bluuebunny/crossref_metadata_2025 huggingface dataset:
What's new: To boldly glow…. Applications of laser scanning confocal microscopy in developmental biology
Authors: Paddock Stephen W.
Published: February 2005

The laser scanning confocal microscope (LSCM)

LSCM: laser scanning confocal microscope; FISH: fluorescence in situ hybridisation; DiO6: 3,3′‐dihexyloxacarbocyanine iodide; NBD‐ceramide: 6‐((N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)amino)‐caproyl)sphingosine; DiO: 3,3′‐dioctadecyloxacarbocyanine perchlorate; DiI: 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethyl‐indocarbocyanine perchlorate; CCD: charge‐coupled device; DIC: differential interference contrast; FURA2: (‐(2‐(5‐carboxyoxazol‐2‐yl)‐6‐aminobenzofuran‐5‐oxy)‐2‐)2′‐amino‐5′‐methylphenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid, sodium salt);BCECF: 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6‐)‐carboxyfluorescein;fluo‐3: 1‐(2‐amino‐5‐(2,7‐dichloro‐6‐hydroxy‐3‐oxo‐3H‐xanthen‐9‐yl)‐2‐(2′amino‐5′‐methylphenoxy)‐ethane‐N,N,N′,N′,‐tetraacetic acid, ammonium salt; DAPI: 4′,6‐diamidino‐2‐phenylindole, dihydrochloride; PET: positron emission tomogrophy; CT: computer‐assisted tomogrophy; CiD: cubitus interruptus dominus; MRC: Medical Research Council; TOTO‐1: benzothiazolium‐4‐quinolinium dimer; YOYO‐1: benzoxazolium‐4‐quinolinium dimer; ex.: excitation wavelength; em.: emission wavelength.

is now established as an invaluable tool in developmental biology for improved light microscope imaging of fluorescently labelled eggs, embryos and developing tissues. The universal application of the LSCM in biomedical research has stimulated improvements to the microscopes themselves and the synthesis of novel probes for imaging biological structures and physiological processes. Moreover the ability of the LSCM to produce an optical series in perfect register has made computer 3‐D reconstruction and analysis of light microscope images a practical option.
Cellular mechanisms of signal transduction for neurotrophins
Authors: Saltiel Alan R. , Decker Stuart J.
Published: February 2005

The molecular cloning of new neuroactive growth factors and their receptors has greatly enhanced our understanding of important interactions among receptors and singnaling molecules. These studies have begun to illuminate some of the mechanisms that allow for specificity in neuronal signaling. Model cell systems, such as the PC‐12 pheochromocytoma cell line, express receptors for these different neurotirophic factors, leading to comparisons of signaling pathways for these factors. Upon binding their ligands, these receptors undergo phosphorylation on tyrosine residues, which directs their interaction with signaling proteins containing src homology (SH2) domains, sequences that mediate associations with tyrosine‐phosphorylated proteins. These SH2 proteins translate the tyrosine kinase activity of receptors into downstream events that result in the specific cellular response. Investigations such as these have revealed that molecular specificity in signaling pathways may arise from combinatorial diversity in interactions between receptors and key regulatory proteins.
Hormones, neuroblasts and the adult insect
Authors: Shepherd David
Published: February 2005

Insect neurogenesis has been subjected to extensive study and as a result is regarded as being well understood. It is, therefore, all the more surprising when a fundamentally novel aspects of the process is uncovered. Until recently it was thought that the production of central neurons ceased before the emergence of the adult. Recently, however, Cayre et al. have shown that neurogenesis also occurs in the adult brain. Their studies also show that the rate at which adult neuroblasts divide is controlled by hormones, suggesting that hormones may play a more important role in regulating neurogenesis than previously suspected.
A pattern confirmed and refined – synaptic, nonsynaptic and parasynaptic exocytosis
Authors: Golding David W.
Published: February 2005

Neurons are now known to produce a variety of types of chemical transmitters. Classical transmitters are stored within synaptic vesicles which undergo synaptic exocytosis in association with presynaptic thickenings. The larger, dense‐cored secretory granules present in most neurons contain neuropeptides and mainly discharge their contents at morphologically undifferentiated (i.e.nonsynaptic) sites. The synaptic character of vesicle discharge enables transmitters to exercise a highly focal action, whereas nonsynaptic release probably relates to the slow rate of degradation of many neuropeptides and their consequent widespread diffusion and sphere of action. However, one variant of the basic pattern, involving the restriction of granule discharge to areas of the terminal plasmalemma situated adjacent to the postsynaptic cells (i.e. a parasynaptic configuration), enables a degree of targeted peptide discharge to be achieved. The diversity of patterns of neural exocytosis adds a further dimension to the complexity of nervous function.
Roadblocks and detours during DNA replication: Mechanisms of mutagenesis in mammalian cells
Authors: Naegeli Hanspeter
Published: February 2005

