Molecular chaperones in cells constantly monitor and bind to exposed hydrophobicity in newly synthesized proteins and assist them in folding or targeting to cellular membranes for insertion. However, proteins can be misfolded or mistargeted, which often causes hydrophobic amino acids to be exposed to the aqueous cytosol. Again, chaperones recognize exposed hydrophobicity in these proteins to prevent nonspecific interactions and aggregation, which are harmful to cells. The chaperone‐bound misfolded proteins are then decorated with ubiquitin chains denoting them for proteasomal degradation. (...) It remains enigmatic how molecular chaperones can mediate both maturation of nascent proteins and ubiquitination of misfolded proteins solely based on their exposed hydrophobic signals. In this review, we propose a dynamic ubiquitination and deubiquitination model in which ubiquitination of newly synthesized proteins serves as a “fix me” signal for either refolding of soluble proteins or retargeting of membrane proteins with the help of chaperones and deubiquitinases. Such a model would provide additional time for aberrant nascent proteins to fold or route for membrane insertion, thus avoiding excessive protein degradation and saving cellular energy spent on protein synthesis. Also see the video abstract here: https://youtu.be/gkElfmqaKG4. (shrink)

Early research on the cell cycle revealed correlations between protein accumulation and cell proliferation. In this review, I describe the data showing that abnormality of cell growth and tumor development are dependent upon oncogene‐induced increases in the levels and activity of factors that determine the rate of protein synthesis. It is proposed that the establishment of a vicious circle, namely oncoproteins → increase in translation → oncoproteins, is a major biological mechanism that fuels neoplastic growth. The constitutively (...) high rates of protein synthesis and accumulation of proteins, including those necessary for DNA replication and mitosis, would drive cells to excessive proliferation. (shrink)

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an anti‐tumourigenic mechanism. We describe (...) how hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. (shrink)

The lateral mobility of membrane lipids and proteins is presumed to play an important functional role in biomembranes. Photobleaching studies have shown that many proteins in the plasma membrane have diffusion coefficients at least an order of magnitude lower than those obtained when the same proteins are reconstituted in artificial bilayer membranes. Depending on the protein, it has been shown that either the cytoplasmic domain or the ectodomain is the key determinant of its lateral mobility. Single particle (...) tracking microscopy, which allows the motions of single or small groups of membrane molecules to be followed, promises not only to reveal new features of membrane dynamics, but also to help explain longstanding puzzles presented by the photobleaching studies, particularly the so‐called immobile fraction. The combination of the two complementary technologies should measurably enhance our understanding of membrane microstructure. (shrink)

A diploid human genome contains approximately six billion nucleotides. This enormous amount of genetic information can be replicated with great accuracy in only a few hours. However, because DNA strands are oriented antiparallel while DNA polymerization only occurs in the 5′ → 3′ direction, semi‐conservative replication of double‐stranded DNA is an asymmetric process, i.e., there is a leading and a lagging strand. This provides a considerable opportunity for non‐random error rates, because the architecture of the two strands as well (...) as the DNA polymerases that replicate them may be different. In addition, the proteins that start or finish chains may well be different from those that perform the bulk of chain elongation. Furthermore, while replication fidelity depends on the absolute and relative concentrations of the four deoxyribonucleotide precursors, these are not equal in vivo, not constant throughout the cell cycle, and not necessarily equivalent in all cell types. Finally, the fidelity of DNA synthesis is sequence‐dependent and the eukaryotic nuclear genome is a heterogeneous substrate. It contains repetitive and non‐repetitive sequences and can actually be considered as two subgenomes that differ in nucleotide composition and gene content and that replicate at different times. The effects that each of these asymmetries may have on error rates during replication of the eukaryotic genome are discussed. (shrink)

Both prokaryotic and eukaryotic cells share the basic mechanisms of secretory protein synthesis. However, unlike prokaryotes, eukaryotic cells posses a system of compartments, the so-called endomembrane system, which are involved in the synthesis process. A comparison of the prokaryotic and eukaryotic protein synthesis processes and particularly the observation of the functional and structural similarity between the prokaryotic cell membrane (the interface to the cell exterior) and the membrane of the eukaryotic endoplasmic reticulum (one (...) of the compartments within the endomembrane system) inspire a description that refers to either the eukaryotic endoplasmic reticulum or its membrane or the endomembrane system altogether as a representation of the extracellular medium. However, unless the terms in such a statement are carefully analysed and refined the description would be just a colloquial usage of the concept of “representation” rather than a biosemiotic statement. Another problem associated with employing the concept of “representation” in a biosemiotic context is due to the fact that it may evoke the impression of a conscious mind as the “owner” of the representation. In this paper theories about the emergence of the eukaryotic endomembrane system, as well as its functionality within secretory protein synthesis will be analysed in order to specify in what sense the concept of “representation” can be employed in this context without implying consciousness. Such a study is expected not only to provide an insight into the conditions and assumptions under which this concept can be used for lower level biological processes but also to shed some light on how representations emerge in general. (shrink)

The final assembly of the protein synthesis machinery occurs during translation initiation. This delicate process involves both ends of eukaryotic messenger RNAs as well as multiple sequential protein–RNA and protein–protein interactions. As is expected from its critical position in the gene expression pathway between the transcriptome and the proteome, translation initiation is a selective and highly regulated process. This synopsis summarises the current status of the field and identifies intriguing open questions. BioEssays 25:1201–1211, 2003 © (...) 2003 Wiley Periodicals, Inc. (shrink)

