The assembly of the major small nuclear ribonucleoprotein (snRNP)d̊ particles begins in the cytoplasm where large pools of common core proteins are preassembled in several RNA‐free intermediate particles. Newly synthesized snRNAs transiently enter the cytoplasm and complex with core particles to form pre‐snRNP particles. Subsequently, the cap structure at the 5/end of the snRNA is hypermethylated. The Resulting trimethylguanosine (TMG) cap is an integral part of the nuclear localization signal for snRNP particles and the pre‐snRNP particles are rapidly transported into (...) the nucleus. SnRNP particles mature when snRNA‐specific proteins complex with the particles, in some cases, just before or during nuclear transport, but in most instances after the particles are in the nucleus. In addition, U6 snRNA hybridizes with U4 snRNA to form a U4/U6 snRNP in the nucleus. The transport signals are retained on the snRNP particles and proteins since existing particles and proteins enter the reformed nucleus after mitosis. (shrink)

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

Intracellular pH (pHi) regulation is a homeostatic function of all cells. Additionally, the plasma membrane‐based transporters controlling pHi are involved in growth factor activation, cell proliferation and salt transport – all processes active in early embryos. pHi regulation in the early embryos of many species exhibits unique features: in mouse preimplantation embryos, mechanisms for correcting excess acid apparently are inactive, while excess base is removed by the mechanism common in differentiated cells. Additionally, unlike differentiated cells, mouse preimplantation embryos (...) are highly permeable to H+ until the blastocyst stage, where the epithelial cells surrounding the embryo are impermeable. In several non‐mammalian species, of which the best‐studied is sea urchin, cytoplasmic alkalinization at fertilization is necessary for development of the embryo, and elevated pHi must be maintained during early development. Thus, pHi regulatory mechanisms appear to be important for early embryo development in many species. (shrink)

Adenosine transport in cultured human umbilical vein endothelial cells (HUVEC) was characterized and shown to be mediated by a single facilitated diffusion mechanism. Initial rates of adenosine influx at 22 degrees C were saturable [apparent Michaelis constant, 69 +/- 10 mu M; maximum velocity (V-max), 600 +/- 70 pmol.10(6) cells(-1).s(-1)] and inhibited by nitrobenzylthioinosine (NBMPR). Formycin B had an unusually high affinity [inhibitory constant K-i), 18 +/- 4.3 mu M], whereas inosine had a low affinity (K-i, 440 +/- 68 (...) mu M) and nucleobases were without effect on adenosine influx. The number of transporters (1.2 x 10(6) sites/cell) was estimated by NBMPR equilibrium binding (apparent dissociation constant, 0.11 +/- 0.01 nM; maximum binding, 2.0 +/- 0.15 pmol/10(6) cells). In addition, we compared these endothelial cells with those obtained from cords from pregnancies complicated by diabetes (HUVEC-D), since embriopathy may occur in these conditions. HUVEC-D exhibited a 2.3-fold reduction in both the V-max for adenosine influx and the maximum number of NBMPR binding sites (260 +/- 40 pmol.10(6) cells(-1).s(-1) and 0.86 +/- 0.08 pmol/10(6) cells, respectively). However, the turnover number for each nucleoside transporter in normal and diabetic HUVEC was similar (approximate to 300 adenosine molecules/s). Adenosine metabolism at 10 mu M in HUVEC-D was modified compared with normal cells. Intracellular phosphorylation (> 90%) was the predominant pathway in normal HUVEC, whereas in HUVEC-D, substantial levels of adenine and adenosine were detected. The present results demonstrate therefore the downregulation of the NBMPR-sensitive nucleoside transporter and changes in adenosine metabolism in HUVEC from diabetic pregnancies. (shrink)

A tight control of intracellular [Ca2+\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{2+}$$\end{document}] is essential for the survival and normal function of cells. In this study we investigate key mechanistic steps by which calcium is regulated and calcium oscillations could occur using in silico modeling of membrane transporters. To do so we give a deterministic description of intracellular Ca2+\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{2+}$$\end{document} dynamics using nonlinear dynamics in order to understand Ca2+\documentclass[12pt]{minimal} (...) \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{2+}$$\end{document} signaling. We first present the ordinary differential equations system for cell calcium kinetics and make a preliminary work on Sobol indices. We then describe and analyze complex transporters action. Besides, we analyze the whole system. We finally perform numerical simulations and compare our results to real data. (shrink)

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

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of (...) SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. (shrink)