Mutations in specific genes result in birth defects, cancer, inherited diseases or lethality. The frequency with which DNA damage is converted to mutations increases dramatically when the cellular genome is replicated. Although DNA damage poses special problems to the fidelity of DNA replication, efficient mechanisms exist in mammalian cells which function to replicate their genome despite the presence of many damaged sites. These mechanisms operate in either error‐prone or error‐free modes of DNA synthesis, and frequently involve DNA strand‐pairing reactions. Genetic studies in yeast and other eukaryotes suggest that replication through DNA damage is highly regulated and catalysed by complex biochemical machineries composed of many specialised gene products. Knowledge of the molecular details by which such factors facilitate the replication of damaged DNA in mammalian cells should reveal basic rules about how DNA damage induces mutagenesis and carcinogenesis.
Mitosis
Authors: Earnshaw William C. , Pluta Ann F.
Published: February 2005

Within the last decade, the study of mitosis has evolved into a multidisciplinary science in which findings from fields as diverse as chromosome biology and cytoskeletal architecture have converged to present a more cohesive understanding of the complex events that occur when cells divide. The largest strides have been made in the identification and characterization of regulatory enzymes (kinases and phosphatases) that modulate mitotic activity, as well as a number of the proteins and structural components (spindle, chromosomes, nuclear envelope) which carry out the mitotic instructions. One emerging theme appears to be that molecular signalling, which can involve modification of components (such as phosphorylation) or even their specific destruction, monitors the state of the mitotic cell at all stages. One of the major challenges for the future will be the identification of addititonal targets of the signalling machinery, as well as new regulatory components and their targets on the chromosomes, on the spindle, and at the cleavage furrow.
Transcription by RNA polymerase II: A process linked to DNA repair
Authors: Chalut Christian , Moncollin Vincent , Egly Jean Marc
Published: February 2005

The proteins that are implicated in the basal transcription of protein coding genes have now been identified. Although little is known about their function, recent data demonstrate the ability of these proteins, previously called class II transcription factors, to participate in other reactions: TBP, the TATA‐box binding factor, is involved in class I and III transcription, while TFIIH has been shown to possess components that are involved in the DNA repair mechanism. The involvement of some if not all of the TFIIH subunits in transcription and repair may explain the heterogeneity of the various and sometimes completely unrelated symptoms observed in xeroderma pigmentosum, Cockayne Syndrome and trichothiodystrophy disorders.
Advances in immunology
Authors: Flanik Martin F.
Published: February 2005

Much was accomplished in the last decade in understanding how the adaptive immune system evolved to combat pathogens. Essential features of antigen presentation and T lymphocyte recognition were decipherd, setting the stage for further studies that elucidated basic elements of lymphocyte differentiation (including positive and negative selection during lymphocyte ontogeny) and the major interactions that occur among cells in secondary lymphoid organs in an ongoing immune response. The major challenges of today are found in the burgeoning fields of programmed cells death, enzymology of recombination and somatic mutation, development of memory, and the recognition of pathogens by unconventional lymphocytes.
The molecular basis for dominant yellow agouti coat color mutations
Authors: Perry William L. , Copeland Neal G. , Jenkins Nancy A.
Published: February 2005

Agouti expression during the middle portion of the mouse hair growth cycle induces melanocytes to synthesize yellow instead of black pigment, generating black hairs with a yellow band. Dominant agouti alleles increase the amount of yellow pigment in the coat and are associated with pleiotropic effects including obesity, diabetes and increased tumor susceptibility. Four dominant agouti alleles (Aiapy, Aiy, Asy and Avy) were recently shown to result from insertions that cause ubiquitous expression of chimeric transcripts encoding a wild‐type agouti protein(1,2). Three insertions were identified as intracisternal A‐particles, which helps explain the variable coat colors and parental imprinting effects associated with some dominat agouti alleles.
Subcellular localization and trafficking of the GLUT4 glucose transporter isoform in insulin‐responsive cells
Authors: Holman Geoffrey D. , Cushman Samuel W.
Published: February 2005

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.
Model phylogenies to explain the real world
Authors: Harvey Paul H. , Holmes Eddie C. , Nee Sean
Published: February 2005

Phylogenetic trees based on gene sequence data contain information about the evolutionary processes responsible for their genesis. Methods have now been developed which help to reveal those processes. The methods are based on simple models of evolutionary change but, when applied across individuals in a population, rather than across species in a higher‐level taxon, they can reveal the past history of population change. Examples from salamanders and viruses are used to illustrate how the past history of changes in speciation rate and the origin of epidemics can be inferred in the absence of fossil material or historical documentation.
Specificity in splicing
Authors: Holliday Robin , Murray Vincent
Published: February 2005