Ductin is the highest conserved membrane protein yet found in eukaryotes. It is multifunctional, being the subunit c or proteolipid component of the vacuolar H+‐ATPase and at the same time the protein component of a form of gap junction in metazoan animals. Analysis of its structure shows it to be a tandem repeat of two 8‐kDa domains derived from the subunit c of the F0 proton pore from the F1F0 ATPase. Each domain contains two transmembrane α‐helices, which (...) together may form a four‐helix bundle. In both the V‐ATPase and gap junction channel, ductin is probably arranged as a hexamer of subunits forming a central channel of gap junction‐like proportions. The two functions appear to be seggregated by ductin having two orientations in the bilayer. Ductin is also the major component of the mediatophore, a protein complex which may aid in the release of neurotransmitters across the pre‐synaptic membrane. It is also a target for a class of poorly understood viral polypeptides. These polypeptides are small and highly hydrophobic and some have oncogenic activity. Ductin thus appears to be at the crossroads of a number of biological processes. (shrink)

In this paper, we compare the mechanisms of protein synthesis and natural selection. We identify three core elements of mechanistic explanation: functional individuation, hierarchical nestedness or decomposition, and organization. These are now well understood elements of mechanistic explanation in fields such as protein synthesis, and widely accepted in the mechanisms literature. But Skipper and Millstein have argued that natural selection is neither decomposable nor organized. This would mean that much of the current mechanisms literature does not (...) apply to the mechanism of natural selection.We take each element of mechanistic explanation in turn. Having appreciated the importance of functional individuation, we show how decomposition and organization should be better understood in these terms. We thereby show that mechanistic explanation by protein synthesis and natural selection are more closely analogous than they appear—both possess all three of these core elements of a mechanism widely recognized in the mechanisms literature. (shrink)

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit a variety (...) of effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (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)

This review is primarily concerned with two key issues in research on dystrophin: (1) how the protein interacts with the plasma membrane of skeletal muscle fibres and (2) how an absence of dystrophin gives rise to Duchenne muscular dystrophy. In relation to the first point, we suggest that the post‐translational acylation of dystrophin may contribute to its interaction with the plasma membrane. Regarding the second point, it is generally considered that an absence of dystrophin makes the plasma (...) membrane susceptible to damage by contraction/relaxation cycles. In this connection, we propose that the progressive nature of Duchenne dystrophy, and the phenotypic characteristics of mdx mice, are more consistent with dystrophin functioning as a mechanical transducer that transmits growth stimuli from the enlarging skeleton to the muscle. On the basis of this hypothesis, dystrophin‐deficient muscles would be unable to grow at the same rate as the skeleton. (shrink)

Amyloid fibril formation plays a central role in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer and Parkinson diseases. Transient prefibrillar oligomers forming during the aggregation process, exhibiting a small size and a large hydrophobic surface, can aberrantly interact with a number of molecular targets on neurons, including the lipid bilayer of plasma membranes, resulting in a fatal outcome for the cells. By contrast, the mature fibrils, despite presenting generally a high hydrophobic surface, are endowed with a low (...) diffusion rate and poorly penetrate the interior of the lipid bilayer. However, increasing evidence shows that both intracellular α‐synuclein fibrils, as well and as extracellular amyloid‐β and β2‐microglobulin fibrils, can release oligomers over time that quickly diffuse to reach the membrane of the neighboring cells. The persistent leakage of harmful oligomers from fibrils triggers an ongoing cascade of events resulting in a sustained injury to neurons and glia and also provides aggregates with the ability to cross biological membranes and diffuse between cells or cellular compartments. (shrink)

One major milestone in the development of the sea urchin embryo is the assembly of a single cilium on each blastomere just before hatching. These cilia are constructed both from pre‐existing protein building blocks, such as tubulin and dynein, and from a number of 9+2 architectural elements that are synthesized de novo at ciliogenesis. The finite or quantal synthesis of certain key architectural proteins is coincident with ciliary elongation and proportional to ciliary length. Upon deciliation, the synthesis (...) of architectural proteins occurs anew, a new cilium grows, and the stores of various building blocks are replenished. This routine of coordinated ciliary gene expression may be replayed experimentally many times without delaying normal development. The ability to regenerate cilia has allowed elucidation of these various protein synthetic relationships and has led to the discovery of the pathways by which membrane‐associated tubulin and axoneme‐associated architectural proteins are conveyed into the highly compartmentalized growing cilium. The sea urchin embryo thus provides a very convenient model system for studies of ciliary assembly and maintenance, coordinate gene expression and membrane dynamics. (shrink)

Cytoplasmic dynein is the major minus‐end‐directed motor protein in eukaryotes, and has functions ranging from organelle and vesicle transport to spindle positioning and orientation. The mode of regulation of dynein in the cell remains elusive, but a tantalising possibility is that dynein is maintained in an inhibited, non‐motile state until bound to cargo. In vivo, stable attachment of dynein to the cell membrane via anchor proteins enables dynein to produce force by pulling on microtubules and serves to organise (...) the nuclear material. Anchor proteins of dynein assume diverse structures and functions and differ in their interaction with the membrane. In yeast, the anchor protein has come to the fore as one of the key mediators of dynein activity. In other systems, much is yet to be discovered about the anchors, but future work in this area will prove invaluable in understanding dynein regulation in the cell. (shrink)