Endosomes shuttle select cargoes between cellular compartments and, in doing so, maintain intracellular homeostasis and enable interactions with the extracellular space. Directionality of endosomal transport critically impinges on cargo fate, as retrograde (microtubule minus‐end directed) traffic delivers vesicle contents to the lysosome for proteolysis, while the opposing anterograde (plus‐end directed) movement promotes recycling and secretion. Intriguingly, the endoplasmic reticulum (ER) is emerging as a key player in spatiotemporal control of late endosome and lysosome transport, through the establishment (...) of physical contacts with these organelles. Earlier studies have described how minus‐end‐directed motor proteins become discharged from vesicles engaged at such contact sites. Now, Raiborg et al. implicate ER‐mediated interactions, induced by protrudin, in loading plus‐end‐directed motor kinesin‐1 onto endosomes, thereby stimulating their transport toward the cell's periphery. In this review, we recast the prevailing concepts on bidirectional late endosome transport and discuss the emerging paradigm of inter‐compartmental regulation from the ER‐endosome interface viewpoint. (shrink)

Regulation of the subcellular localization of certain proteins is a mechanism for the regulation of their biological activities. FGF‐2 can be produced as distinct isoforms by alternative initiation of translation on a single mRNA and the isoforms are differently sorted in cells. High molecular weight FGF‐2 isoforms are not secreted from the cell, but are transported to the nucleus where they regulate cell growth or behavior in an intracrine fashion. 18 kDa FGF‐2 can be secreted to the extracellular medium where (...) it acts as a conventional growth factor by binding to and activation of cell‐surface receptors. Furthermore, following receptor‐mediated endocytosis, the exogenous FGF‐2 can be transported to the nuclei of target cells, and this is of importance for the transmittance of a mitogenic signal. The growth factor is able to interact with several intracellular proteins. Here, the mode of action and biological role of intracellular FGF‐2 are discussed. BioEssays 28: 504–514, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Regulation of the subcellular localization of certain proteins is a mechanism for the regulation of their biological activities. FGF‐2 can be produced as distinct isoforms by alternative initiation of translation on a single mRNA and the isoforms are differently sorted in cells. High molecular weight FGF‐2 isoforms are not secreted from the cell, but are transported to the nucleus where they regulate cell growth or behavior in an intracrine fashion. 18 kDa FGF‐2 can be secreted to the extracellular medium where (...) it acts as a conventional growth factor by binding to and activation of cell‐surface receptors. Furthermore, following receptor‐mediated endocytosis, the exogenous FGF‐2 can be transported to the nuclei of target cells, and this is of importance for the transmittance of a mitogenic signal. The growth factor is able to interact with several intracellular proteins. Here, the mode of action and biological role of intracellular FGF‐2 are discussed. BioEssays 28: 504–514, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The cellular machinery responsible for conveying proteins between the endoplasmic reticulum and the Golgi is being investigated using genetics and biochemistry. A role for vesicles in mediating protein traffic between the ER and the Golgi has been established by characterizing yeast mutants defective in this process, and by using recently developed cell‐free assays that measure ER to Golgi transport. These tools have also allowed the identification of several proteins crucial to intracellular protein trafficking. The characterization and possible functions (...) of several GTP‐binding proteins, peripheral membrane proteins, and an integral membrane protein during ER to Golgi transport are discussed here. (shrink)

The acidic (leucine‐rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N‐terminal leucine‐rich repeat domain and a C‐terminal low‐complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having (...) a whip‐like structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context‐dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities. (shrink)

The rate‐limiting step in the uptake and metabolism of Dglucose by insulin target cells is thought to be glucose transport mediated by glucose transporters (primarily the GLUT4 isoform) localized to the plasma membrane. However, subcellular fractionation, photolabelling and immunocytochemical studies have shown that the pool of GLUT4 present in the plasma membrane is only one of many subcellular pools of this protein. GLUT4 has been found in occluded vesicles at the plasma membrane, clathrin‐coated pits and vesicles, early endosomes, and (...) tubulo‐vesicular structures; the latter are analogous to known specialized secretory compartments. Tracking the movement of GLUT4 through these compartments, and defining the mechanism and site of action of insulin in stimulating this subcellular trafficking, are major topics of current investigation. Recent evidence focuses attention on the exocytosis of GLUT4 as the major site of insulin action. Increased exocytosis may be due to decreased retention of glucose transporters in an intracellular pool, or possibly to increased assembly of a vesicle docking and fusion complex. Although details are unknown, the presence in GLUT4 vesicles of a synaptobrevin homologue leads us to propose that a process analogous to that occurring in synaptic vesicle trafficking is involved in the assembly of GLUT4 vesicles into a form suitable for fusion with the plasma membrane. Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3‐kinase, is discussed. (shrink)

