bluuebunny/crossref_metadata_2025 huggingface dataset:
UV damage and repair mechanisms in mammalian cells
Authors: Tornaletti Silvia , Pfeifer Gerd P.
Published: February 2005

The formation of DNA photoproducts by ultraviolet (UV) light is responsible for induction of mutations and development of skin cancer. To understand UV mutagenesis, it is important to know the mechanisms of formation and repair of these lesions. Cyclobutane pyrimidine dimers and (6–4)photoproducts are the two major classes of UV‐induced DNA lesions. Their distribution along DNA sequences in vivo is strongly influenced by nucleosomes and other DNA binding proteins. Repair of UV photoproducts is dependent on the transcriptional status of the sequences to be repaired and on the chromatin environment. Sensitive techniques are now available to study repair of UV damage at the level of nucleotide resolution in mammalian cells. With the aid of in vitro systems, the entire nucleotide excision repair process has been reconstituted from purified protein components with naked DNA as a substrate. Future work will focus on the development of in vitro assays for transcription‐coupled repair and repair in chromatin.
Involvement of the neuregulins and their receptors in cardiac and neural development
Authors: Carraway Kermit L.
Published: February 2005

The neuregulin gene encodes a series of polypeptide growth factors that can influence the growth state of target vertebrate cells in culture. Recently, three studies have explored the in vivo function of the neuregulin signaling system in mice by disrupting the genes encoding the neuregulin ligand(1) and two of its receptors, ErbB2(2) and ErbB4(3). Each of the genes is essential for development, and aberrations in cardiac and neural development are particularly prominent in mutant embryos. The observed defects, together with the localization of expression of the neuregulin signaling components within these tissues, highlight a paracrine mechanism for neuregulin‐mediated intercellular communication.
Hierarchical guidance cues in the developing nervous system of C. elegans
Authors: Wadsworth William G. , Hedgecock Edward M.
Published: February 2005

During embryogenesis, the basic axon scaffold of the nervous system is formed by special axons that pioneer pathways between groups of cells. To find their way, the pioneer growth cones detect specific cues in their extracellular environment. One of these guidance cues is netrin. Observations and experimental manipulations in vertebrates and nematodes have shown that netrin is a bifunctional guidance cue that can simultaneously attract and repel axons. During the formation of this basic axon scaffold in Caenorhabditis elegans, the netrin UNC‐6 is expressed by neuroglia and pioneer neurons, providing hierarchical guidance cues throughout the animal. Each cue has a characteristic role depending on the cell type, its position and the developmental stage. These roles include activities as global, decussation and labeled‐pathway cues. This hierarchical model of UNC‐6 netrin‐mediated guidance suggests a method by which guidance cues can direct formation of basic axon scaffolds in developing nervous systems.
Meiotic recombination: A mechanism for tracking and eliminating mutations?
Authors: McKee Bruce D.
Published: February 2005

The function of meiotic recombination has remained controversial, despite recent inroads into mechanisms. Ideas concerning a possible role of recombination in the elimination or efficient incorporation of mutations have been backed by theoretical studies but have lacked empirical support. Recent investigations into the basis for local variations in recombination frequency in yeast have uncovered a strong association between recombination initiation sites and transcriptional regulatory sequences. Other recent studies indicate a strong correlation between transcription and mutation rates in yeast genes. Taken together, these data imply that distributions of recombination and mutation frequencies may be strongly correlated. This suggests that recombination may be targeted to genomic sites of high mutation frequency; such a ‘mutation‐tracking’ function would clearly aid in the shuffling of mutations to break up unfavorable and create favorable allelic combinations. Moreover, recent insights into the mechanism of gene conversion in yeast reveal a very strong inherent bias in favor of alleles on the non‐initiating homolog. Combined with mutation tracking, these findings suggest a novel and general mechanism by which allelic gene conversion may act to eliminate mutations.
Genes, cellular interactions and cell lineages in the determination of plant trichome spacing
Authors: Sachs Tsvi
Published: February 2005

Conceptual developments have defined concrete questions about the timing and precise location of cellular pattern formation. Plants in general, and the trichomes of Arabidopsis in particular, are remarkably suited for research on these problems. Genetic analysis requires the quantitative characterizations of the developmental processes by which patterning occurs. Larkin et al.(1) have provided measures of the non‐random distances between trichomes. They have also obtained evidence about the cell lineages leading to trichome development, and this evidence constrains the possible role of intracellular programs. Continued genetic analysis may call for the identification of mutations that are expressed only during development and whose effects are corrected before the phenotype matures.
Green life: Control of chloroplast gene transcription
Authors: Link Gerhard
Published: February 2005