Considerable information about the process of premRNA splicing has accmulated, but the mechanism by which highly accurate splicing is achieved is unresolved. Fifteen years ago we proposed that accuracy in splicing might depend on small RNA molecules (splicer RNAs) which hybridise across adjacent exon termini, or intron termini. Gene expression, including alternative splicing, could be controlled by the transcription of specific splicer RNA genes. We re‐assess our model here, in the light of subsequent developments.
Leech segmentation: A molecular perspective
Authors: Shankland Marty
Published: February 2005

A variety of leech homeobox genes have been identified by homology with genes that are known to bring about the regionalization and segmentation of the anteroposterior body axis in other organisms. Embryonic expression patterns suggest a number of interphyletic similarities in the way that these genes are utilized. However, several interesting differences have also been observed. In particular, transplantation experiments in the leech embryo have shown that axially aligned patterns of homeobox gene expression are not specified by a global pattern of positional cues. Rather, the leech independently establishes anteroposterior patterns of gene expression in each of five discrete stem cell lineages, and these patterns are brought into their final alignment through a process of morphogenetic assembly.
Bee vision of pattern and 3D. The Bidder Lecture 1994
Authors: Horridge Adrian
Published: February 2005

Insect vision is nothing if not active. The regular head movements, called saccades, enable the fly Drosophila to keep a straight path in flight despite inequalities in the thrust of the wings. Using their own motion, bees in flight measure the ranges of nearby objects. A long history of research shows that bees discriminate visually in ways that depend on their activity or task, so we must distinguish between vision during flying, fixating or hovering and landing.

Bees return again and again for a reward of sugar solution and use their eyes to find their way. In an apparatus that makes them discriminate between two simulataneously visible but regularly interchanged targets, seen at a distance of 27 cm, bees are able to distinguish a remarkable number of simple patterns, but they fail in certain critical cases. The results can be explained with the hypothesis that bees have several broadly tuned overlapping filters with large fields that respond to the predominant orientation in a region of the image, and others for radial and circular patterns. Together with colour, these filters are independent of range. Bees prefer to use landmarks where they can, then global pattern at the largest scale, and lastly the detail around the goal. The way that discrimination of one visual feature is independent of other variables can be explained by models analogous to the colour triangle in colour discrimination.
Cell polarity and the mechanism of asymmetric cell division
Authors: Way Jeffrey C. , Wang Lili , Run Jin‐Quan , Hung Ming‐Shiu
Published: February 2005

During development one mechanism for generating different cell types is asymmetric cell division, by which a cell divides and contributes different factors to each of its daughter cells. Asymmetric cell division occurs through out the eukaryotic kingdom, from yeast to humans. Many asymmetric cell divisions occur in a defined orientation. This implies a cellular mechanism for sensing direction, which must ultimately lead to differences in gene expression between two daughter cells. In this review, we describe two classes of molecules: regulatory factors that are differentially expressed upon asymmetric cell division, and components of a signal transduction pathway that may define cell polarity. The lin‐11 and mec‐3 genes of C. elegans, the Isl‐1 gene of mammals and the HO gene of yeast, encode regulatory factors that determine cell type of one daughter after asymmetric cell division. The CDC24 and CDC42 genes of yeast affect both bud positioning and orientation of mating projections, and thus may define a general cellular polarity. We speculate that molecules such as Cdc24 and Cdc42 may regulate expression of genes such as lin‐11, mec‐3, Isl‐1 and HO upon asymmetric cell division.
A parallel between development and evolution: Germ cell recruitment by the gonads
Authors: Denis Herman
Published: February 2005

In gonad‐bearing animals gametogenesis can be divided into three main phases. During embryonic development the primordial gem cells move towards the gonadal primordia. A long, intra‐gonadal phase follows during which the germ cells grow and differentiate. Mature germ cells are finally released from the gonads and brought to the exterior. Thus, germ cells are successively motile, non‐motile and motile again. This complex life history is given here a simple evolutionary interpretation. The basic assumption is that primitive Metazoa already had germ cells, but no gonads to harbour them. Higher animals acquired gonads, which sequestered the germ cells, thus creating the temporary confinement experienced by germ cells in most present‐day Metazoa. This evolutionalry scheme may explain why several steps of germ cell differentation are totally or partially independent of the gonads. These steps presumably existed in primitive, gonad‐free Metazoa, and conserved their autonomy in higher animals.
Giant leap for p53, small step for drug design
Authors: Anderson Mary E. , Tegtmeyer Peter
Published: February 2005

We review the findings of Cho et al.(1) on the crystal structure of a p53 tumor suppressor‐DNA complex. The core DNA binding domain of p53 folds into a structure termed a β‐sandwich, which organizes two loops and a loop‐sheet‐helix structure on one surface of p53 to interact with the consensus DNA recognition sequence of p53. These structures help to explain the functions of wild‐type p53 and the effects of tumor‐associated mutations on p53 DNA binding, transactivation and suppression of cellular proliferation.
The formation and functioning of yeast mitotic spindles
Authors: Masuda Hirohisa
Published: February 2005