The subcellular location and function of many proteins are regulated by nuclear–cytoplasmic shuttling. BRCA1 and BARD1 provide an interesting model system for understanding the influence of protein dimerization on nuclear transport and localization. These proteins function predominantly in the nucleus to regulate cell cycle progression, DNA repair/recombination and gene transcription, and their export to the cytoplasm has been linked to apoptosis. Germ‐line mutations in the BRCA1/BRCA2 and BARD1 genes predispose to risk of breast/ovarian cancer, and certain mutations impair protein (...) function and nuclear accumulation. BRCA1 and BARD1 shuttle between the nucleus and cytoplasm; however heterodimerization masks the nuclear export signals located within each protein, causing nuclear retention of the BRCA1–BARD1 complex and potentially influencing its role in DNA repair, cell survival and regulation of centrosome duplication. This review discusses BRCA1, BRCA2 and BARD1 subcellular localization with emphasis on regulation of transport by protein dimerization and its functional implications. BioEssays 27:884–893, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

It has become customary to conceptualize the living cell as an intricate piece of machinery, different to a man-made machine only in terms of its superior complexity. This familiar understanding grounds the conviction that a cell's organization can be explained reductionistically, as well as the idea that its molecular pathways can be construed as deterministic circuits. The machine conception of the cell owes a great deal of its success to the methods traditionally used in molecular biology. However, the recent introduction (...) of novel experimental techniques capable of tracking individual molecules within cells in real time is leading to the rapid accumulation of data that are inconsistent with an engineering view of the cell. This paper examines four major domains of current research in which the challenges to the machine conception of the cell are particularly pronounced: cellular architecture, protein complexes, intracellular transport, and cellular behaviour. It argues that a new theoretical understanding of the cell is emerging from the study of these phenomena which emphasizes the dynamic, self-organizing nature of its constitution, the fluidity and plasticity of its components, and the stochasticity and non-linearity of its underlying processes. (shrink)

The cytoskeleton has a central role in eukaryotic biology, enabling cells to organize internally, polarize, and translocate. Studying cytoskeletal machinery across the tree of life can identify common elements, illuminate fundamental mechanisms, and provide insight into processes specific to less‐characterized organisms. Red algae represent an ancient lineage that is diverse, ecologically significant, and biomedically relevant. Recent genomic analysis shows that red algae have a surprising paucity of cytoskeletal elements, particularly molecular motors. Here, we review the genomic and cell biological evidence (...) and propose testable models of how red algal cells might perform processes including cell motility, cytokinesis, intracellular transport, and secretion, given their reduced cytoskeletons. In addition to enhancing understanding of red algae and lineages that evolved from red algal endosymbioses (e.g., apicomplexan parasites), these ideas may also provide insight into cytoskeletal processes in animal cells. (shrink)

Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic αβ chains associated with invariant CD3‐γδε components and ζ chains, collectively referred to as the T cell antigen receptor complex (TCR). Expression of the TCR complex is dynamically regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of αβ TCR complexes on their surfaces expressed by mature CD4+ and CD8+ T cells. Recent (...) evidence demonstrates that low surface TCR density on CD4+CD8+ thymocytes results from the limited survival of a single TCR component within the ER, the TCRα chain, which has a half life of only 15 minutes in immature thymocytes, compared to >75 minutes in mature T cells. Instability of TCRα proteins in immature CD4+CD8+ thymocytes represents a novel mechanism by which expression of the multisubunit TCR complex is quantitatively regulated during T cell development. In the current review we discuss our recent findings concerning the assembly, intracellular transport, and expression of αβ TCR complexes in CD4+CD8+ thymocytes and comment on the functional significance of TCRα instability during T cell development. (shrink)