Microfilament interactions with the plasma membranes of animal cells appear to vary with cell type and localization. In the erythrocyte, actin oligomers are associated with the membrane via spectrin and ankyrin. The ends of stress fibers in cultured cells, such as fibroblasts, are attached to the plasma membrane at focal adhesion sites and may involve the protein vinculin as a linking protein. In intestinal brush border microvilli a 110,000 dalton protein links the microfilament bundles to (...) sites on the microvillus. A transmembrane complex containing actin stably associated with a cell surface glycoprotein can be isolated from ascites tumor cell microvilli and can be obtained still associated with microfilaments by gentle extraction and gradient centrifugation of the microvilli. These varied interaction mechanisms are believed to be needed to satisfy the different structural and dynamic requirements of the particular systems. (shrink)

The synthesis of biological membranes requires the insertion of proteins into a lipid bilayer. The rough endoplasmic reticulum of eukaryotic cells is a principal site of membrane biogenesis. The insertion of proteins into the membrane of the endoplasmic reticulum is mediated by a resident proteinaceous machinery. Over the last five years several different experimental approaches have provided information about the components of the machinery and how it may function.

We propose protein localization dependent signal activation (PLDSA) as a model to describe pre‐existing protein partitioning between the cytosol, and membrane surface, as a means to modulate signal activation, specificity, and robustness. We apply PLDSA to explain possible molecular links between type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) by describing Ca+2‐mediated interactions between the Src non‐receptor tyrosine kinase and p52Shc adaptor protein. We suggest that these interactions may serve as a contributing factor to disease (...) development and progression. In particular, we propose that signaling response is regulated, in part, by Ca+2‐mediated partitioning of lipid‐bound and soluble forms of Src and p52shc. Thus, protein‐protein interactions that drive signaling in response to extracellular ligand binding are also mediated by partitioning of signaling proteins between membrane‐bound and soluble populations. We propose that PLDSA effects may explain, in part, the evolutionary basis of promiscuous protein interaction domains and their importance in cellular function. (shrink)

Assembly of minimal genomes revealed many genes encoding unknown functions. Three overlooked functional categories account for some of them. Cells are prone to make errors and age. As a first key function, discrimination between proper and changed entities is indispensable. Discrimination requires management of information, an authentic, yet abstract, cur- rency of reality. For example proteins age, sometimes very fast. The cell must identify, then get rid of old proteins without destroying young ones. Implementing discrimination in cells leads to the (...) second set of functions, usually ignored. Being abstract, information must nevertheless be embodied into material entities, with unavoidable idiosyncratic properties. This brings about novel unmet needs. Hence, the buildup of cells elicits specific but awkward material implementations, ‘kludges’ that become essential under particular settings, while difficult to identify. Finally, a third functional category char- acterizes the need for growth, with metabolic implementations allowing the cell to put together the growth of its cytoplasm, membranes, and genome, spanning different spatial dimensions. Solving this metabolic quandary, critical for engineering novel synthetic biology chassis, uncovered an unexpected role for CTP synthetase as the coordinator of nonhomothetic growth. Because a significant number of SynBio constructs aim at creating cell factories we expect that they will be attacked by viruses (it is not by chance that the function of the CRISPR system was identified in industrial settings). Substantiating the role of CTP, natural selection has dealt with this hurdle via synthesis of the antimetabolite 30-deoxy-30,40-didehydro- CTP, recruited for antiviral immunity in all domains of life. (shrink)

The living world is one of complexity, the result of innumerable interactions among organisms, cells, molecules. In analyzing a problem, the biologist is constrained to focus on a fragment of reality, on a piece of the universe which he arbitrarily isolates to define certain of its parameters.In biology, any study thus begins with the choice of a “system.” On this choice depend the experimenter's freedom to maneuver, the nature of the questions he is free to ask, and even, often, the (...) type of answer he can obtain. (shrink)

In this article two questions are discussed with regard to semiosis in protein biosynthesis for nano engines. (1) What kind of semiosis is involved in the construction of these proteins? and (2) How can we explain the semiotic process observed? With regard to the first issue we draw attention to comparisons between semiosis in protein biosynthesis and human natural language. The notion of normativity appears to be of great importance for both. A comparison also demonstrates differences. Nevertheless, because (...) of the normative symbolic information processing in it, we suggest to employ the term symbolic reference (employed in linguistics as a distinguishing feature of human language) to indicate the semiotic processes in protein biosynthesis. With regard to explaining semiosis in protein synthesis we compare different approaches. We conclude that a Kantian approach should be preferred. In such an approach strengths of the mechanistic and organicist approaches can be combined, and the observed symbolic information processing acknowledged. (shrink)

I present a reconstruction of F.H.C. Crick's two 1957 hypotheses "Sequence Hypothesis" and "Central Dogma" in terms of a contemporary philosophical theory of causation. Analyzing in particular the experimental evidence that Crick cited, I argue that these hypotheses can be understood as claims about the actual difference-making cause in protein synthesis. As these hypotheses are only true if restricted to certain nucleic acids in certain organisms, I then examine the concept of causal specificity and its potential to counter (...) claims about causal parity of DNA and other cellular components. I first show that causal specificity is a special kind of invariance under interventions, namely invariance of generalizations that range over finite sets of discrete variables. Then, I show that this notion allows the articulation of a middle ground in the debate over causal parity. (shrink)

