry. Giere does not question the major findings of modern science: for example, that the universe is expanding or that inheritance is carried by DNA molecules with a double helical structure. But like many critics of modern science, he rejects the widespread notion of science--deriving ultimately from the Enlightenment--as a uniquely rational activity leading to the discovery of universal truths underlying all natural phenomena. In these highly readable essays, Giere argues that it is better to understand scientists as merely constructing more or less abstract models of limited aspects of the world. Such an understanding makes possible a resolution of the issues at stake in the science wars. The critics of science are seen to be correct in rejecting the Enlightenment idea of science, and its defenders are seen to be correct in insisting that science does produce genuine knowledge of the natural world. Giere is utterly persuasive in arguing that to criticize the Enlightenment ideal is not to criticize science itself, and that to defend science one need not defend the Enlightenment ideal. Science without Laws thus stakes out a middle ground in these debates by showing us how science can be better conceived in other ways. (shrink)

Enzymes are remarkable molecules which make metabolism possible. Their processing powers are considerable for not only are they catalysts they also contribute to information processing, integration, coherence and memory in the cell. This complex of attributes suggests that a complementary perspective to enzyme nature and activity is needed related to what enzymes and verbs have in common. The value of this kind of thinking is that it shifts the focus from objects and mechanisms to processes and information. In order (...) to support this idea a number of features which enzymes and verbs share are discussed including, context-dependence, occurrence, cases, voice, mood and glue/integrative capacities. The paper concludes with some reflections on the utility of a view of enzymes as verbs. (shrink)

Competence is an active state that defines the way in which cells respond to an inductive signal. A challenge of developmental biology is to explain not just the nature of the signalling molecules that promote cell specification or differentiation, but also how cells acquire competence to respond to these signals and what that reflects in molecular terms. A recent paper by Carmena et al.(1) has revealed how several signalling mechanisms are used sequentially and in specific combinations to specify (...) two mesodermal lineages in Drosophila. BioEssays 21:455–458, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Wnt glycoproteins are signaling molecules that control a wide range of developmental processes in organisms ranging from the simple metazoan Hydra to vertebrates. Wnt signaling also plays a key role in the development of the nematode C. elegans, and is involved in cell fate specification and determination of cell polarity and cell migration. Surprisingly, the first genetic studies of Wnt signaling in C. elegans revealed major differences with the established (canonical) Wnt signaling pathways of Drosophila and vertebrates. Thus, the (...) Wnt-dependent induction of endoderm in the early embryo and the specification of several asymmetric cell divisions during larval development are mediated by as yet novel Wnt signaling pathways that repress, rather than activate the TCF/LEF-1 transcription factor POP-1. Recently, however, it has been shown that, in addition to these divergent Wnt pathways, C. elegans also has a canonical Wnt pathway that converts POP-1 into an activator and controls the expression of several homeobox genes. Interestingly, these different Wnt pathways use distinct beta-catenins to control POP-1 function: the endoderm induction pathway requires the beta-catenin WRM-1 and parallel input from a mitogen-activated kinase (MAPK) pathway to downregulate POP-1, whereas the canonical Wnt pathway employs the beta-catenin BAR-1 to activate Wnt target gene expression. (shrink)