Chloroplasts and other plastids are plant cell organelles that account for major biochemical functions. They contain their own gene expression system but are integrated into the signaling network of the entire cell. Both nuclear and plastid genes are involved in chloroplast biogenesis, and the gene expression pathways both inside and outside the organelle are subject to developmental and environmental control. The plastid transcription apparatus reflects this general scheme, with a basic organelle‐encoded enzymatic machinery surrounded by factors that may be encoded by nuclear genes. Among the transcription regulatory mechanisms thought to play a role during plastid development are: (1) differential usage of promoter elements; (2) phosphorylation of transcription factors by a protein kinase, which is itself subject to phosphorylation and redox control; (3) dynamic changes in the composition of the transcription apparatus. In etioplasts, the dominating polymerase ‘B’ is a bacterial‐type enzyme, whereas the major chloroplast polymerase ‘A’ is a much larger enzyme reminiscent of those in the nucleus. These two enzyme forms may share common components and recruit others during development.
Control and integration of cell signaling pathways during C. Elegans vulval development
Authors: Sundaram Meera , Han Min
Published: February 2005

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to identify and analyze components that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction.
Is something wrong with the tree of life?
Authors: Martin William F.
Published: February 2005

A recent study(1) of sequence data from many different proteins has suggested that contemporary prokaryotes and eukaryotes may have shared a common ancestor as recently as 2 billion years ago (the molecular clock). Strong evidence from the geological record, however, indicates that oxygen‐producing microorganisms, perhaps similar to modern cyanobacteria, existed 3.5 billion years ago. The fossil evidence, therefore, suggests that any common ancestor of prokaryotes and eukaryotes must have existed at least 1.5 billion years earlier than suggested by the molecular clock evidence. The discrepancy between molecular and geological evidence for the age of modern cells is considered here, as are aspects of gene descent in the tree of life that might help to account for it.
Modulation by nitric oxide of metalloprotein regulatory activities
Authors: Drapier Jean‐Claude , Bouton CéCile
Published: February 2005

In many cells, a nitric oxide (NO) synthase inducible by immunological stimuli produces a sustained flow of NO that lasts a long time. NO is a short‐lived molecule but it is a diffusibel ligand believed to be capable of reaching distal target sites. Further, several lines of evidence indicate that cysteine‐rich motifs of metal‐binding proteins, as well as redox‐sensitive metal clusters of metalloproteins, are natural sensors of bioradicals like NO. In metalloregulatory proteins, metals are often conveniently located at binding sites and bound to cysteine residues. Accordingly, disruption of the metal‐thiolate polymetallic clusters should trigger significant remodelling of the protein structure involved in regulation. We can therefore postulate that the nitrosation reaction occurring at metal centres or cysteine‐rich motifs will preclude correct binding to regulatory sites. Several examples are given of metalloregulatory proteins whose metal is bound to thiols and may then become sensitive to NO. Recent observations indicate that in response to NO synthesis, iron regulatory protein, a eukaryotic bifunctional [Fe‐S] protein, switches from acting as aconitase to being an RNA‐binding regulator, and we suggest that the interplay between NO or a NO‐derived molecule and metal clusters at critical allosteric sites may be a crucial component of the cellular response to environmental stress.
Cytokinins in plant senescence: From spray and pray to clone and play
Authors: Gan Susheng , Amasino Richard M.
Published: February 2005

Three approaches have been used to investigate the inhibitory role of the cytokinin class of phytohormones in plant senescence: external application of cytokinins, measurement of endogenous cytokinin levels before and during senescence, and manipulation of endogenous cytokinin production in transgenic plants. In transgenic plant studies, endogenous cytokinin levels are manipulated by expression of IPT, a gene encoding isopentenyl transferase. Transgenic plants expressing IPT from a variety of promoters exhibit developmental and morphological alterations and often display retarded leaf senescence. A recently developed autoregulatory senescence‐inhibition system targets cytokinin production quantitatively, spatially and temporally, and results in transgenic plants that exhibit significantly delayed senescence without abnormalities. These transgenic studies not only confirm the regulatory role of cytokinins in plant senescence, but also provide a way to manipulate senescence for potential agricultural applications.
Protein kinase cascades activated by stress and inflammatory cytokines
Authors: Kyriakis John M. , Avruch Joseph
Published: February 2005

Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the extracellular signal‐regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferentially by the inflammatory cytokines TNF‐α and IL‐1‐β, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc. One pathway converges on the ERK subfamily known as the ‘stress activated’ protein kinases (SAPKs, also termed Jun N‐terminal kinases, JNKs), whereas the second pathway recruits the p38 kinases. Upstream inputs are diverse, and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other kinase subfamilies (e.g. GC kinase) and ceramide, a putative second messenger for certain TNF‐α actions. These two cascades signal cell cycle delay, cellular repair or apoptosis in most cells, as well as activation of immune and reticuloendothelial cells.
A new lease of life for an old enzyme
Authors: Martini Giuseppe , Ursini Matilde Valeria
Published: February 2005

