The export of processed RNA molecules from the nucleus is an intricately regulated process, subject to various developmental and physiological controls. The structural and biochemical properties of the nuclear envelope that are involved in this process are described here.

Abstract3′ untranslated regions (3′ UTRs) of mRNAs have many functions, including mRNA processing and transport, translational regulation, and mRNA degradation and stability. These different functions require cis‐elements in 3′ UTRs that can be either sequence motifs or RNA structures. Here we review the role of secondary structures in the functioning of 3′ UTRs and discuss some of the trans‐acting factors that interact with these secondary structures in eukaryotic organisms. We propose potential participation of 3′‐UTR secondary structures in (...) cytoplasmic polyadenylation in the model organism Drosophila melanogaster. Because the secondary structures of 3′ UTRs are essential for post‐transcriptional regulation of gene expression, their disruption leads to a wide range of disorders, including cancer and cardiovascular diseases. Trans‐acting factors, such as STAU1 and nucleolin, which interact with 3′‐UTR secondary structures of target transcripts, influence the pathogenesis of neurodegenerative diseases and tumor metastasis, suggesting that they are possible therapeutic targets. (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)

Cytoplasmic messenger ribonucleoprotein particles (mRNPs) represent the cellular transcriptome, and recent data have challenged our current understanding of their architecture, transport, and complexity before translation. Pre‐translational mRNPs are composed of a single transcript, whereas P‐bodies and stress granules are condensates. Both pre‐translational mRNPs and actively translating mRNPs seem to adopt a linear rather than a closed‐loop configuration. Moreover, assembly of pre‐translational mRNPs in physical RNA regulons is an unlikely event, and co‐regulated translation may occur locally following extracellular cues. We (...) envisage a stochastic mRNP transport mechanism where translational repression of single mRNPs—in combination with microtubule‐mediated cytoplasmic streaming and docking events—are prerequisites for local translation, rather than direct transport. (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 noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P‐TEFb. Release of P‐TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P‐TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene expression programs (...) that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA‐binding proteins. Some of these novel 7SK subcomplexes exert non‐canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine‐tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi‐functional RNA scaffold that is integral for neuron homeostasis. (shrink)

In many mammalian cell types, increases in the level of nonpolymerized tubulin cause an inhibition in tubulin synthesis which is accompanied by a decrease in tubulin mRNA levels. To see whether inhibition is caused by nuclear or cytoplasmic events, two groups have recently examined the ability of enucleated cells to autoregulate tubulin synthesis.1,2 These experiments have demonstrated that transcription, processing, and transport of tubulin mRNAs from the nucleus to the cytoplasm are not major sites of autoregulation. Instead, monomeric (...) tubulin must reduce, either directly or indirectly, the translatability of its own message. (shrink)

When rates of transcription from specific genes change, delays of variable length intervene before the corresponding mRNAs and proteins attain new levels. For most mammalian genes, the time required to complete transcription, processing, and transport of mRNA is much shorter than the period needed to achieve a new, steady‐state level of protein. Studies of inducible genes have shown that the period required to attain new levels of individual mRNAs and proteins is related to their unique half‐lives. The basis (...) for this is a physical principle that predicts rates of accumulation of particles in compartmental systems. The minimum period required to achieve a new level is directly proportional to product half‐lives because rates of decay control the ratio between the rate of synthesis and the concentration of gene products at steady state. This kinetic model suggests that sensitivity of gene products to degradation by ribonucleases and proteinases is an important determinant of the time scale of gene expression. (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 multistep pathway of eukaryotic gene expression involves a series of highly regulated events in the nucleus and cytoplasm. In the nucleus, genes are transcribed into pre‐messenger RNAs which undergo a series of nuclear processing steps. Mature mRNAs are then transported to the cytoplasm, where they are translated into protein and degraded at a rate dictated by transcript‐ and cell‐type‐specific cues. Until recently, these individual nuclear and cytoplasmic events were thought to be primarily regulated by different RNA‐ and DNA‐binding proteins (...) that are localized either only in the nucleus or only the cytoplasm. Here, we describe multifunctional proteins that control both nuclear and cytoplasmic steps of gene expression. One such class of multifunctional proteins (e.g., Bicoid and Y‐box proteins) regulates both transcription and translation whereas another class (e.g., Sex‐lethal) regulates both nuclear RNA processing and translation. Other events controlled by multifunctional proteins include assembly of spliceosome components, spliceosome recycling, RNA editing, cytoplasmic mRNA localization, and cytoplasmic RNA stability. The existence of multifunctional proteins may explain the paradoxical involvement of the nucleus in an RNA surveillance pathway (nonsense‐mediated decay) that detects cytoplasmic signals (premature termination codons). We speculate that shuttling multifunctional proteins serve to efficiently link RNA metabolism in the cytoplasmic and nuclear compartments. BioEssays 23:775–787, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