The mitotic spindle contains the machinery responsible for sister chromatid segregation. It is composed of a complex and dynamic array of microtubules, which are nucleated from the spindle poles. Studies of yeast spindle functions by molecular genetic analysis and by in vitro functional analysis have identified proteins that are mitosis‐specific and present at very low concentrations in the cell, and have revealed the molecular bases of several processes required for the formation and functioning of the mitotic spindle. Here I review the current knowledge of the processes that are common to most eukaryotes: microtubule nucleation at the spindle poles, bipolar spindle assembly, maintenance of the spindle structure, chromosome attachment to the spindle and chromosome separation on the spindle.
Are there DNA damage checkpoints in E. coli?
Authors: Bridges Bryn A.
Published: February 2005

The concept of regulatory ‘checkpoints’ in the eukaryotic cycle has proved to be a fruitful one. Here, its applicability to the bacterial cell cycle is examined. A primitive DNA damage checkpoint operates in E. coli such that, after exposure to ultraviolet light, while excision repair occurs, chromosome replication continues very slowly with the production of discontinuous daughter strands. The slower the rate of excision of photoproducts, the greater the delay before the normal rate of DNA replication is restored, the additional time for repair ensuring that normal survival is maintained. A model is proposed in which replication rate is controlled by the ratio of RecAcoated to uncoated single stranded regions of DNA in the replication fork. There are also two cell division inhibitors SulA (=SfiA) and SfiC under the control of the SOS system and sensitive to DNA damage, but they are irrelevant to the survival of wild‐type bacteria under normal conditions. In strains where SulA and SfiC do not operate, inhibition is not influenced by the rate of excision repair and so fails one of the criteria for a DNA damage checkpoint, namely the monitoring of the DNA for the level of residual damage.
Moving up the hierarchy: A hypothesis on the evolution of a genetic sex determination pathway
Authors: Wilkins Adam S.
Published: February 2005

A hypothesis on the evolutionary origin of the genetic pathway of sex determination in the nematode Caenorhabditis elegans is presented here. It is suggested that the pathway arose in steps, driven by frequency‐dependent selection for the minority sex at each step, and involving the sequential acquisition of dominant negative, neomorphic genetic switches, each one reversing the action of the previous one. A central implication is that the genetic pathway evolved in reverse order from the final step in the hierarchy up to the first. The possible applicability of the model to the other well‐characterized sex determination pathway, that of Drosophila melanogaster, and to sex determination in mammals, is discussed, along with some potential implications for pathway evolution in general. Finally, the specific molecular and population genetic questions that the model raises are described and some tests are proposed.
Left‐right asymmetry in vertebrates
Authors: Almirantis Y.
Published: February 2005

A mechanism for the generation of the morphological left‐right asymmetry in higher organisms is proposed, based on the idea that chirality at the molecular level is the primordial source for macroscopic asymmetry. This mechanism accounts for a variety of experimental results on artificial production of situs inversus and fits well with mutations in mice causing visceral transposition.
Eukaryotic DNA methyltransferases – structure and function
Authors: Adams Roger L. P.
Published: February 2005

Methylation of DNA plays an important role in the control of gene expression in higher eukaryotes. This is largely achieved by the packaging of methylated DNA into chromatin structures that are inaccessible to transcription factors and other proteins. Methylation involves the addition of a methyl group to the 5‐position of the cytosine base in DNA, a reaction catalysed by a DNA (cytosine‐5) methyltransferase. This reaction occurs in nuclear replication foci where the chromatin structure is loosened for replication, thereby allowing access to methyltransferases. Partly as a result of their recognising the presence of a methylcytosine on the parental strand following replication, these large enzymes are able to maintain the distribution of methyl groups along the DNA of somatic cells and, thereby, maintain tissue‐specific patterns of gene expression.
Nucleosomal anatomy – where are the histones?
Authors: Pruss Dmitry , Hayes Jeffrey J. , Wolffe Alan P.
Published: February 2005

The recent surge of discoveries concerning the structural organization of nucleosomes, together with genetic evidence of highly specialized roles for the histones in gene regulation, have brought a renewed need for a detailed understanding of nucleosomal anatomy. Here we review recent structural advances leading to a new level of understanding of the nucleosome and chromatin fibre structure. We discuss the problems and challenges for existing models of chromatin structure and, in particular, consider how linker histones may bind within the nucleosome, together with the implications of their association for the structure of the chromatin fibre.
The enigmatic oxygen‐avid hemoglobin of Ascaris
Authors: Goldberg Daniel E.
Published: February 2005

The parasitic nematode Ascaris lives in the low‐oxygen intestinal folds of over one billion people world‐wwide. The worm has an octameric hemoglobin that binds oxygen four orders of magnitude more tightly than does human hemogobin. Our studies have focused on elucidating the molecular mechanism of oxygen avidity, the basis of multimerization and the function of this remarkable molecule. We now believe that we understand a fair amount about the molecular interactions that result in enhanced avidity, have some preliminary ideas on octamer formation, and have some hypotheses about possible function. Along the way we have stumbled into the disciplines of intron evolution, sterol biosynthesis and oxygen‐regulated gene expression.
Retinoic acid and the differentiation of lymphohaemopoietic stem cells
Authors: Göttgens Bertholdm , Green Anthony R.
Published: February 2005