We review here some recent data about glucose‐6‐phosphate dehydrogenase (G6PD), the first and key regulatory enzyme of the pentose phosphate pathway. New evidence has been presented to suggest that malaria is a selective agent for G6PD deficiency, which is the most common enzymopathy in man, and that G6PD deficiency, generally considered to be a mild and benign condition, is significantly disadvantageous in certain environmental conditions. At the molecular level, the enzyme structure has recently been elucidated and mechanisms regulating G6PD gene expression have been determined. A G6PD knock‐out mutation introduced in mouse cells makes them exquisitely sensitive to oxidative stress, indicating that this ubiquitous metabolic enzyme has a major role in the defence against oxidative stress, even in eukaryotic nucleated cells, which have several alternative routes for providing the same protection. Because of the high prevalence of G6PD deficiency in many populations, it is expected that these findings will prompt further studies to ascertain the putative role of G6PD deficiency in conditions such as carcinogenesis and ageing.
A new role for the stromal cells in kidney development
Authors: Bard Jonathan
Published: February 2005

New observations by Hatini et al.(1) on the ‘winged helix’ transcription factor BF‐2 will make us change our views about kiney development. This gene is only expressed in stromal cells associated with the kidney medulla and cortex, but the BF‐2 knockout has unexpected abnormalities. Although the stromal cells appear normal, the kidney is small, the ducts have limited branching and, instead of the many normal nephrogenic aggregates, there are relatively few large mesenchymal aggregates that fail to differentiate. The stromal cells thus seem to produce factors regulating other aspects of kidney development, while the abnormalities highlight a series of unsolved problems in kidney morphogenesis.
The cellular internet: On‐line with connexins
Authors: Bruzzone Roberto , White Thomas W. , Goodenough Daniel A.
Published: February 2005

Most cells communicate with their immediate neighbors through the exchange of cytosolic molecules such as ions, second messengers and small metabolites. This activity is made possible by clusters of intercellular channels called gap junctions, which connect adjacent cells. In terms of molecular architecture, intercellular channels consist of two channels, called connexons, which interact to span the plasma membranes of two adjacent cells and directly join the cytoplasm of one cell to another. Connexons are made of structural proteins named connexins, which compose a multigene family. Connexin channels participate in the regulation of signaling between developing and differentiated cell types, and recently there have been some unexpected findings. First, unique ionic‐ and size‐selectivities are determined by each connexin; second, the establishment of intercellular communication is defined by the expression of compatible connexins; third, the discovery of connexin mutations associated with human diseases and the study of knockout mice have illustrated the vital role of cell‐cell communication in a diverse array of tissue functions.
Myelin mutants: Model systems for the study of normal and abnormal myelination
Authors: Griffiths Ian R.
Published: February 2005

Spontaneous mutations that perturb myelination occur in a range of species including man, and together with engineered mutations have been used to study disease, normal myelination and axon/glial inter‐relationships. Only a minority of the currently defined mutations have an apparently simple pathogenesis due to lack of a functional protein. Mutations in the myelin basic protein gene lead to a lack of protein, resulting in changes in the structure of myelin, which can be rescued by transgenic complementation. The pathogenesis of autosomal dominant and X‐linked mutations affecting either oligodendrocytes or Schwann cells is more complex. Point mutations may act in a dominant negative manner and gene dosage is clearly linked to phenotypic change. Mutations in regulatory genes, such as those encoding transcription factors, can also disturb myelination by selected cell types. Other less‐well studied and unexpected consequences of myelin mutations, such as seizures in mutations affecting genes expressed in Schwann cells and axonal changes associated with dysmyelination, are also considered. With the major developments in gene mapping and cloning it is now relevant to study mutations in a variety of species with the real prospect of defining their molecular basis. Examples are given of unusual, but potentially useful, uncharacterised mutations in dog and bovine.
Dynamin GTPase, a force‐generating molecular switch
Authors: Warnock Dale E. , Schmid Sandra L.
Published: February 2005

Dynamin is a GTPase that regulates late events in clathrin‐coated vesicle formation. Our current working model suggests that dynamin is targeted to coated pits in its unoccupied or GDP‐bound form, where it is initially distributed uniformly throughout the clathrin lattice. GTP/GDP exchange triggers its release from these sites and its assembly into short helices that encircle the necks of invaginated coated pits like a collar. GTP hydrolysis, which is required for vesicle detachment, presumably induces a concerted conformation change, tightening the collar. Unlike most of its GTPase cousins that serve as molecular switches, dynamin has a low affinity for GTP, a very high intrinsic rate of GTP hydrolysis and functions as a homo‐oligomer. A concerted conformational change resulting from coordinated GTP hydrolysis by the dynamin oligomer might be sufficient to generate force. In this case, dynamin would be the first GTPase identified that acts as a structural protein with mechano‐chemical function.
Cooperation between soluble factors and integrin‐mediated cell anchorage in the control of cell growth and differentiation
Authors: Juliano Rudy
Published: February 2005