Many pigmented heterokonts are able to synthesize elements of their cell walls (the frustules) of dense biogenic silica. These include diatom algae, which occupy a significant place in the biosphere. The siliceous frustules of diatoms have species‐specific patterns of surface structures between 10 and a few hundred nanometers. The present review considers possible mechanisms of uptake of silicic acid from the aquatic environment, its transport across the plasmalemma, and intracellular transport and deposition of silica inside the specialized (...) Silica Deposition Vesicle (SDV) where elements of the new frustule are formed. It is proposed that a complex of silicic acid with positively charged proteins silaffins and polypropylamines remains a homogeneous solution during the intracellular transport to SDV, where biogenic silica precipitates. The high density of the deposited biogenic silica may be due to removal of water from the SDV by aquaporins followed by syneresis—a process during which pore water is expelled from the network of the contracting gel. The pattern of aquaporins in the silicalemma, the membrane embracing the SDV, can determine the pattern of species‐specific siliceous nanostructures. BioEssays 30:328–337, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Microtubules are protein cylinders with functions in cell motility, signal sensing, cell organization, intracellular transport, and chromosome segregation. One of the key properties of microtubules is their dynamic architecture, allowing them to grow and shrink in length by adding or removing copies of their basic subunit, the heterodimer αβ‐tubulin. In higher eukaryotes, de novo assembly of microtubules from αβ‐tubulin is initiated by a 2 MDa multi‐subunit complex, the gamma‐tubulin ring complex (γ‐TuRC). For many years, the structure of the (...) γ‐TuRC and the function of its subunits remained enigmatic, although structural data from the much simpler yeast counterpart, the γ‐tubulin small complex (γ‐TuSC), were available. Two recent breakthroughs in the field, high‐resolution structural analysis and recombinant reconstitution of the complex, have revolutionized our knowledge about the architecture and function of the γ‐TuRC and will form the basis for addressing outstanding questions about biogenesis and regulation of this essential microtubule organizer. (shrink)

The cellular processes of transport, division and, possibly, early development all involve microtubule‐based motors. Recent work shows that, unexpectedly, many of these cellular functions are carried out by different types of kinesin and kinesin‐related motor proteins. The kinesin proteins are a large and rapidly growing family of microtubule‐motor proteins that share a 340‐amino‐acid motor domain. Phylogenetic analysis of the conserved motor domains groups the kinesin proteins into a number of subfamilies, the members of which exhibit a common molecular organization (...) and related functions. The kinesin proteins that belong to different subfamilies differ in their rates and polarity of movement along microtubules, and probably in the particles/organelles that they transport. The kinesins arose early in eukaryotic evolution and gene duplication has allowed functional specialization to occur, resulting in a surprisingly large number of different classes of these proteins adapted for intracellular transport of vesicles and organelles, and for assembly and force generation in the meiotic and mitotic spindles. (shrink)

Imagine cells that live in a high‐gradient magnetic field (HGMF). Through what mechanisms do the cells sense a non‐uniform magnetic field and how such a field changes the cell fate? We show that magnetic forces generated by HGMFs can be comparable to intracellular forces and therefore may be capable of altering the functionality of an individual cell and tissues in unprecedented ways. We identify the cellular effectors of such fields and propose novel routes in cell biology predicting new biological (...) effects such as magnetic control of cell‐to‐cell communication and vesicle transport, magnetic control of intracellular ROS levels, magnetically induced differentiation of stem cells, magnetically assisted cell division, or prevention of cells from dividing. On the basis of experimental facts and theoretical modeling we reveal timescales of cellular responses to high‐gradient magnetic fields and suggest an explicit dependence of the cell response time on the magnitude of the magnetic field gradient. (shrink)

Carotenoids play pivotal roles in vision as light filters and precursor of chromophore. Many vertebrates also display the colorful pigments as ornaments in bare skin parts and feathers. Proteins involved in the transport and metabolism of these lipids have been identified including class B scavenger receptors and carotenoid cleavage dioxygenases. Recent research implicates members of the Aster protein family, also known as GRAM domain‐containing (GRAMD), in carotenoid metabolism. These multi‐domain proteins facilitate the intracellular movement of carotenoids from their (...) site of cellular uptake by scavenger receptors to the site of their metabolic processing by carotenoid cleavage dioxygenases. We provide a model how the coordinated interplay of these proteins and their differential expression establishes carotenoid distribution patterns and function in tissues, with particular emphasis on the human retina. (shrink)

Parvalbumins (PVs) are acidic, intracellular Ca2+‐binding proteins of low molecular weight. They are associated with several Ca2+‐mediated cellular activities and physiological processes. It has been suggested that PV might function as a “Ca2+ shuttle” transporting Ca2+ from troponin‐C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus, PV may contribute to the performance of rapid, phasic movements by accelerating the contraction–relaxation cycle of fast‐twitch muscle fibers. Interestingly, PVs promote the generation of power stroke in fish by (...) speeding up the rate of relaxation and thus provide impetus to attain maximal sustainable speeds. However, immunological monitoring of diverse tissues demonstrated that PVs are also present in non‐muscle cells. The axoplasmic transport and various intracellular secretory mechanisms including the endocrine secretions seem to be controlled by the Ca2+ regulation machinery. Any defect in the Ca2+ handling apparatus may cause several clinical problems; for instance, PV deficiency alters the neuronal activity, a key mechanism leading to epileptic seizures. Moreover, atypical relaxation of the heart results in diastolic dysfunction, which is a major cause of heart failure predominantly among the aged people. PV may offer a unique potential to correct defective relaxation in energetically compromised failing hearts through PV gene transfer. Consequently, PV gene transfer may present a new therapeutic approach to correct cellular disturbances in Ca2+ signaling pathways of diseased organs. Hence, PVs appear to be amazingly useful candidate proteins regulating a variety of cellular functions through action on Ca2+ flux management. (shrink)