The study of haemopoiesis enables us to address one of the central questions of developmental biology, concerning the molecular mechanisms by which a multipotent cell develops into distinct differentiated progeny. Recent work(1) suggests specific roles for retinoic acid receptors at two distinct stages of haemopoiesis. Continuous cell lines of lymphohaemopoietic progenitors were established by infection with a retrovirus containing a dominant negative retinoic acid receptor. The cell lines depend on stem cell factor for their proliferation and can be induced to diffentiate into B‐lymphocytes, erythrocytes, neutrophils, monocytes, mast cells and megakaryocytes. Since lymphohaemopoietic progenitors represent less than 0.01% of nucleated marrow cells, immortalised progenitors provide a valuable system with which to study haemopoiesis on a molecular level.
Epigenetic regulation of the maize Spm transposon
Authors: Fedoroff Nina , Schläppi Michael , Raina Ramesh
Published: February 2005

Expression and transposition of the Suppressor‐mutator (Spm) transposon of maize are controlled by interacting epigenetic and autoregulatory mechanisms. Methylation of critical element sequences prevents both transcription and transposition, heritably inactivating the element. The promoter, comprising the terminal 0.2 kb of the element, and a 0.35‐kb, highly GC‐rich, downstream sequence are the methylation target sequences. The element encodes two proteins necessary for transposition, TnpA and TnpD. There are multiple TnpA binding sites, both in the 5′ terminal promoter region and at the element's 3′ end. In addition to its role in transposition, TnpA is both a positive and a negative regulator of transcription. TnpA represses the element's promoter when it is not methylated. When the element is inactive and its promoter methylated, TnpA activates the methylated promoter and facilitates both its transient and heritable demethylation.
Precursor cell types in the germinal zone of the cerebral cortex
Authors: Williams Brenda P.
Published: February 2005

Retroviral lineage tracing experiments suggest that the cortical ventricular zone is composed of a mixture of precursor cell types. The majority generate a single cell type (neurones, astrocytes or oligodendrocytes) and the remainder generate neurones and a single type of glial cell. Pluripotential precursor cells, that have the ability to generate all three cell types, are not observed. A recent paper, however, reports that when single ventricular zone cells are cultured in isolation, a small percentage of these cells are pluripotential(1). This review will discuss what this knowledge tells us about cortical development.
Determinants of blastomere identity in the early C. elegans embryo
Authors: Bowerman Bruce
Published: February 2005

Genetic and molecular studies of development in Caenorhabiditis elegans have identified regulators that appear to control pattern formation in the cellularized nematode embryo. Two genes, skn‐1 and pie‐1, are required for specifying the different identities of two sister blastomeres in a 4‐cell embryo, called P2 and EMS. The skn‐1 gene encodes a DNA binding protein that may control blastomere development by regulating transcription in EMS and its descendants. ABa and ABp, the other two sisters in a 4‐cell embryo, are influenced to develop differently by cell signaling events that require the two genes apx‐1 and glp‐1. In this review, I summarize evidence that some or all of these genes may encode embryonic determinants of blastomere identity.
A model for repair of radiation‐induced DNA double‐strand breaks in the extreme radiophile Deinococcus radiodurans
Authors: Minton Kenneth W. , Daly Michael J.
Published: February 2005

The bacterium Deinococcus (formerly Micrococcus) radiodurans and other members of the eubacterial family Deinococaceae are extremely resistant to ionizing radiation and many other agents that damage DNA. Stationary phase D. radiodurans exposed to 1.0‐1.5 Mrad γ‐irradiation sustains >120 DNA double‐strand breaks (dsbs) per chromosome; these dsbs are mended over a period of hours with 100% survival and virtually no mutagenesis. This contrasts with nearly all other organisms in which just a few ionizing radiation induced‐dsbs per chromosome are lethal. In this article we present an hypothesis that resistance of D. radiodurans to ionizing radiation and its ability to mend radiation‐induced dsbs are due to a special form of redundancy wherein chromosomes exist in pairs, linked to each other by thousands of four‐stranded (Holliday) junctions. Thus, a dsb is not a lethal event because the identical undamaged duplex is nearby, providing an accurate repair template. As addressed in this article, much of what is known about D. radiodurans suggests that it is particularly suited for this proposed novel form of DNA repair.
Calcium signalling and cell proliferation
Authors: Berridge Michael J.
Published: February 2005