Recently it has become clear that integrins and other adhesive receptors play an important role in the control of cell growth and differentiation. In various cell types, anchorage to the extracellular matrix via integrins strongly influences the ability of the cell to respond to soluble mitogens or to differentiation factors. Thus adhesive receptors must generate signals that influence cell behavior. Some of the pathways of adhesion receptor signaling are now beginning to be worked out, but there is still much to learn. In particular, the mechanistic basis for the cooperation between anchorage signals and signals from soluble growth and differentiation factors remains ill‐defined. This review will examine some of the current information linking adhesion receptors to control of mitogenesis and differentiation.
Archaebacterial genomics: The complete genome sequence of Methanococcus jannaschii
Authors: Edgell David R. , Doolittle W. Ford
Published: February 2005

The first complete sequence of an archaebacterial genome, that of Methanococcus jannaschii, has recently been published(1). Less than half of the open reading frames (ORFs) can be assigned a function based on similarity to known sequences in databases. These assignable ORFs fall into two general classes; those involved in transcription, translation and replication are more similar to eukaryotic homologs, while those determining metabolic processes are more similar to eubacterial versions. The immense but very rewarding task of making biological and evolutionary sense of all this information has only just begun.
Synthesis and function of mos: The control switch of vertebrate oocyte meiosis
Authors: Gebauer Fátima , Richter Joel D.
Published: February 2005

One distinguishing feature of vertebrate oocyte meiosis is its discontinuity; oocytes are released from their prophase I arrest, usually by hormonal stimulation, only to again halt at metaphase II, where they await fertilization. The product of the c‐mos proto‐oncogene, Mos, is a key regulator of this maturation process. Mos is a serine‐threonine kinase that activates and/or stabilizes maturation‐promoting factor (MPF), the master cell cycle switch, through a pathway that involves the mitogen‐activated protein kinase (MAPK) cascade. Oocytes arrested at prophase I lack detectable levels of Mos, which must be synthesized from a pool of maternal mRNAs for proper maturation. While Mos is necessary throughout maturation in Xenopus, it seems to be required only for meiosis II in the mouse. The translational activation of c‐mos mRNA at specific times during meiosis requires cytoplasmic polyadenylation. Cis‐ and trans‐acting factors for polyadenylation are, therefore, essential elements of maturation.
Integrin‐mediated calcium signaling and regulation of cell adhesion by intracellular calcium
Authors: Sjaastad Michael D. , Nelson W. James
Published: February 2005

Integrins are ubiquitous trans‐membrane adhesion molecules that mediate the interaction of cells with the extracellular matrix (ECM). Integrins link cells to the ECM by interacting with the cell cytoskeleton. In cases such as leukocyte binding, integrins mediate cell‐cell interactions and cell‐ECM interactions. Recent research indicates that integrins also function as signal transduction receptors, triggering a number of intracellular signaling pathways that regulate cell behavior and development. A number of integrins are known to stimulate changes in intracellular calcium levels, resulting in integrin activation. Although changes in intracellular calcium regulate a vast number of cellular functions, this review will discuss the stimulation of calcium signaling by integrins and the role of intracellular calcium in the regulation of integrin‐mediated adhesion.
Untangling the role of DNA topoisomerase II in mitotic chromosome structure and function
Authors: Warburton Peter E. , Earnshaw William C.
Published: February 2005

DNA topoisomerase II (topo II) is involved in chromosome structure and function, although its exact location and role in mitosis are somewhat controversial. This is due in part to the varied reports of its localization on mitotic chromosomes, which has been described at different times as uniformly distributed, axial on the chromosome arms and predominantly centromeric. These disparate results are probably due to several factors, including use of different preparation and fixation techniques, species differences and changes in distribution during the cell cycle. Recently, several papers have re‐investigated the distribution of topo II on chromosomes as a function of cell cycle and species(1–3). The new studies suggest that Topo II has a dynamic pattern of distribution on the chromosomes, in general becoming axial as chromosomes condense during prophase and then concentrating at centromeres during metaphase. These experiments suggest a novel role for topo II in centromere structure and function.
The Drosophila fusome, organelle biogenesis and germ cell differentiation: If you build it…
Authors: McKearin Dennis
Published: February 2005

From stem cells to oocyte, Drosophila germ cells undergo a short, defined lineage. Molecular genetic analyses of a collection of female sterile mutations have indicated that a germ cell‐specific organelle called the fusome has a central role at several steps in this lineage. The fusome grows from a prominent spherical organelle to an elongated and branched structure that connects all mitotic sisters in a germ cell syncytium. The organelle is assembled from proteins normally found in the membrane skeleton and, additionally, contains an extensive membranous reticulum, the probable product of differentiation‐dependent vesicle trafficking. This review briefly summarizes a current view of the processes that drive germ cell differentiation, particularly the various roles that the fusome might play in regulating the developmental events. Future efforts will consider to what extent an organelle assembly‐dependent model for differentiation is heuristic and whether the Drosophila fusome represents a homolog of a similar organelle in vertebrate lymphocytes.
Good things in small packages: The tiny genomes of chlorarachniophyte endosymbionts
Authors: Gilson Paul R. , McFadden Geoffrey I.
Published: February 2005