Coronins constitute an evolutionarily conserved family of WD‐repeat actin‐binding proteins, which can be clearly classified into two distinct groups based on their structural features. All coronins possess a conserved basic N‐terminal motif and three to ten WD repeats clustered in one or two core domains. Dictyostelium and mammalian coronins are important regulators of the actin cytoskeleton, while the fly Dpod1 and the yeast coronin proteins crosslink both actin and microtubules. Apart from that, several coronins have been shown to be involved (...) in vesicular transport. C. elegans POD‐1 and Drosophila coro regulate the actin cytoskeleton, but also govern vesicular trafficking as indicated by mutant phenotypes. In both organisms, defects in cytoskeleton and trafficking lead to severe developmental defects ranging from abnormal cell division to aberrant formation of morphogen gradients. Finally, mammalian coronin 7 appears not to execute any cytoskeleton‐related functions, but rather participates in regulating Golgi trafficking. Here, we review recent data providing more insight into molecular mechanisms underlying the regulation of F‐actin structures, cytoskeletal rearrangements and intracellular membrane transport by coronin proteins and the way that they might link cytoskeleton with trafficking in development and disease. BioEssays 27:625–632, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In a previous paper, an integrated account of Rosen’s relational biology and Peirce’s semiosis has been proposed. Both theories have been compared and basic concepts have been posited for the definition of a unified framework for the study of biology, as well as a method for the identification and analysis of the presence of signs in an organism. The analysis of the existence of semiotic actions in an organism must, without a doubt, begin by considering each of the rules that (...) constitute the genetic code as a candidate for a semiotic relation. Transcription and translation, which constitute protein synthesis, are the basis of the specificity that the organism needs to maintain itself in its environment and reproduce, and the precondition of the existence of any other possible semiosis. Applying the concepts and method of the aforementioned work, this paper analyzes which of the biological processes involved in protein synthesis correspond to semiotic actions and the type of the signs identified, according to Peirce’s classification of icons, indices and symbols. The results of this work demonstrate the theoretical consistency and the practical utility of integrating the theories of Rosen and Peirce, offer a way to identify other signs in an organism, and support a critical analysis of code biology and protosemiosis, two accounts that deny the possibility of explaining the signs in an organism with Peirce’s semiosis. (shrink)

Clonal expansion of T‐lymphocyte populations results from interactions of antigenic structures presented in combination with accessory cells (macrophages) and antibody recognition sites on the surface of T cells. The resulting activation of a membrane phospholipase C plays a crucial role in lymphocyte responses by releasing diglyceride and PIP3. The released diglyceride activates a cellular protein kinase C while PIP3 stimulates Ca2+ influx. Arachidonic acid released by the action of diglyceride lipase serves as substrate for the synthesis of (...) bioactive eicosanoids (prostaglandins and leukotrienes) which in turn modulate cellular adenyl and guanyl cyclases. The eicosanoids serve as both intra‐ and extra‐cellular signals for lymphocytes, regulating the production and expression of lymphokines and mediating the complex interactions between the monocyte‐macrophage components and helper and suppressor T cells.Aspirin and other anti‐inflammatory drugs stimulate mitogenesis by inhibiting production of the negative modulator prostaglandin E2 in accessory cells and by enhancing the production of the lymphokine 1L‐2 by producer T‐cells. (shrink)

Calcium ions act as modulators of many fundamental processes in eukaryotic cells. Although these processes apparently involve initial interactions between calcium ions and cell membranes, the identity of the putative membrane Ca2+‐binding proteins has until recently been obscure. This article describes a recently discovered family of mammalian membrane proteins, of perhaps ancient origin, that may fulfil this function.

Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane elements implicated in neurodegenerative diseases. Both proteins undergo endoproteolysis. Evidence is adduced from the literature hinting that the process in the two proteins could be related, their functions may overlap and their distributions coincide. It is proposed that PrP catalyses its own cleavage, the C-terminal fragment functions as an α secretase and the N-terminal segment chaperones the active site; the α secretase releases anticoagulant and neurotrophic (...) ectodomains from APP. The proposals explain some features of spongiform encephalopathies. BioEssays 23:456–462, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In biology proteins are uniquely important. They are not to be classed with polysaccharides, for example, which by comparison play a very minor role. Their nearest rivals are the nucleic acids....The main function of proteins is to act as enzymes....In the protein molecule Nature has devised a unique instrument in which an underlying simplicity is used to express great subtlety and versatility; it is impossible to see molecular biology in proper perspective until this peculiar combination of virtues has been (...) clearly grasped. (shrink)

Microfluidic technology – the manipulation of fluids at micrometer scales – has revolutionized many areas of synthetic biology. The bottom‐up synthesis of “minimal” cell models has traditionally suffered from poor control of assembly conditions. Giant unilamellar vesicles (GUVs) are good models of living cells on account of their size and unilamellar membrane structure. In recent years, a number of microfluidic approaches for constructing GUVs has emerged. These provide control over traditionally elusive parameters of vesicular structure, such as size, (...) lamellarity, membrane composition, and internal contents. They also address sophisticated cellular functions such as division and protein synthesis. Microfluidic techniques for GUV synthesis can broadly be categorized as continuous‐flow based approaches and droplet‐based approaches. This review presents the state‐of‐the‐art of microfluidic technology, a robust platform for recapitulating complex cellular structure and function in synthetic models of biological cells. (shrink)