The orderly sequence of events that constitutes the cell cycle is carefully regulated. A part of this regulation depends upon the ubiquitous calcium signalling system. Many growth factors utilize the messenger inositol trisphosphate (InsP3) to set up prolonged calcium signals, often organized in an oscillatory pattern. These repetitive calcium spikes require both the entry of external calcium and its release from internal stores. One function of this calcium signal is to activate the immediate early genes responsible for inducing resting cells (G0) to re‐enter the cell cycle. It may also promote the initiation of DNA synthesis at the G1/S transition. Finally, calcium contributes to the completion of the cell cycle by stimulating events at mitosis. The role of calcium in cell proliferation is highlighted by the increasing number of anticancer therapies and immunosuppressant drugs directed towards this calcium signalling pathway.
A 200‐amino acid ATPase module in search of a basic function
Authors: Confalonieri Fabrice , Duguet Michel
Published: February 2005

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle‐mediated transport, peroxisome assembly, 26S protease function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non‐exclusive) such possibilities are: (1) ATP‐dependent proteasome function and (2) ATP‐dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP‐dependent protein clamp.
Disease lesion mimics of maize: A model for cell death in plants
Authors: Johal Gurmukh S. , Hulbert Scot H. , Briggs Steven P.
Published: February 2005

A class of maize mutants, collectively known as disease lesion mimics, display discrete disease‐like symptoms in the absence of pathogens. It is intriguing that a majority of these lesion mimics behave as dominant gain‐of‐function mutations. The production of lesions is strongly influenced by light, temperature, developmental state and genetic background. Presently, the biological significance of this lesion mimicry is not clear, although suggestions have been made that they may represent defects in the plants' recognition of, or response to, pathogens. One feature that is common to all lesion mimics is their association with cell death. In plants, as in animals, a number of developmental and pathological processes exist where controlled cell death, whether programmed or triggered in response to physiological or environmental stimuli, constitutes the normal aspect of life. Might disease lesion mimic mutations represent variants where regulation of desirable cell death has gone awry? In this paper we argue that this might be the case, and further conjecture that these mutants offer a unique opportunity for studying the genetic and cellular mechanisms of cell death in plants.
Mhox and vertebrate skeletogenesis: The long and the short of it
Authors: Brickell Paul M.
Published: February 2005

The development of the vertebrate skeleton is under complex genetic control, and good progress is being made towards identifying the genes responsible. A recent paper(1) contributes to this progress by describing transgenic mice in which the homeobox‐containing MHox gene has been disrupted. MHox(−/−) mice have a range of skeletal defects, involving loss or shortening of structures in the skull, face and limb. Puzzling features of the MHox(−/−) mutation, which has similar effects on bones with very different embryological origins and yet spares other bones completely, may hold clues to the mechanisms that shape the skeleton. MHox(−/−) mice, used in conjunction with other skeletal mutants, will be important tools for exploring these mechanisms further.
DNA topoisomerase II mutations and resistance to anti‐tumor drugs
Authors: Vassetzky Yegor S. , Alghisi Gian‐Carlo , Gasser Susan M.
Published: February 2005

Mutations in DNA topoisomerase II are often correlated with drug‐resistance in tumor cell lines. Studies of topoisomerase II‐mediated drug‐resistance in various model systems, as well as the sequencing of such mutations from drug‐resistant tumors, have shed light on the functional domains of topoisomerase II, on how it interacts with inhibitors, and on the different mechanisms by which cells avoid the toxic effects of many clinically important anti‐tumor drugs.
Structure‐function relationships in smooth muscle: The missing links
Authors: Small J. Victor
Published: February 2005

Smooth muscle cells have developed a contractile machinery that allows them to exert tension on the surrounding extracellular matrix over their entire length. This has been achieved by coupling obliquely organized contractile filaments to a more‐or‐less longitudinal framework of cytoskeletal elements. Earlier structural data suggested that the cytoskeleton was composed primarily of intermediate filaments and played only a passive role. More recent findings highlight the segregation of actin isotypes and of actin‐associated proteins between the contractile and cytoskeletal domains and raise the possibility that the cytoskeleton performs a more active function. Current efforts focus on defining the relative contributions of myosin cross‐bridge cycling and actin‐associated protein interactions to the maintenance of tension in smooth muscle tissue.
Sex determination in hymenoptera: A need for genetic and molecular studies
Authors: Beukeboom Leo W.
Published: February 2005

Sex‐determining mechanisms appear to be very diverse in invertebrates. Haplodiploidy is a widespread mode of reproduction in insects: males are haploid and females are diploid. Several models have been proposed for the genetic mechanisms of sex determination in haplodiploid Hymenoptera. Although a one‐locus multi‐allele model is valid for several species, sex determination in other species cannot be explained by any of the existing models. Evidence for and predictions of two recently proposed models are discussed. Some genetic and molecular approaches are proposed to study sex determination in Hymenoptera.
Keeping the beat: Form meets function in the Chlamydomonas flagellum
Authors: Johnson Karl A.
Published: February 2005