This article describes the discovery of nuclear DNA‐like RNA (dRNA or hnRNA) and ribonucleoprotein particles in eukaryotes. Native hnRNA particles were isolated by sucrose gradient sedimentation and their structural organisation – nucleic acid (i.e. RNA) wrapped in a regular way on the surface of a series of globular protein particles – was determined. This led to the formulation of the informofer cycle hypothesis for the synthesis of hnRNA as a giant precursor molecule, its transport in informosomes within the nucleus, (...) and subsequent splicing before export from the nucleus as free mRNA. (shrink)

Ribosome biogenesis includes the making and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins from their mRNAs in the cytosol and their transport to the nucleolus to assemble pre‐ribosomal particles. Several stresses including cellular senescence reduce nucleolar rRNA synthesis and maturation increasing the availability of ribosome‐free ribosomal proteins. Several ribosomal proteins can activate the p53 tumor suppressor pathway but cells without p53 can still arrest their proliferation in response to an imbalance between ribosomal proteins and mature rRNA production. (...) Recent results on senescence‐associated ribogenesis defects (SARD) show that the ribosomal protein S14 (RPS14 or uS11) can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression. This work offers new insights into the regulation of the cell cycle and suggests novel avenues to design anticancer drugs. (shrink)

Members of the serine/arginine (SR)‐rich protein family of splicing factors play versatile roles in RNA processing steps and are often essential for normal development. Dynamic changes in RNA processing and turnover allow fast cellular adaptions to a changing microenvironment and thereby closely cooperate with transcription factor networks that establish cell identity within tissues. SR proteins play fundamental roles in the processing of pre‐mRNAs by regulating constitutive and alternative splicing. More recently, SR proteins have also been implicated in other aspects of (...) RNA metabolism such as mRNA stability, transport and translation. The‐ emerging noncanonical functions highlight the multifaceted functions of these SR proteins and identify them as important coordinators of gene expression programmes. Accordingly, most SR proteins are essential for normal cell function and their misregulation contributes to human diseases such as cancer. (shrink)

Asymmetric RNA localization is required for many developmental processes in a wide range of organisms. For example, wingless and pair‐rule transcripts are localized to the apical membrane of polarized cells. It has been unclear, however, if this localization is important for biological activity and, in addition, how the transcripts are transported. Two recent studies(1,2) have identified cis‐elements and trans‐acting factors that are required for the asymmetric localization of mRNAs. Correct localization is shown to be required for biological activity, and a (...) mechanism of RNA transport involving the microtubule motor dynein has been revealed. BioEssays 23:869–872, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Neuronal signalling involves multiple neuropeptides that are diverse in structure and function. Complex patterns of tissue‐specific expression arise from alternate RNA splicing of neuropeptide‐encoding gene transcripts. The pattern of expression and its role in cell signalling is diffecult to study at the level of single neurons in the complex vertebrate brain. However, in the model molluscan system, Lymnaea, it is possible to show that alternate mRNA expression of the FMRFamide gene is specific to single identified neurons. Two different transcripts (...) are expressed in a mutually exclusive manner in different neurons. Post‐translational processing of the two precursor proteins leads to completely distinct sets of neuropeptide transmitters. The function of these transmitter cocktails, resulting from alternate mRNA splicing, was studied physiologically in identified neurons forming part of a behaviourally important network regulating heartbeat. (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.