Chlorarachniophytes are amoeboflagellate, marine protists that have acquired photosynthetic capacity by engulfing and retaining a green alga. These green algal endosymbionts are severely reduced, retaining only the chloroplast, nucleus, cytoplasm and plasma membrane. The vestigial nucleus of the endosymbiont, called the nucleomorph, contains only three small linear chromosomes and has a haploid genome size of just 380 kb ‐ the smallest eukaryotic genome known. Initial characterisation of nucleomorph DNA has revealed that all chromosomes are capped with inverted repeats comprising a telomere and a single ribosomal RNA operon. The nucleomorph genome is the quintessence of compactness; average space between genes is a mere 65 bp, some genes overlap, others are cotranscribed. Intense reductive pressures upon nucleomorph genes have apparently squeezed their spliceosomal‐type introns down to only 18, 19 or 20 bases in length. Studies to date indicate the nucleomorph ‐ essentially a stripped‐down eukaryotic genome ‐ encodes principally genetic housekeeping functions such as translation, transcription and splicing.
The mammalian acrosome reaction: Gateway to sperm fusion with the oocyte?
Authors: Allen Catherine A. , Green David P. L.
Published: February 2005

Mammalian sperm undergo discharge of a single, anterior secretory granule following their attachment to the zona pellucida surrounding the oocyte. This secretory discharge is known for historical reasons as the acrosome reaction. It fulfils a number of purposes and without it, sperm are unable to penetrate the zona pellucida and fuse with the oocyte. In this review, we focus on the role of the acrosome reaction in the development of fusion competence in sperm. Any naturally occurring membrane fusion has two major sequential steps: a docking or adhesion step, in which two membranes adhere, and a fusion step, in which their lipid bilayers are destabilized and merged and a cellular compartment is either created or destroyed. Recent evidence suggests that there is an important role for oocyte integrins and sperm‐bound disintegrins in mammalian sperm/oocyte adhesion and fusion. The fusion mechanism employed by sperm remains poorly understood, however, and circumstantial evidence suggests it is more complex than the interaction between a single protein species and its target. Sperm/oocyte fusion is probably the most accessible eukaryotic model for intercellular fusion currently available, partly because it is temporally separated from gene expression. Elucidation of the mechanism of sperm/oocyte fusion may throw light on the mechanism of other intercellular fusions such as myoblast fusion, and the evolutionary relationship of intercellular membrane fusion to intracellular membrane fusion.
Canalization: A molecular genetic perspective
Authors: Wilkins Adam S.
Published: February 2005

The phenomenon of ‘canalization’ ‐ the genetic capacity to buffer developmental pathways against mutational or environmental perturbations ‐ was first characterized in the late 1930s and early 1940s. Despite enormous subsequent progress in understanding the nature of the genetic material and the molecular basis of gene expression, there have been few attempts to interpret the classical work on canalization in molecular genetic terms. Some recent findings, however, bear on one form of canalization, ‘genetic canalization’, the stabilization of development against mutational effects. These data indicate that co‐expressed paralogous genes can function as mutual ‘back‐up’ elements in developmental processes. Paralogues, however, are far from the only basis of canalization: other genetic sources can be readily envisaged and some of these are described here. The evolutionary questions about genetic canalization and the mechanistic questions about developmental instability that still need to be addressed are also briefly discussed.
Left‐right asymmetry in vertebrate embryogenesis
Authors: Levin Michael
Published: February 2005

Embryonic development results in animals whose body plans exhibit a variety of symmetry types. While significant progress has been made in understanding the molecular events underlying the early specification of the antero‐posterior and dorso‐ventral axes, little information has been available regarding the basis for left‐right (LR) differences in animal morphogenesis. Recently however, important advances have been made in uncovering the molecular mechanisms responsible for LR patterning. A number of genes (including well‐known signaling molecules such as Sonic hedgehog and activin) are asymmetrically expressed in early chick embryos, well before the appearance of morphological asymmetries. One of these, nodal, is asymmetrically expressed in frogs and mice as well, and its expression is altered in mouse mutants exhibiting defects in laterality. In the chick, these genes regulate each other in a sequential cascade, which independently determines the situs of the heart and other organs.
Receptor tyrosine kinase‐dependent neural crest migration in response to differentially localized growth factors
Authors: Wehrle‐Haller Bernhard , Weston James A.
Published: February 2005