Recent studies in the green alga Chlamydomonas and other flagellated cells have revealed new insights into the relationships between the structure and function of the eukaryotic flagellum. These advances provide a basis from which a unified view can be constructed of how a flagellum operates. In addition, investigations of flagellar assembly offer new perspectives revealing the mechanisms used by cells to create these nanoscale structures. New developments in the molecular biology of Chlamydomonas provide powerful tools for the continued exploration of flagellar biology in this cell. These studies are of interest not only within the field of biology, but also in physics and materials science; the problems of fabrication, assembly, function and regulation of nanoscale machines have been elegantly solved during the evolution of biological systems, providing models from which much remains to be learned.
The complexity in regulating the expression of tenascins
Authors: Chiquet‐Ehrismann Ruth , Hagios Carmen , Schenk Susanne
Published: February 2005

The tenascins are a growing family of extracellular matrix proteins of typical multidomain structure. The prototype to be discovered was tenascin‐C. It shows a highly regulated expression pattern during embryonic development and is often transiently associated with morphogenetic tissue interactions during organogenesis. In the adult organism reexpression of tenascin‐C occurs in tumors and many other pathological conditions. Tenascin‐C expression can be regulated by many different growth factors and hormones. Furthermore, mechanical strain exerted by fibroblasts seems to induce the expression of tenascin‐C. This could represent a mechanism of translating mechanical forces into protein patterns, a step of potential relevance in the organization of embryogenesis. Tenascin‐C as well as tenascin‐R are believed to counteract the cell adhesion and spreading activity of fibronectin, thereby facilitating cell movement.
A unique role for enhancers is revealed during early mouse development
Authors: Majumder Sadhan , Depamphilis Melvin L.
Published: February 2005

Transcription and replication of genes in mammalian cells always requires a promoter or replication origin, respectively, but the ability of enhancers to stimulate these regulatory elements and the interactions that mediate this stimulation are developmentally acquired. The primary function of enhancers is to prevent repression, which appears to result from particular components of chromatin structure. Factors responsible for this repression are present in the maternal nucleus of oocytes and its descendant, the maternal pronucleus of mouse 1‐cell embryos and in mouse 2‐cell embryos, but are absent in the paternal pronucleus. Thus, enhancers are not needed to achieve efficient transcription and replication in paternal pronuclei. However, enhancers, even in the presence of their specific activation protein, are inactive prior to formation of a 2‐cell embryo, suggesting that a coactivator essential for enhancer function is not available until zygotic gene expression begins. Furthermore, enhancer stimulation of transcription appears to be mediated through a promoter transcription factor, but this interaction can change as cells undergo differentiation, switching from a TATA‐box independent to a TATA‐box dependent mode.
Stress signaling in yeast
Authors: Ruis Helmut , Schüller Christoph
Published: February 2005

In the yeast Saccharomyces cerevisiae three positive transcriptional control elements are activated by stress conditions: heat shock elements (HSEs), stress response elements (STREs) and AP‐1 responsive elements (AREs). HSEs bind heat shock transcription factor (HSF), which is activated by stress conditions causing accumulation of abnormal proteins. STREs mediate transcriptional activation by multiple stress conditions. They are controlled by high osmolarity via the HOG signal pathway, which comprises a MAP kinase module and a two‐component system homologous to prokaryotic signal transducers. AREs bind the transcription factor Yap1p. The three types of control elements seem to have overlapping, but distinct functions. Some stress proteins encoded by HSE‐regulated genes are necessary for growth of yeast under moderate stress, products of STRE‐activated genes appear to be important for survival under severe stress and ARE‐controlled genes may mainly function during oxidative stress and in the response to toxic conditions, such as caused by heavy metal ions.
Does replication‐induced transcription regulate synthesis of the myriad low copy number proteins of Escherichia coli?
Authors: Guptasarma Purnananda
Published: February 2005

Over 80% of the genes in the E. coli chromosome express fewer than a hundred copies each of their protein products per cell. It is argued here that transcription of these genes is neither constitutive nor regulated by protein factors, but rather, induced by the act of replication. The utility of such replication‐induced (RI) transcription to the temporal regulation of synthesis of determinate quantities of low copy number (LCN) proteins is described. It is suggested that RI transcription may be necessitated, as well as facilitated, by the folding of the bacterial chromosome into a compact nucleoid. Mechanistic aspects of the induction of transcription by replication are discussed with respect to the modulation of transcriptional initiation by negative supercoiling effects, promoter methylation status and derepression. It is shown that RI transcription offers plausible explanations for the constancy of the C period of the E. coli cell cycle and the remarkable conservation of gene order in the chromosomes of enteric bacteria. Some experimental tests of the hypothesis are proposed.
Microsatellite instability and a TGFβ receptor: Clues to A growth control pathway
Authors: Benson John R. , Wells K.
Published: February 2005