Two enzymes involved in the synthesis of pyrimidine and purine nucleotides, CTP synthase (CTPS) and IMP dehydrogenase (IMPDH), can assemble into a single or very few large filaments called rods and rings (RR) or cytoophidia. Most recently, asymmetric cytoplasmic distribution of organelles during cell division has been described as a decisive event in hematopoietic stem cell fate. We propose that cytoophidia, which could be considered as membrane‐less organelles, may also be distributed asymmetrically during mammalian cell division as previously (...) described for Schizosaccharomyces pombe. Furthermore, because each type of nucleotide intervenes in distinct processes (e.g., membrane synthesis, glycosylation, and G protein‐signaling), alterations in the rate of synthesis of specific nucleotide types could influence cell differentiation in multiple ways. Therefore, we hypothesize that whether a daughter cell inherits or not CTPS or IMPDH filaments determines its fate and that this asymmetric inheritance, together with the dynamic nature of these structures enables plasticity in a cell population. (shrink)

Neurotrophins (NTs) are {?AUTHOR} a family of structurally related, secreted proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons.1,2 Among these, BDNF (brain‐derived neurotrophic factor) has drawn considerable interest because both its synthesis and secretion are increased by physiological levels of activity, indicating a unique role of this neurotrophin in coupling neuronal activity to structural and functional properties of neuronal circuits. In addition to its classical neurotrophic effects, which are evident (...) within hours or days and which usually result from changes in cellular gene expression, BDNF exerts acute effects on synaptic transmission and is involved in the induction of long‐term potentiation. Many of these rapid effects of BDNF are mediated by its modulation of ion channel properties following TrkB‐mediated activation of intracellular second messenger cascades and protein phosphorylation. However, recent reports have shown that BDNF not only acts as a modulator of ion channels, but can also directly and rapidly gate a Na+ channel, thereby assigning BDNF the properties of a classical excitatory transmitter. Thus, BDNF, in addition its role as a potent neuromodulator, emerges as an excitatory transmitter‐like substance which acutely controls resting membrane potential, neuronal excitability, synaptic transmission and participates in the induction of synaptic plasticity. BioEssays 26:1185–1194, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The quantitative study of regulation of cell growth and proliferation began with the development of the technique for monolayer culture of vertebrate cells in the late 1960s. The basic parameters were defined in the early physiological studies, which continued through the next decade. These included specific and non-specific growth factors and the requirement for continuous exposure to such factors through most of the G1 period for progression to S. In the course of this work, the diversity of biochemical responses and (...) the critical role of increased protein synthesis and accumulation for the onset of DNA synthesis were elucidated. In particular, a central role of free cytosolic Mg2+ in direct regulation of protein synthesis and in ancillary processes as a response to membrane perturbation was established. Eventually, the physiological era was superseded by the molecular era beginning in the 1980s. This work focussed on specific receptors for growth factors that entrained a protein kinase cascade, which terminated in a higher frequency of initiation of protein synthesis. However, the molecular studies virtually ignored the key results of the physiological era. Recent studies of the penultimate molecular steps in the regulatory pathway of protein synthesis, however, have supported a model of growth regulation involving membrane perturbation and MgATP2− concentration, results that integrate the findings of the physiological and molecular eras. The resulting relatively simple “membrane, magnesium mitosis” (MMM) model of proliferation control can explain the seeming paradox of the variety of specific and non-specific growth-enhancing treatments that are mediated by the plasma membrane and which bring about a shared, complex but coordinated growth response that drives cell proliferation. BioEssays 27:311–320, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As (...) the LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon‐like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs. (shrink)

Passage through the cell cycle requires the successive activation of different cyclin‐dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the (...) profound structural reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation‐related diseases. (shrink)

Viruses have generally been thought of as infectious agents. New data on mimivirus, however, suggests a reinterpretation of this thought. Earth’s biosphere seems to contain many more viruses than previously thought and they are relevant in the maintenance of ecosystems and biodiversity. Viruses are not considered to be alive because they are not free-living entities and do not have cellular units. Current hypotheses indicate that some viruses may have been the result of genomic reduction of cellular life forms. However, new (...) studies relating to the origins of biological systems suggest that viruses could also have originated during the transition from First to the Last Universal Common Ancestor. Within this setting, life has been established as chemical informational system and could be interpreted as a macrocode of multiple layers. The first entity to acquire these features was the First Universal Common Ancestor that evolved to an intermediate ancestral that could be named T-LUCA and be equated to Woese’s concept of progenotes. T-LUCA may have remained as undifferentiated subsystems with viruses-like structures. The net result is that both cellular life forms and viruses shared protein synthesis apparatuses. In short, virus is a strategy of life reached by two paths: T-LUCAs like entities and the reduction of cellular life forms. (shrink)