How different neural crest derivatives differentiate in distinct embryonic locations in the vertebrate embryo is an intriguing issue. Many attempts have been made to understand the underlying mechanism of specific pathway choices made by migrating neural crest cells. In this speculative review we suggest a new mechanism for the regulation of neural crest cell migration patterns in avian and mammalian embryos, based on recent progress in understanding the expression and activity of receptor tyrosine kinases during embryogenesis. Distinct subpopulations of crest‐derived cells express specific receptor tyrosine kinases while residing in a migration staging area. We postulate that the differential expression of receptor tyrosine kinases by specific subpopulations of neural crest cells allows them to respond to localized growth factor ligand activity in the embryo. Thus, the migration pathway taken by neural crest subpopulations is determined by their receptor tyrosine kinase response to the differential localization of their cognate ligand.
A novel signalling mechanism for generating ca2+ oscillations at fertilization in mammals
Authors: Swann Karl , Lai F. A.
Published: February 2005

At fertilization in mammals the sperm activates the egg by triggering a series of oscillations in the intracellular free Ca2+ concentration. The precise sequence of events that occur between sperm‐egg contact and the increases in intracellular Ca2+ remains unknown. Here, we discuss recent evidence supporting the hypothesis that a cytosolic sperm protein enters the egg after gamete membrane fusion and triggers Ca2+ oscillations from within the egg cytoplasm. Biochemical studies suggest that there exists a novel sperm protein, named oscillin, that specifically comigrates with Ca2+ oscillation‐inducing activity. Oscillin has been immunolocalised to the region of the sperm that first fuses with the egg. The concept of a specific protein that triggers Ca2+ oscillations may have wider physiological significance since sperm oscillin can induce Ca2+ oscillations in somatic cells, such as neurons and hepatocytes. Unravelling the novel signalling system involved in mammalian fertilization may help reveal some fundamental molecular mechanisms responsible for triggering cytoplasmic Ca2+ oscillations.
The role of phosphotyrosine phosphatases in haematopoietic cell signal transduction
Authors: Frearson Julie A. , Alexander Denis R.
Published: February 2005

Phosphotyrosine phosphatases (PTPases) are the enzymes which remove phosphate groups from protein tyrosine residues. An enormous number of phosphatases have been cloned and sequenced during the past decade, many of which are expressed in haematopoietic cells. This review focuses on the biochemistry and cell biology of three phosphatases, the transmembrane CD45 and the cytosolic SH2‐domain‐containing PTPases SHP‐1 and SHP‐2, to illustrate the diverse ways in which PTPases regulate receptor signal transduction. The involvement of these and other PTPases has been demonstrated in haematopoietic cell development, apoptosis, activation and non‐responsiveness. A common theme in the actions of many haematopoietic cell PTPases is the way in which they modulate the thresholds for receptor signalling, thereby regulating critical events in the positive and negative selection of lymphocytes. There is growing interest in haematopoietic PTPases and their associated regulatory proteins as targets for pharmaceutical intervention and in the involvement of these enzymes in human disease.
Developmental phenotypic plasticity: Where ecology and evolution meet molecular biology
Authors: Callahan Hilary S. , Pigliucci Massimo , Schlichting Carl D.
Published: February 2005

The plastic response of phenotypic traits to environmental change is a common research focus in several disciplines ‐ from ecology and evolutionary biology to physiology and molecular genetics. The use of model systems such as the flowering plantArabidopsis thalianahas facilitated a dialogue between developmental biologists askinghowplasticity is controlled (proximate causes) and organismal biologists askingwhyplasticity exists (ultimate causes). Researchers studying ultimate causes and consequences are increasingly compelled to reject simplistic, ‘black box’ models, while those studying proximate causes and mechanisms are increasingly obliged to subject their interpretations to ecological ‘reality checks.’ We review the successful multidisciplinary efforts to understand the phytochrome‐mediated shade‐avoidance and light‐seeking responses of flowering plants as a pertinent example of convergence between evolutionary and molecular biology. In this example, the two‐way exchange between reductionist and holist camps has been essential to rapid and sustained progress. This should serve as a model for future collaborative efforts towards understanding the responses of organisms to their constantly changing environments.
Homeosis and polyposis: A tale from the mouse
Authors: He Tong‐Chuan , Da Costa Luis T. , Thiagalingam Sam
Published: February 2005

Homeobox genes play essential roles in specifying the fates of different cell types during embryogenesis. In Drosophila, the homeotic gene caudal is important for the generation of posterior structures. In the mouse, the caudal homologue Cdx2 has been implicated in directing early processes in intestinal morphogenesis and in the maintenance of the differentiated phenotype. A recent study showed that Cdx2 null mutation was embryonically lethal, whereas Cdx2+/− mice developed multiple intestinal polyps in the proximal colon in addition to developmental defects(1). There are striking phenotypic similarities and differences between Cdx2+/− and other mice predisposed to intestinal neoplasia. The possible role of Cdx2 in human colorectal tumorigenesis is discussed.
Structural studies on myosin II: Communication between distant protein domains
Authors: Gulick Andrew M. , Rayment Ivan
Published: February 2005