Six years ago, the Singer lab published a landmark paper which described how individual mRNA particles cross the nuclear pore complex in mammalian tissue culture cells. This involved the simultaneous imaging of mRNAs, each labeled by a large number of tethered fluorescent proteins and fluorescently tagged nuclear pore components. Now two groups have applied this technique to the budding yeast Saccharomyces cerevisiae. Their results indicate that in the course of nuclear export, mRNAs likely engage complexes that are present on (...) either side of the pore and that these interactions are modulated by proteins present in the messenger ribonucleoprotein (mRNP) complex. These findings lend support to the notion that just before and/or after the completion of nuclear export, mRNPs undergo one or more maturation steps that prepare the packaged mRNAs for translation. These results represent new and exciting insights into the mechanism of mRNA nuclear export. (shrink)

Nuclear pre‐mRNAs must be precisely processed to give rise to mature cytoplasmic mRNAs. This maturation process, known as splicing, involves excision of intron sequences and ligation of the exon sequences. One of the major problems in understanding this process is how splice sites, the sequences which form the boundaries between introns and exons, can be accurately selected. A number of studies have defined conserved sequences within introns which were later shown to interact with small nuclear ribonucleoproteins (snRNPs). However, due to (...) the simplicity of these conserved sequences it has become clear that other elements must be involved and a number of studies have indicated the importance of secondary structures within pre‐mRNAs. Using various examples, we shall show that such structures can help to specify splice sites by modifying physical distances within introns or by being involved in the definition of exons and, lastly, that they can be part of the regulation of alternative splicing. (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)

Messenger RNA is a flexible tool box that plays a key role in the dynamic regulation of gene expression. RNA modifications variegate the message conveyed by the mRNA. Similar to DNA and histone modifications, mRNA modifications are reversible and play a key role in the regulation of molecular events. Our understanding about the landscape of RNA modifications is still rudimentary in contrast to DNA and histone modifications. The major obstacle has been the lack of sensitive detection methods since (...) they are non-editing events. However, with the advent of next-generation sequencing techniques, RNA modifications are being identified precisely at single nucleotide resolution. In recent years, methylation at the N6 position of adenine has gained the attention of RNA biologists. The m6A modification has a set of writers, erasers, and readers. Here, we provide a summary of interesting facts, conflicting findings, and recent advances in the technical and functional aspects of the m6A epitranscriptome. The recent outburst of studies has brought the key role of mRNA N6-methyladenosine modification in post-transcriptional processing steps into the limelight. This review summarizes the current progress and the future prospective of m6A methylome. We addressed the debatable function of m6A modification and related modifiers in tumorigenesis and tumor progression. (shrink)

The essential biological processes that sustain life are catalyzed by protein nano-engines, which maintain living systems in far-from-equilibrium ordered states. To investigate energetic processes in proteins, we have analyzed the system of generalized Davydov equations that govern the quantum dynamics of multiple amide I exciton quanta propagating along the hydrogen-bonded peptide groups in α-helices. Computational simulations have confirmed the generation of moving Davydov solitons by applied pulses of amide I energy for protein α-helices of varying length. The stability and mobility (...) of these solitons depended on the uniformity of dipole-dipole coupling between amide I oscillators, and the isotropy of the exciton-phonon interaction. Davydov solitons were also able to quantum tunnel through massive barriers, or to quantum interfere at collision sites. The results presented here support a nontrivial role of quantum effects in biological systems that lies beyond the mechanistic support of covalent bonds as binding agents of macromolecular structures. Quantum tunneling and interference of Davydov solitons provide catalytically active macromolecular protein complexes with a physical mechanism allowing highly efficient transport, delivery, and utilization of free energy, besides the evolutionary mandate of biological order that supports the existence of such genuine quantum phenomena, and may indeed demarcate the quantum boundaries of life. (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)

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)