Defects of growth inhibitory pathways have an important role in disorders of cell growth and differentiation. The discovery of a mutation in one of the principle components of the transforming growth factor β (TGFβ) receptor system which is linked to a DNA repair defect(1) represents one possible mechanism of escape from negative regulatory influences acting upon cells. TGFβ is a pre‐eminent negative growth factor and this article discusses (1) the role of TGFβ in maintaining epithelial homeostasis; (2) how breakdown of inhibitory pathways can promote neoplastic development; (3) the significance of a receptor defect in a negative signalling pathway; and (4) the potential therapeutic sequelae resulting from restoration of cellular responsiveness to TGFβ.
The therapeutic potential of antisense oligonucleotides
Authors: Sharma Harsh W. , Narayanan Ramaswamy
Published: February 2005

Specific inhibition of gene expression by antisense agents provides the basis for rational drug discovery based on molecular targets. Due to the specificity of Watson‐Crick base‐pair hybridization, antisense oligodeoxynucleotides have been used extensively in attempts to inhibit gene expression in both in vitro and in vivo models. Analogues modified from normal phosphodiester oligodeoxynucleotides have entered clinical trials against diseases including AIDS and cancer. Although the precise mechanism of action of these drugs has not been clarified, these oligodeoxynucleotides offer considerable promise as novel molecular therapeutics. We review the recent attempts to harness the therapeutic potential of these oligodeoxynucleotides and appraise the near‐term prospects for antisense technology.
Transformations in null mutants of hox genes: Do they represent intercalary regenerates?
Authors: Crawford Michael
Published: February 2005

In the minds of many, Hox gene null mutant phenotypes have confirmed the direct role that these genes play in specifying the pattern of vertebrate embryos. The genes are envisaged as defining discrete spatial domains and, subsequently, conferring specific segmental identities on cells undergoing differentiation along the antero‐posterior axis. However, several aspects of the observed mutant phenotypes are inconsistent with this view. These include: the appearance of other, unexpected transformations along the dorsal axis; the occurrence of mirror‐image duplications; and the development of anomalies outside the established domains of normal Hox gene expression. In this paper, Hox gene disruptions are shown to elicit regeneration‐like responses in tissues confronted with discontinuities in axial identity. The polarities and orientations of transformed segments which emerge as a consequence of this response obey the rules of distal transformation and intercalary regeneration. In addition, the incidence of periodic anomalies suggests that the initial steps of Hox‐mediated patterning occurs in Hensen's node. As gastrulation proceeds, mesoderm cell cycle kinetics impose constraints upon subsequent cellular differentiation. This results in the delayed manifestation of transformations along the antero‐posterior axis. Finally, a paradigm is sketched in which temporal, rather than spatial axial determinants direct differentiation. Specific, testable predictions are made about the role of Hox genes in the establishment of segmental identity.
The small nuclear GTPase Ran: How much does it run?
Authors: Rush Mark G. , Drivas George , D'eustachio Peter
Published: February 2005

Ran is one of the most abundant and best conserved of the small GTP binding and hydrolyzing proteins of eukaryotes. It is located predominantly in cell nuclei. Ran is a member of the Ras family of GTPases, which includes the Ras and Ras‐like proteins that regulate cell growth and division, the Rho and Rac proteins that regulate cytoskeletal organization and the Rab proteins that regulate vesicular sorting. Ran differs most obviously from other members of the Ras family in both its nuclear localization, and its lack of sites required for post‐translational lipid modification. Ran is, however, similar to other Ras family members in requiring a specific guanine nucleotide exchange factor (GEF) and a specific GTPase activating protein (GAP) as stimulators of overall GTPase activity. In this review, the multiple cellular functions of Ran are evaluated with respect to its known biochemistry and molecular interactions.
Expanded glutamines and neurodegeneration – a gain of insight
Authors: Bates Gillian
Published: February 2005

Glutamine repeat expansion has been established as the mutation underlying five inherited neurodegenerative diseases. The mechanism by which this apparently universal mutation, in ubiquitously expressed proteins, causes highly selective neurodegeneration is unknown. The proteins containing the glutamine expansions are otherwise unrelated and likely to have different functions. Two recently published papers(1,2) provide evidence of a conformational change occurring in polyglutamine expansions, which may allow novel interactions and is consistent with a toxic gain‐of‐function hypothesis. HAP1, a protein that interacts with huntingtin (Huntington's disease protein), has an expression profile that intriguingly mirrors the selective neurodegeneration seen in Huntington's disease(2).
The role of MCM proteins in the cell cycle control of genome duplication
Authors: Kearsey Stephen E. , Maiorano Domenico , Holmes Eddie C. , Todorov Ivan T.
Published: February 2005

The regulatory mechanism which ensures that eukaryotic chromosomes replicate precisely once per cell cycle is a basic and essential cellular property of eukaryotes. This fundamental aspect of DNA replication is still poorly understood, but recent advances encourage the view that we may soon have a clearer picture of how this regulation is achieved. This review will discuss in particular the role of proteins in the minichromosome maintenance (MCM) family, which may hold the key to understanding how DNA is replicated once, and only once, per cell cycle.