A variety of intracellular motile processes involve the directed movement of particles along microtubules, including organelle transport, endoplasmic reticulum extension, and movements in mitosis. Recently, a microtubule‐dependent motor protein, kinesin, was purified and was found to be present in a soluble form in a wide variety of organisms and tissues. Because microtubules provide polar pathways over long distances within cells, kinesin and the motors which move in the opposite direction to kinesin on microtubules provide a mechanism for directed (...) communications within cells. The possible roles of kinesin and other soluble microtubule‐dependent motors in intracellular motile functions are discussed in the light of recent studies of the reconstitution of organelle motility with isolated components. (shrink)

Inner membranes of mitochondria are extensively folded, forming cristae. The observed overall correlation between efficient eukaryotic ATP generation and the area of internal mitochondrial inner membranes both in unicellular organisms and metazoan tissues seems to explain why they evolved. However, the crucial use of molecular oxygen (O2) as final acceptor of the electron transport chain is still not sufficiently appreciated. O2 was an essential prerequisite for cristae development during early eukaryogenesis and could be the factor allowing cristae retention upon (...) loss of mitochondrial ATP generation. Here I analyze illuminating bacterial and unicellular eukaryotic examples. I also discuss formative influences of intracellular O2 consumption on the evolution of the last eukaryotic common ancestor (LECA). These considerations bring about an explanation for the many genes coming from other organisms than the archaeon and bacterium merging at the start of eukaryogenesis. (shrink)

The human major histocompatibility complex (MHC), on the short arm of chromosome 6, represents one of the most extensively characterised regions of the human genome. This ∼4 Mb segment of DNA contains genes encoding the polymorphic MHC class I and class II molecules which are involved in antigen presentation during an immune response. Recently the whole of the MHC has been cloned in cosmids and/or yeast artificial chromosomes (YACs) and large portions have been characterised for the presence of novel genes. (...) Many unrelated genes, both housekeeping and tissue specific, have been identified and the gene density in some regions is now approaching one gene every few kilobases. Some of the novel genes encode proteins involved in the intracellular processing and transport of antigens that are presented by MHC class I molecules. Others, however, have no obvious role in the immune response. The MHC is located in the chromosome band 6p21.3 which is a Giemsa (G)‐light band. The detection of such a large number of functional genes (at least 70) in this region is compatible with the idea that both housekeeping and tissue‐specific genes are localised predominantly in G‐light bands. (shrink)

Sperm motility and respiration are tightly coupled processes, both activated by an increased intracellular pH (pHi). As the sperm pHi increases, the flagellar motor driving motility is activated, leading to ATP consumption. Energy for motility is provided by mitochondrial respiration; energy transport from sperm mitochondrion to tail involves distinct isozymes of creatine kinase that effect a phosphorylcreatine shuttle. The activation of sperm motility and respiration can be described as a linked series of biochemical reactions that form a cell (...) behavioural pathway analogous to the reaction sequences of intermediary metabolism. (shrink)

Sperm motility and respiration are tightly coupled processes, both activated by an increased intracellular pH (pHi). As the sperm pHi increases, the flagellar motor driving motility is activated, leading to ATP consumption. Energy for motility is provided by mitochondrial respiration; energy transport from sperm mitochondrion to tail involves distinct isozymes of creatine kinase that effect a phosphorylcreatine shuttle. The activation of sperm motility and respiration can be described as a linked series of biochemical reactions that form a cell (...) behavioural pathway analogous to the reaction sequences of intermediary metabolism. (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)