The genetic code is a set of instructions that determine how the information in our genetic material is translated into amino acids. In general, it is universal for all organisms, from viruses and bacteria to humans. However, in the last few decades, exceptions to this rule have been identified both in pro‐ and eukaryotes. In this review, we discuss the 16 described alternative eukaryotic nuclear genetic codes and observe theories of their appearance in evolution. We consider possible molecular mechanisms that (...) allow codon reassignment. Most reassignments in nuclear genetic codes are observed for stop codons. Moreover, in several organisms, stop codons can simultaneously encode amino acids and serve as termination signals. In this case, the meaning of the codon is determined by the additional factors besides the triplets. A comprehensive review of various non‐standard coding events in the nuclear genomes provides a new insight into the translation mechanism in eukaryotes. (shrink)

The Gram-negative outer membrane is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals (...) the existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries. (shrink)

Eukaryotic gene expression is extensively controlled at the level of mRNA stability and the mechanisms underlying this regulation are markedly different from their archaeal and bacterial counterparts. We propose that two such mechanisms, nonsense‐mediated decay (NMD) and motif‐specific transcript destabilization by CCCH‐type zinc finger RNA‐binding proteins, originated as a part of cellular defense against RNA pathogens. These branches of the mRNA turnover pathway might have been used by primeval eukaryotes alongside RNA interference to distinguish their own messages from (...) those of RNA viruses and retrotransposable elements. We further hypothesize that the subsequent advent of “professional” innate and adaptive immunity systems allowed NMD and the motif‐triggered mechanisms to be efficiently repurposed for regulation of endogenous cellular transcripts. This scenario explains the rapid emergence of archetypical mRNA destabilization pathways in eukaryotes and argues that other aspects of post‐transcriptional gene regulation in this lineage might have been derived through a similar exaptation route. -/- . (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)

Defined as the ability to understand and share others' feelings and suffering, empathy seems to come naturally to mind when we consider Simone Weil's life and works. If this concept doesn't explicitly appear in her writings, "pity", "sympathy" and "compassion" are pervasive: the purpose of this paper is to demonstrate how these notions converge on the contemporary understanding of "empathy". Since the turn of the century, this concept has known such a development that it has become difficult to clearly identify (...) its object, and to appreciate its ethical value. To study Simone Weil's works from the angle of empathy offers both a new approach of the concept, and a very relevant point of view to put in light the great continuity between all the fields of the philosopher's thought. Our main hypothesis is that the weilian theory of empathy is based on the idea of "transposition", a process that allows someone to transport himself into another person, and from the natural to the supernatural dimension. It is in this last dimension that Simone Weil can found intersubjectivity, and solve the ethical problem of empathy: the right distance between the Self and the Other. (shrink)

The expression of certain eukaryotic genes is – at least in part – controlled at the level of mRNA translation. The step of translational initiation represents the primary target for regulation. The regulation of the intracellular iron storage protein ferritin in response to iron levels provides a good example of translational control by a reversible RNA/protein interaction in the 5' untranslated region of an mRNA. We consider mechanisms by which mRNA/protein interactions may impede translation initiation and discuss (...) recent data suggesting that the ferritin example may represent the ‘tip of the iceberg’ of a more general theme for translational control. (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)

Despite a library full of literature on miRNA biology, core issues relating to miRNA target detection, biological effect, and mode of action remain controversial. This essay proposes that the predominant mechanism of direct miRNA action is translational inhibition, whereas the bulk of miRNA effects are mRNA based. It explores several issues confounding miRNA target detection, and discusses their impact on the dominance of “miRNA seed” dogma and the exploration of non‐canonical binding sites. Finally, it makes comparisons between miRNA target (...) prediction and transcription factor binding prediction, and questions the value of characterizing miRNA binding sites based on which miRNA nucleotides are paired with an mRNA. (shrink)

A recently developed formalism which gives a unified picture of the linear transport of moving frames is extended to include a particular type of transport under the 10-parameter Poincaré group. The frame coordinates are expressed in a 5 × 5 matrix representation which includes the position four-vector plus orthonormal tetrads for the internal coordinates. This provides a general description of the kinematics of physical systems which can be represented by moving frames. Several examples are given, including systems moving (...) with spin and Zitterbewegung along both timelike and null paths. The concept of boost or Poincaré momentum is related to system kinematics. Lagrangians of these systems are also discussed. (shrink)