Viruses have generally been thought of as infectious agents. New data on mimivirus, however, suggests a reinterpretation of this thought. Earth’s biosphere seems to contain many more viruses than previously thought and they are relevant in the maintenance of ecosystems and biodiversity. Viruses are not considered to be alive because they are not free-living entities and do not have cellular units. Current hypotheses indicate that some viruses may have been the result of genomic reduction of cellular life forms. However, new (...) studies relating to the origins of biological systems suggest that viruses could also have originated during the transition from First to the Last Universal Common Ancestor. Within this setting, life has been established as chemical informational system and could be interpreted as a macrocode of multiple layers. The first entity to acquire these features was the First Universal Common Ancestor that evolved to an intermediate ancestral that could be named T-LUCA and be equated to Woese’s concept of progenotes. T-LUCA may have remained as undifferentiated subsystems with viruses-like structures. The net result is that both cellular life forms and viruses shared protein synthesis apparatuses. In short, virus is a strategy of life reached by two paths: T-LUCAs like entities and the reduction of cellular life forms. (shrink)

Barley aleurone cells have long served as a model system for studying the regulation of gene expression in plants. In this review we survey what is known about hormone‐regulated gene expression in aleurone cells. We also describe the effects of heat stress on gene expression in this system, and speculate how the aleurone cell prioritizes its response between hormone‐induced and environment‐induced programs of gene expression.

Husserl’s theories, which systematise the role of reflection and consciousness, can be used to give an alternative view of organisational evolution as the flow of presence punctuated by absence. This perspective adopts a contrasting approach to that of the poststructuralist. A synthesis of the Identity metaphor with the theory of strategy allows us to contextualise an application of Husserl’s theory of the epoche (the intentional reduction) and link both ontological and epistemic dimensions in a theory of organisation. The firm (...) is seen as acquiring a temporal dimension through the consciousness of strategic policy and its successive images are modelled as analogous with the epoche. This modelling process also links in with the collective belief system of the organisational paradigm, which is represented to the organisation and unfolded extrinsically as a series of images which are the discernible face of Strategic policy. This facilitates a modified social-constructivism which is better able to accommodate the actuality of organisational development than more extreme process-orientated accounts of organisation. A debate is re-opened on these themes which have influenced organisation studies from a philosophical slant. (shrink)

The primary function of smooth muscle cells is to contract and alter the stiffness or diameter of hollow organs such as blood vessels, the airways and the gastrointestinal and urogenital tracts. In addition to purely structural functions, smooth muscle cells may play important metabolic roles, particularly in various inflammatory responses. In cell culture, these cells have been shown to be metabolically dynamic, synthesizing and secreting extracellular matrix proteins, glycosaminoglycans and a wide variety of cell–cell signaling proteins, such as interleukins, chemokines (...) and peptide growth factors. Secreted cell signaling proteins participate in the inflammatory response of smooth muscle‐containing organs, and some can also stimulate smooth muscle migration, proliferation and contraction. The cellular signaling pathways controlling synthesis of these signaling proteins are similar to those used by cells mediating innate immunity and may contribute to pathogenesis of diverse diseases including atherosclerosis, asthma, inflammatory bowel diseases and preterm labor. Appreciating the role of smooth muscle cells in these diseases may lead to better understanding of the beneficial effects of anti‐inflammatory drugs as well as identification of new targets for anti‐inflammatory therapy. BioEssays 26:646–655, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Introduction. Observing the production and consumer area of modern cinematography makes it possible to draw conclusions about the value dominants of modern society, to conduct its sociocultural analysis. Cinema, both auteur and mass, is a way of reflecting and modeling the society spiritual state and its analysis makes it possible to draw quite serious and justified philosophical and social conclusions. The film in a philosophical sense is ontologized by the dominant intention of the era. Such a dominant intention of modernity (...) is hedonism. Pleasure, enjoyment, happiness, according to the humanities, is the basic values of the 21st century society. Cinema is the most comprehensive reaction to the needs of hedonism, since hedonistic prerequisites are to some degree laid down in its technical (movement, photographic phenomenology) and social nature (art and entertainment). In this regard, it seems relevant to conduct a philosophical analysis of the ontological level of modern cinema. The aim of the study is to conduct a philosophical analysis of the ontological level of modern cinema; identify ontological models, variations and combinations of which provide its artistic diversity. Methods: the authors use the general scientific methods of analysis and synthesis, the phenomenological method, since they identify the sensory intentions that underlie modern cinema. The authors also use the hermeneutic method, since they reveal the hidden meanings of the film, determined by the time and conditions of its creation, as well as the semiotic approach, which makes it possible to analyze the structural-semiotic whole of the film. The scientific novelty of the study lies in the fact that the authors analyze films from philosophical aspects, and not just cultural studies, as is customary. In modern cinema, the authors look for a reflection of the “social soul”, identify those intentions that underlie modern cinema, both auteur and mass. This makes it possible to deduce a typology of film models that have not previously been applied to the analysis of the film process. Results. During the analysis, the authors developed a hedonistic-ontological typology of cinematic models, identified five generative models of cinema, four of which have a hedonistic orientation: an alimentary model that pleases the recipient by intensively stimulating his perceptual sphere; a parkour model that gives pleasure to light and unhindered movement, minimizing the severity and resistance of the environment; an arcade model that provides the viewer the pleasure of victory through virtual immersion in the ups and downs of the “action film”; a detective model that gives the viewer pleasure through the removal of cognitive uncertainty. The fifth model, tentatively called existential, should lead the viewer into a complex philosophical state of being-with-self-self, an experience of one’s own fulfillment, associated with the experience of suffering. However, due to the hedonistic orientations of modern culture, this model is not relevant in the first decades of the 21st century. Conclusions. Philosophical analysis of modern cinema has revealed that at the ontological level it is based on the philosophy of hedonism. Modern cinema delivers the following types of pleasures to the recipient: enjoyment of the flesh of the world, enjoyment of bodily freedom in motion, enjoyment of peace, cognitive enjoyment. (shrink)