Understanding how chemical energy is converted into directed movement is a fundamental problem in biology. In higher organisms this is accomplished through the hydrolysis of ATP by three families of motor proteins: myosin, dynein and kinesin. The most abundant of these is myosin, which operates against actin and plays a central role in muscle contraction. As summarized here, great progress has been made towards understanding the molecular basis of movement through the determination of the three‐dimensional structures of myosin and actin and through the establishment of systems for site‐directed mutagenesis of this motor protein. It now appears that the generation of movement is coupled to ATP hydrolysis by a series of domain movements within myosin.
In pursuit of influenza: Fort monmouth to valhalla (and back)
Authors: Kilbourne Edwin D.
Published: February 2005

In reviewing 50 years of personal research on influenza, I have journeyed, literally and figuratively, from an army camp epidemic in Fort Monmouth NJ in 1947 to a (literal and figurative) Valhalla, where I now conduct my research. Having entered the field as a physician, I have always sought practical applications of my work, yet in every instance, such applications have led me to seek further answers in basic research as new questions arose. I entered the area of influenza virus genetics by the back door through an interest in the effects of corticosteroid hormones on viral replication, used the genetic approach in analyzing the morphological variation of the virus and, in so doing, exploited the finding of a linkage of high‐yield growth to spherical morphology. Today, all influenza vaccine viruses are high‐yield genetic reassortants. Subsequent study of reassortant viruses facilitated the identification and isolation of the two major antigens of the virus in antigenic hybrids and showed their differing functions in the induction of immunity. In turn, a new approach to influenza vaccination has been discovered and is presently under clinical investigation.
Spatial features of calcium‐regulated gene expression
Authors: Finkbeiner Steven , Greenberg Michael E.
Published: February 2005

A key characteristic of an animal's nervous system is that it can respond to brief environmental stimuli with lasting changes in its structure and function. These changes are triggered by specific patterns of neuronal electrical activity and are manifested as changes in the strength and patterns of synaptic connectivity between activated neurons. The biochemical mechanisms that control these changes are unclear, but cytoplasmic rises in Ca2+ levels may play a critical role, especially in regulating neuronal gene expression for making activity‐induced synaptic changes permanent. Recently, two reports have explored the spatial features by which activity‐induced rises in Ca2+ levels activate transcription factors and gene expression(1,2). The reports suggest that Ca2+ influx acts both locally at the synapse and distantly within the nucleus to regulate transcription factors and gene expression. The results also show that regulatory elements within genes can respond differentially, depending on spatial differences in intracellular Ca2+ rises. These reports suggest new spatial mechanisms by which Ca2+‐dependent gene expression could contribute to activity‐dependent synaptic changes.
Epithelial differentiation in Drosophila
Authors: Tepass Ulrich
Published: February 2005

Our understanding of epithelial development in Drosophila has been greatly improved in recent years. Two key regulators of epithelial polarity, Crumbs and DE‐cadherin, have been studied at the genetic and molecular levels and a number of additional genes are being analyzed that contribute to the differentiation of epithelial cell structure. Epithelial architecture has a profound influence on morphogenetic movements, patterning and cell‐type determination. The combination of embryological and genetic/molecular tools in Drosophila will help us to elucidate the complex events that determine epithelial cell structure and how they relate to morphogenesis and other developmental processes.
Challenges: Selective compartments for resistant microorganisms in antibiotic gradients
Authors: Baquero Fernando , Negri María‐Cristina
Published: February 2005

The development of bacterial resistance to antibiotics is one of the best documented examples of contemporary biological evolution. Variability in the mechanisms of resistance depends on the diversity of genotypes in the huge bacterial populations, and also on the diversity of selective pressures that are produced along the antibiotic concentration gradients formed in the highly compartmentalized human body during therapy. These antibiotic gradients can be conceived as comprising selective compartments, each one of them defined as the concentration able to select a particular genetic variant.In vitroexperimental models confirm that some antibiotic resistant variants are selected only at certain selective concentrations of antibiotics. The correspondence between selective compartments and selectable variants could offer a way of describing more accurately the antibiotic selective landscapes and for taking measures to prevent the development of a major threat to the future of modern medicine.
Pax genes and organogenesis
Authors: Dahl Edgar , Koseki Haruhiko , Balling Rudi
Published: February 2005

Pax genes are a family of development control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA‐binding activity. Originally, paired‐box‐containing genes were detected in Drosophila malenogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out of nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (PAX3), Aniridia (PAX6), Peter's anomaly (PAX6), renal coloboma syndrome (PAX2), Small eye (Pax6), (Pax21Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate Pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax genes are involved in pattern formation during embryogenesis, possibly by determiing the time and place of organ initiation of morphogenesis. For most tissues, however, the nature of the primary development action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position‐specific regulation of cell proliferation.
Molecular events in neutrophil transepithelial migration
Authors: Parkos Charles A.
Published: February 2005