Most of the essential cellular components, like nucleic acids, lipids and sugars, are phosphorylated. The phosphate equilibrium in Escherichia coli is regulated by the phosphate (Pi) input from the surrounding medium. Some 90 proteins are synthesized at an increased rate during Pi starvation and the global control of the cellular metabolism requires cross‐talk with other regulatory mechanisms. Since the Pi concentration is normally low in E. coli's natural habitat, these cells have devised a mechanism for synthesis of about 15 proteins (...) to accomplish two specific functions: transport of Pi and its intracellular regulation. The synthesis of these proteins is controlled by two genes (the phoB‐phoR operon), involving both negative and positive functions. PhoR protein is a histidine protein kinase, induced in Pi starvation and is a transmembrane protein. It phosphorylates the regulator protein PhoB which is also Pi starvation‐induced. The PhoB phosphorylated form binds specifically to a DNA sequence of 18 nucleotides (the pho Box), which is part of the promoters of the Pho genes. The genes controlled by phoB constitute the Pho regulon.The repression of phoA (the gene encoding alkaline phosphatase) by high Pi concentrations in the medium requires the presence of an intact Pst operon (pstS, pstC, pstA, pstB and phoU) and phoR. The products of pstA and pstC are membrane bound, whereas the product of pstS is periplasmic and PstB and PhoU proteins are cytoplasmic. The function of the PhoU protein may be regulated by cofactor nucleotides and may be involved in signaling the activation of the regulon via PhoR. (shrink)

We present here the hypothesis that the unique microenvironmental pH landscape of acid‐base transporting epithelia is an important factor in development of epithelial cancers, by rendering the epithelial and stromal cells pre‐adapted to the heterogeneous extracellular pH (pHe) in the tumor microenvironment. Cells residing in organs with net acid‐base transporting epithelia such as the pancreatic ductal and gastric epithelia are exposed to very different, temporally highly variable pHe values apically and basolaterally. This translates into spatially and temporally non‐uniform intracellular (...) pH (pHi) patterns. Disturbed pHe‐ and pHi‐homeostasis contributes to essentially all hallmarks of cancer. Our hypothesis, that the physiological pHe microenvironment in acid‐base secreting epithelia shapes cancers arising in these tissues, can be tested using novel imaging tools. The acidic tumor pHe in turn might be exploited therapeutically. Pancreatic cancers are used as our prime example, but we propose that this concept is also relevant for other cancers of acid‐base transporting epithelia. (shrink)

The human serum protein α1‐antitrypsin is the major source of antiprotease activity found in the blood. The protein is synthesised primarily by liver cells but, to a lesser extent, by at least one other cell type. Expression of the gene has provided a paradigm for studies on transcriptional regulation in liver and of tissue‐specific promoter activity. The pleiomorphic nature of the gene has given rise to a variety of α1‐antitrypsin variants some of which are clinically important. These abnormal variants may (...) be poorly synthesised, rapidly degraded or inefficiently secreted; studies on the molecular mechanisms which underly these events are providing interesting insights into the general processes of protein transport and intracellular protein degradation. (shrink)

Proteins of the exocytotic (secretory) pathway are initially targeted to the endoplasmic reticulum (ER) and then translocated across and/or inserted into the membrane of the ER. During their anterograde transport with the bulk of the membrane flow along the exocytotic pathway, some proteins are selectively retained in various intracellular compartments, while others are sorted to different branches of the pathway. The signals or structural motifs that are involved in these selective targeting processes are being revealed and investigations into (...) the mechanistic nature of these processes are actively underway. (shrink)

Chloride channels are probably found in every cell, from bacteria to mammals. Their physiological tasks range from cell volume regulation to stabilization of the membrane potential, signal transduction, transepithelial transport and acidification of intracellular organelles. These different functions require the presence of many distinct chloride channels, which are differentially expressed and regulated by various stimuli. These include various intracellular messengers (like calcium and cyclic AMP), pH, extracellular ligands and transmembrane voltage. Three major structural classes of chloride channels (...) are known to date, but there may be others not yet identified. After an overview of the general functions of chloride channels, this review will focus on these cloned chloride channels: the CLC chloride channel family, which includes voltage‐gated chloride channels, and the cystic fibrosis transmembrane regulator (CFTR), which performs other functions in addition to being a chloride channel. Finally, a short section deals with GABA and glycine receptors. Diseases resulting from chloride channel defects will be specially emphasized, together with the somewhat limited information about how these proteins work at the molecular level. (shrink)

NPC1 plays a central role in cholesterol egress from endolysosomes, a critical step for maintaining intracellular cholesterol homeostasis. Despite recent advances in the field, the full repertoire of molecules and pathways involved in this process remains unknown. Emerging evidence suggests the existence of NPC1‐independent, alternative routes. These may involve vesicular and non‐vesicular mechanisms, as well as release of extracellular vesicles. Understanding the underlying molecular mechanisms that bypass NPC1 function could have important implications for the development of therapies for lysosomal (...) storage disorders. Here we discuss how cholesterol may be exported from lysosomes in which NPC1 function is impaired. (shrink)

Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory (...) will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metabolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science. (shrink)