Forty years’ experience as a bacterial geneticist has taught me that bacteria possess many cognitive, computational and evolutionary capabilities unimaginable in the first six decades of the twentieth century. Analysis of cellular processes such as metabolism, regulation of protein synthesis, and DNA repair established that bacteria continually monitor their external and internal environments and compute functional outputs based on information provided by their sensory apparatus. Studies of genetic recombination, lysogeny, antibiotic resistance and my own work on transposable elements (...) revealed multiple widespread bacterial systems for mobilizing and engineering DNA molecules. Examination of colony development and organization led me to appreciate how extensive multicellular collaboration is among the majority of bacterial species. Contemporary research in many laboratories on cell–cell signaling, symbiosis and pathogenesis show that bacteria utilise sophisticated mechanisms for intercellular communication and even have the ability to commandeer the basic cell biology of ‘higher’ plants and animals to meet their own needs. This remarkable series of observations requires us to revise basic ideas about biological information processing and recognise that even the smallest cells are sentient beings. Previous article in issue. (shrink)

It has long been known that the red blood cell contains a membrane skeleton that stabilizes the plasma membrane, determines its shape, and regulates the lateral distribution of the membrane glyco‐proteins to which it is attached. The way in which these functions are regulated in other cells has not been understood. It has now been shown that platelets also contain a membrane skeleton. In contrast to the membrane skeleton of the red blood cell, the platelet (...) membrane skeleton has actin‐binding protein, not spectrin, as a major component. The platelet membrane skeleton regulates the same cellular functions as the red blood cell membrane skeleton. Other cells may contain a membrane skeleton that is critical to their viability and normal functioning. (shrink)

Introduction A Brief Conceptual Framework for Biology PART ONE: UNDERSTANDING NATURE 1. The Antecedents of Scientific Thought Animism, Totemism, and Shamanism The Paleolithic View Mesopotamia Egypt 2. Aristotle and the Greek View of Nature The Science of Animal Biology The Parts of Animals The Classification of Animals The Aristotelian System Basic Questions 3. Those Rational Greeks? Theophrastus and the Science of Botany The Roman Pliny Hippocrates, the Father of Medicine Erasistratus Galen of Pergamum The Greek Miracle 4. The Judeo-Christian Worldview (...) The Bishop of Hippo Scholastic Thought Islamic Science Books on Beasts Antecedents of a Revolution 5. The Revival of Science Andreas Vesalius and the Study of Structure William Harvey and the Study of Function Sir Francis Bacon’s Great Instauration Induction, Hypothesis, Deduction The Very Small--Animalcules Robert Hooke and the Discovery of Cells 6. Figur’d Stones and Plastick Virtue Marine Life on Mountain Tops? Figured Stones of Unknown Creatures Baron Cuvier Quarries of the Paris Basin Catastrophism and Uniformitarianism William Smith and the Geological Column Understanding Nature in 1850 PART TWO: THE GROWTH OF EVOLUTIONARY THOUGHT 7. The Paradigm of Evolution First Questions The Paradigm of Natural Theology First Answers 8. Testing Darwins Hypotheses Have Life Forms Changed over Time? Do Species Evolve into Different Species over Time? Has There Been Time Enough for Evolution? Is Natural Selection the Mechanism of Change? The Genetic Basis of Natural Selection Accounting for the Diversity of Life 9. In the Light of Evolution Comparative Anatomy Embryonic Development Classification Microstructure Molecular Processes 10. Life over Time The Origin of Life The Rise of Multicelled Organisms What Is a Phylum? Burgess Shale Metazoans Early Evolution of the Vertebrates The Age of Dinosaurs Birds, Mammals, and Flowering Plants The Rancho La Brea Tar Pits Human Evolution The Role of Extinction in Evolution PART THREE: CLASSICAL GENETICS 11. Pangenesis What Is the Question? Hippocrates and Aristotle The Darwinian Answer Assembling the Data Formulating the Hypothesis by Induction Galton’s Rabbits 12. The Cell Theory The Discovery of Cells: Robert Hooke Schwann and Cells in Animals Gametes as Cells Omnis cellula e cellula? The Technology of Cell Research 13. The Hypothesis of Chromosomal Continuity The Ephemeral Nucleus Schneider, Flemming, and Cell Division The Chromosomes and inheritance Gamete Formation Fertilization 14. Mendel and the Birth of Genetics Model for Monohybrid Crosses Model for Dihybrid Crosses Mendel’s Laws Initial Opposition to Mendelism 15. Genetics + Cytology: 1900-1910 Sutton’s Model The Cytological Basis of Mendel’s Laws Boveri and Abnormal Chromosome Sets Variations in Mendelian Ratios The Discovery of Sex Chromosomes 16. The Genetics of the Fruit Fly Morgan’s First Hypothesis Morgan’s Second Hypothesis The Fly Room Linkage and Crossing-Over The Cytological Proof of Crossing-Over Mapping the Chromosomes The Final Proof The Determinants of Sex The Conceptual Foundations of Classical Genetics 17. The Structure and Function of Genes One Gene, One Enzyme The Substance of Inheritance The Watson-Crick Model of DNA Genes and the Synthesis of Proteins The Genetic Code PART FOUR: THE ENIGMA OF DEVELOPMENT 18. First Principles The Peripatetic Stagirite The Death and Rebirth of Scientific Thought Harvey and Malpighi A Two-Millennial Summing Up Preformation versus Epigenesis 19. The Century of Discovery Von Baer’s Discovery of the Mammalian Ovum Darwin’s Contribution to Embryology Haeckel and Recapitulation 20. Descriptive Embryology Germ Layers The External Development of the Amphibian Embryo The Internal Development of the Amphibian Embryo 21. The Dawn of Analytical Embryology His, Roux, and Mosaic Development Driesch and Regulative Development Novelty in Development Cell Lineage Nucleus or Cytoplasm? Fin de Siècle 22. Interactions during Development Amphibian Organizers Secondary Organizers The Reacting Tissue The Chemical Nature of the Organizer Putting It All Together Conclusion Further Reading References Illustration Credits Index. (shrink)