Neutrophil transepithelial migration is a central component of many inflammatory diseases of the gastrointestinal, respiratory and urinary tracts, and correlates with disease symptoms. In vitro modeling with polarized intestinal epithelial monolayers has shown that neutrophil transepithelial migration can influence crucial epithelial functions, ranging from barrier maintenance to electrolyte secretion. Studies have also demonstrated a dynamic involvement of the epithelium in modulating neutrophil transepithelial migration. Characterization of the molecular interactions between neutrophils and epithelial cells has revealed that transepithelial migration is dependent on the neutrophil β2 integrin CD11b/CD18, and does not appear to involve adhesive interactions with the selectins or intercellular adhesion molecule‐1. Recent studies have implicated another transmembrane glycoprotein, CD47, as a crucial component of the transepithelial migration response. While the precise function of CD47 is not known, current evidence suggests that CD47‐dependent events occur after CD11b/CD18‐mediated neutrophil adhesion to the epithelium. This review will highlight key features of the current understanding of the molecular events important in neutrophil migration across epithelial surfaces.
Mammalian DNA ligases
Authors: Tomkinson Alan E. , Levin David S.
Published: February 2005

DNA joining enzymes play an essential role in the maintenance of genomic integrity and stability. Three mammalian genes encoding DNA ligases, LIG1, LIG3 and LIG4, have been identified. Since DNA ligase II appears to be derived from DNA ligase III by a proteolytic mechanism, the three LIG genes can account for the four biochemically distinct DNA ligase activities, DNA ligases I, II, III and IV, that have been purified from mammalian cell extracts. It is probable that the specific cellular roles of these enzymes are determined by the proteins with which they interact. The specific involvement of DNA ligase I in DNA replication is mediated by the non‐catalytic amino‐terminal domain of this enzyme. Furthermore, DNA ligase I participates in DNA base excision repair as a component of a multiprotein complex. Two forms of DNA ligase III are produced by an alternative splicing mechanism. The ubiqitously expressed DNA ligase III‐α forms a complex with the DNA single‐strand break repair protein XRCC1. In contrast, DNA ligase III‐β, which does not interact with XRCC1, is only expressed in male meiotic germ cells, suggesting a role for this isoform in meiotic recombination. At present, there is very little information about the cellular functions of DNA ligase IV.
Insect societies and the molecular biology of social behavior
Authors: Robinson Gene E. , Fahrbach Susan E. , Winston Mark L.
Published: February 2005

This article outlines the rationale for a molecular genetic study of social behavior, and explains why social insects are good models. Summaries of research on brain and behavior in two species, honey bees and fire ants, are presented to illustrate the richness of the behavioral phenomena that can be addressed with social insects and to show how they are beginning to be used to study genes that influence social behavior. We conclude by considering the problems and potential of this emerging field.
Genes and social skills
Authors: Scourfield Jane , McGuffin Peter , Thapar Anita
Published: February 2005

Evidence for one or more loci on the human X chromosome influencing social cognition was recently presented by Skuse et al.(1). The imprinted locus is only expressed from a paternally inherited X chromosome, which means that boys do not express it because their only X chromosome comes from their mother. This raises the possibility of genetic as well as cultural influences on sex differences in behaviour and cognition. It may also offer some explanation for why boys are more vulnerable to developmental disorders that affect social behaviour, such as autism.
Index for predicting mortality in elderly surgical patients
Authors: Lloyd H , Ahmed I , Taylor S , Blake J R S
Published: February 2005

Background

The aim of the study was to validate a mortality index for use in patients over 65 years of age undergoing operative treatment or conservative management.

Methods

From a study conducted more than 20 years ago of elderly patients admitted with a surgical condition, 11 variables were identified as being significant in predicting mortality: age, white cell count, serum urea concentration, pulse rate, mean blood pressure, type of admission, urgency of operation, complexity of surgery, conservative management, and diagnostic categories of vascular disease and malignancy. Using multivariate logistic regression analysis, a mortality index was devised. This index was validated in a separate study of comparable patients treated in 1999–2001.

Results

Comparison of the derivation and validation data sets showed similarity in the distribution of variables with no significant difference in mortality (overall mortality rate 9·3 per cent for the derivation set versus 9·6 per cent for the validation set; χ2 = 0·084, 1 d.f., P = 0·771). Tests of calibration and discrimination showed no significant difference in predicted to actual deaths, and the receiver–operator characteristic plots of the two data sets showed good discrimination.

Conclusion

This mortality index was derived specifically for patients over 65 years of age receiving either operative or conservative treatment. It could be of use when counselling patients and their relatives about the possible outcome of treatment.