The transport of molecules across the nuclear envelope plays a central role in the metabolism of the cell. Significant advances hi three major areas highlight the limits of our current knowledge and point to the prospect of exciting future developments. Firstly, findings that ions and small proteins do not diffuse freely into the nucleus call into question the current views of nuclear envelope permeability. Secondly, indications that nuclear protein import can be regulated in conjunction with the cell cycle and (...) development have been confirmed by the clear demonstration of regulated nuclear entry of specific transcription factors and morphogens. Thirdly, identification and characterisation of candidate receptor proteins indicates that the recognition of the nuclear targeting sequence occurs in the cytoplasm, suggesting that a different recognition event occurs at the nuclear pore. (shrink)

The nomination of candidate genes underlying complex traits is often focused on genetic variations that alter mRNA abundance or result in non‐conservative changes in amino acids. Although inconspicuous in complex trait analysis, genetic variants that affect splicing or RNA editing can also generate proteomic diversity and impact genetic traits. Indeed, it is known that splicing and RNA editing modulate several traits in humans and model organisms. Using high‐throughput RNA sequencing (RNA‐seq) analysis, it is now possible to integrate the genetics (...) of transcript abundance, alternative splicing (AS) and editing with the analysis of complex traits. We recently demonstrated that both AS and mRNA editing are modulated by genetic and environmental factors, and potentially engender phenotypic diversity in a genetically segregating mouse population. Therefore, the analysis of splicing and RNA editing can expand not only the regulatory landscape of transcriptome and proteome complexity, but also the repertoire of candidate genes for complex traits. (shrink)

In recent years, philosophical examinations of automated vehicles have progressed far beyond initial concerns over the ethical decisions that pertain to programming in the event of a crash. In turn, this paper moves in that direction, focusing on the motivations behind efforts to implement driverless vehicles into urban settings. The author argues that the many perceived benefits of these technologies yield a received view of automated vehicles. This position holds that driverless vehicles can solve most if not all urban mobility (...) issues. However, the problem with such an outlook is that it lends itself to transportation planning for automated vehicles, rather than using them as part of planning efforts that could serve urban mobility. Due to this condition, present efforts aimed at improving transportation systems should resist dogmatic thinking. Instead, they should focus on goals that keep topics such a human flourishing, sustainability, and transportation justice firmly in view. (shrink)

The complex spectral representation of the Liouville operator introduced by Prigogine and others is applied to moderately dense gases interacting through hard-core potentials in arbitrary d-dimensional spaces. Kinetic equations near equilibrium are constructed in each subspace as introduced in the spectral decomposition for collective, renormalized reduced distribution functions. Our renormalization is a nonequilibrium effect, as the renormalization effect disappears at equilibrium. It is remarkable that our renormalized functions strictly obey well-defined Markovian kinetic equations for all d, even though the ordinary (...) distribution functions obey nonMarkovian equations with memory effects. One can now define transport coefficients associated to the collective modes for all dimensional systems including d = 2. Our formulation hence provides a microscopic meaning of the macroscopic transport theory. Moreover, this gives an answer to the long-standing question whether or not transport equations exist in two-dimensional systems. The non-Markovian effects for the ordinary distribution function, such as the long-time tails for arbitrary n-mode coupling, are estimated by superposition of the Markovian evolutions of the dressed distribution functions. (shrink)

Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum‐Golgi intermediate compartment (ERGIC). These membranous vesicular‐tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII‐coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI‐dependent transport on to the cis‐Golgi. The mechanisms underlying (...) formation and maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk‐fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC. -/- . (shrink)

Jonathan A. Oler,1,4 Andrew S. Fox,2,5 Steven E. Shelton,1,4 Bradley T. Christian, 1,3,5 Dhanabalan Murali,3,5 Terrence R. Oakes,5 Richard J. Davidson,1,2,4,5 and Ned H. Kalin1,2,4,5..