Insights into the role of sleep in the molecular mechanisms of memory consolidation may come from studies of activity-dependent synaptic plasticity, such as long-term potentiation (LTP). This commentary posits a specific contribution of sleep to LTP stabilization, in which mRNA transported to dendrites during wakefulness is translated during sleep. Brain-derived neurotrophic factor may drive the translation of newly transported and resident mRNA.

The deep commonality of science and art lies in the fact that both phenomena arose as a means of breaking out of the self-contained shell of the self-sufficient world of everyday consciousness. Science and art arose as a means of escaping from the narrow bounds of natural existence, so as to recognize one's specifically human attitude toward the world, recognize the value of truth, beauty, and the right. In the course of history, science and art have created highly specialized superstructures. (...) Science became a means for technological mastery of the world, and even its deep-lying substrate is perceived by us today primarily from the standpoint of the technological power it attains. In art the primary task of discovering harmony is by no means always identifiable, because it is aimed at creating consumer-oriented esthetic values. Science and art have sharply parted company in pursuit of their utilitarian functions, and this interferes with seeing their basic unity. There float to the surface such secondary phenomena as the fruitfulness of a scientist's efforts in one or another sphere of art, whether it be amateur creativity, deep involvement in esthetic values, or the study of art by the methods of science. When they interact thus, science and art appear in such polar roles that no commonality between them is observed at all. (shrink)

Recent results from engineered and natural samples show that the starkly different lipids of archaea and bacteria can form stable hybrid membranes. But if the two types can mix, why don't they? That is, why do most bacteria and all eukaryotes have only typically bacterial lipids, and archaea archaeal lipids? It is suggested here that the reason may lie on the other main component of cellular membranes: membrane proteins, and their close adaptation to the lipids. Archaeal lipids in modern (...) bacteria could suggest that the last universal common ancestor (LUCA) had both lipid types. However, this would imply a rather elaborate evolutionary scenario, while negating simpler alternatives. In light of widespread horizontal gene transfer across the prokaryotic domains, hybrid membranes reveal that the lipid divide did not just occur once at the divergence of archaea and bacteria from LUCA. Instead, it continues to occur actively to this day. Also see the video abstract here https://youtu.be/TdKjxoDAtsg. (shrink)

MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 (...) in the absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds β‐catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia. BioEssays 25:66–71, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

The history of what we call molecular biology today is not just the story of DNA. Molecular biology emerged from and was supported by a multiplicity of widely scattered, differently embedded, and loosely, if at all connected experimental systems for characterizing living beings to the level of biologically relevant macromolecules. By implementing different modes of technical analysis, these systems created a new space of representation in which the central concepts of molecular biology gradually became articulated. The paper describes the establishment (...) of the rat liverin vitro protein synthesis system of Paul Zamecnik and his group a the Collis P. Huntington Memorial Hospital of Harvard University between 1947 and 1952. Insofar as such systems orient the research activity, they may also prove helpful for the orientation of the historian. Experimental systems „have a life of their own. (shrink)

Off and on, of late years, I have studied the history and development of all religions with immense interest as being for me, at least, the most illuminating case histories of the inner life of man. Eugene O Neill writing to M. C. Sparrow, 1929While it is commonly accepted that Eugene O Neill studied Oriental mystical religions and that this study may be detected in some of his less successful experimental plays "(Lazarus Laughed, The Fountain, Marco Millions) "there has not (...) been an effort to consider systematically his immense interest and the influence it had on O Neill s thought and writing. Robinson explores the tension between Occidental and Oriental elements in the playwright s art, examining both the sources of the conflict and its manifestation in selected plays written between 1916 and 1942.Through an examination of O Neill s correspondence, research library, and manuscript materials (some of which have previously been unavailable for study) Robinson is able to reveal the origins of O Neill s Orientalism. An easy familiarity with the complex interrelationships of Eastern and Western religions and the Oriental thought that underlies the ideas of many Western philosophers, allows Robinson to address the intricate problem of Oriental influences on O Neill s favorite Western sources, including Nietzsche, Schopenhauer, Jung, Strindberg, and Emerson.Finally in a play-by-play exegesis, Robinson traces the course of O Neill s mysticism from its apparent repudiation in the deeply flawed "Dynamo "to its synthesis in "The Iceman Cometh, Long Day s Journey Into Night, "and "Hughie, "where Eastern ideas of "maya, "dynamic polarity, and the emptiness of the universe are again evident.". (shrink)