© 2015 Elsevier Inc.Toxoplasma gondii is a protozoan pathogen in the phylum Apicomplexa that resides within an intracellular parasitophorous vacuole that is selectively permeable to small molecules through unidentified mechanisms. We have identified GRA17 as a Toxoplasma-secreted protein that localizes to the parasitophorous vacuole membrane and mediates passive transport of small molecules across the PVM. GRA17 is related to the putative Plasmodium translocon protein EXP2 and conserved across PV-residing Apicomplexa. The PVs of GRA17-deficient parasites have aberrant morphology, reduced (...) permeability to small molecules, and structural instability. GRA17-deficient parasites proliferate slowly and are avirulent in mice. These GRA17-deficient phenotypes are rescued by complementation with Plasmodium EXP2. GRA17 functions synergistically with a related protein, GRA23. Exogenous expression of GRA17 or GRA23 alters the membrane conductance properties of Xenopus oocytes in a manner consistent with a large non-selective pore. Thus, GRA17 and GRA23 provide a molecular basis for PVM permeability and nutrient access. (shrink)

Researchers have identified how in some rapidly developing countries, road and aviation transportation CO2 emissions are rising faster (over time) when compared to the experiences of the USA at similar levels of economic development. While suggestive of how experiences of the rapidly developing Asia are different from those of the developed world these studies have used only one developed country for comparison, the USA, arguably a special case when it comes to transportation. To address this point this research compares the (...) road transportation CO2 experiences of rapidly developing Asian economies (Hong Kong, Japan, Malaysia, Singapore, South Korea, Taiwan and Thailand) with the USA and six other developed economies (Australia, France, the Netherlands, Italy, Sweden and the United Kingdom). The findings confirm previous results, to wit, Asian economies demonstrate faster annual growth of CO2 emissions in comparison to the experiences of the developed world. (shrink)

Due to the environmental and health impact of the private transport sector, social scientists have largely focused on psychosocial and contextual factors associated with people's choice over transport means. This study aims to contribute to this line of research by applying a user-centered approach, with the objective of taking into account the specific environmental and social context of the metropolitan area of Cagliari city. To accomplish this aim, four groups of people were matched according to their shared starting (...) point: car users vs. public transport users, and light-rail users vs. non-light-rail users. Groups were interviewed using a focus group method. Participants were invited to discuss their everyday travel experiences and to exchange their ideas on different sustainable and less sustainable means of transport. Both consolidated drivers/barriers in the field of environmental psychology and public transportation design features have been investigated. Other than highlighting the importance of socio-psychological factors to promote more sustainable transport choices like in previous studies, the present research offers an insight into how these aspects and factors are shaped and experienced in the narratives of residents. (shrink)

Actors, undercover investigators, and readers of fiction sometimes report “losing themselves” in the characters they imitate or read about. They speak of “taking on” or “assuming” the beliefs, thoughts, and feelings of someone else. I offer an account of this strange but familiar phenomenon—what I call imaginative transportation.

Mitochondria exist in large numbers per cell. Therefore, the strength of natural selection on individual mtDNAs for their contribution to cellular fitness is weak whereas the strength of selection in favor of mtDNAs that increase their own replication without regard for cellular functions is strong. This problem has been solved for most mitochondrial genes by their transfer to the nucleus but a few critical genes remain encoded by mtDNA. Organisms manage the evolution of mtDNA to prevent mutational decay of essential (...) services mitochondria provide to their hosts. Bottlenecks of mitochondrial numbers in female germlines increase the homogeneity of mtDNAs within cells and allow intraorganismal selection to eliminate cells with low quality mitochondria. Mechanisms of intracellular “quality control” allow direct selection on the competence of individual mtDNAs. These processes maintain the integrity of mtDNAs within the germline but are inadequate to indefinitely maintain mitochondrial function in somatic cells. (shrink)

This chapter contains sections titled: The Transportation System Transportation System Benefits, Harms and Hazards Conclusions and Further Questions References and Further Reading.

Citrate, an organic trivalent anion, is a major substrate for generation of energy in most cells. It is produced in mitochondria and used either in the Krebs' cycle or released into cytoplasm through a specific mitochondrial carriers. Citrate can also be taken up from blood through different plasma membrane transporters. In the cytoplasm, citrate can be used ultimately for fatty acid synthesis, which is increased in cancer cells. Here, we review the ways in which citrate can be transported and discuss (...) the changes in transport and metabolism that occur in cancer cells. The primary focus is on the prostate gland, which is known to produce and release large amounts of citrate during its normal secretory function. The significant changes that occur in citrate‐related metabolism and transport in prostate cancer are the second focus. This review strives to relate these mechanisms to molecular biology on the one hand and to clinical applications on the other. (shrink)

In Southeast Asian countries (SEA), road transport accounts for the main energy consumption and CO2 emission. Air pollution is a major concern in densely populated cities such as Bangkok, Manila, and Kuala Lumpur. The main objective of this paper is to give insights on trends of transport development, car ownership, and CO2 emissions in Southeast Asia. This study also attempts to review the successful transportation policies around the globe and to introduce the possible instruments that can help reduce (...) air pollution in Southeast Asian countries. Economic instruments to estimate the benefits of a cleaner environment due to new policies are introduced as well. The results of this research could help policy makers consider approaches that could internalize external costs of transportation and maximize the societal welfare. (shrink)

Protection against bacterial and viral pathogens by antibodies has always been thought to end at the cell surface. Once inside the cell, a pathogen was understood to be safe from humoral immunity. However, it has now been found that antibodies can routinely enter cells attached to viral particles and mediate an intracellular immune response. Antibody‐coated virions are detected inside the cell by means of an intracellular antibody receptor, TRIM21, which directs their degradation by recruitment of the ubiquitin‐proteasome system. (...) In this article we assess how this discovery alters our view of the way in which antibodies neutralise viral infection. We also consider the antiviral function of TRIM21 in the context of its other reported roles in immune signalling and autoimmunity. Finally, we discuss the conceptual implications of intracellular antibody immunity and how it alters our view of the discrete separation of extracellular and intracellular environments. (shrink)

Actin performs structural as well as motor‐like functions in eukaryotic cells. Orthologues of actin have also been identified in bacteria, where they perform an essential function during cell growth. Bacterial actins are implicated in the maintenance of rod‐shaped cell morphology, and appear to form a cytoskeletal structure, localising as helical filaments underneath the cell membrane. Recently, a plasmid‐borne actin orthologue has been shown to perform a mitotic‐like function during segregation of a plasmid, and chromosomally encoded actin proteins were found to (...) play an important role in chromosome segregation. Based on the findings that actin filaments are dynamic structures in two bacterial species, we propose that actins perform motor functions rather than a purely structural role in bacteria. We suggest that an intracellular motor exists in bacteria that could be derived from an ancestral actin motor that was present in cells early in evolution. BioEssays 26:1209–1216, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The DNA‐passage activity of topoisomerase II accidentally produces DNA knots and interlinks within and between chromatin fibers. Fortunately, these unwanted DNA entanglements are actively removed by some mechanism. Here we present an outline on DNA knot formation and discuss recent studies that have investigated how intracellular DNA knots are removed. First, although topoisomerase II is able to minimize DNA entanglements in vitro to below equilibrium values, it is unclear whether such capacity performs equally in vivo in chromatinized DNA. Second, (...) DNA supercoiling could bias topoisomerase II to untangle the DNA. However, experimental evidence indicates that transcriptional supercoiling of intracellular DNA boosts knot formation. Last, cohesin and condensin could tighten DNA entanglements via DNA loop extrusion (LE) and force their dissolution by topoisomerase II. Recent observations indicate that condensin activity promotes the removal of DNA knots during interphase and mitosis. This activity might facilitate the spatial organization and dynamics of chromatin. (shrink)

We all know that problems of transportation and allocation appear frequently in practical life. We need to transfer materials from production centers to consumption centers to secure the areas’ need for the transported material or allocate machines or people to do a specific job at the lowest cost, or in the shortest time. We know that the cost factors Time is one of the most important factors that decision-makers care about because it plays an “important” role in many of the (...) practical and scientific issues that we face in our daily lives, and we need careful study to enable us to avoid losses. For this, the linear programming method was used, which is one of the research methods. Processes, where the problem data is converted into a linear mathematical model for which the optimal solution achieves the desired goal. Since these models are linear models, we can solve them using the direct simplex method and its modifications, but the specificity that these models enjoy has enabled scholars and researchers to find special methods that help us in obtaining the optimal solution. Whatever the method used, the goal is to determine the number of units transferred from any material from production centers to consumption centers, or to allocate a machine or person to do a job so that the cost or time is as short as possible. These issues were addressed according to classical logic, but the ideal solution was a specific value appropriate to the conditions in which the data was collected and does not take into account the changes that may occur in the work environment. In order to obtain results that are more accurate and enjoy a margin of freedom, we present in this book a study of transport issues and neutrosophic allocation issues and some methods for solving them. By neutrosophic issues we mean These are the problems in which the data are neutrosophic values, i.e. the required quantities and the available quantities. (shrink)