bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of zygotic gene activation in the mouse
Authors: Schultz Richard M. 
Published: February 2005

AbstractZygotic gene activation (ZGA) is the critical event that governs the transition from maternal to embryonic control of development. In the mouse, ZGA occurs during the 2‐cell stage and appears to be regulated by the time following fertilization, i.e. a zygotic clock, rather than by progression through the first cell cycle. The onset of ZGA must depend on maternally inherited proteins, and post‐translational modification of these maternally derived proteins is likely to play a role in ZGA. Consistent with this prediction is that protein phosphorylation catalyzed by the cAMP‐dependent protein kinase is involved in ZGA and that protein synthesis is not required for ZGA. Recent results suggest that ZGA may occur earlier than previously thought, i.e. not during the 2‐cell stage, but rather in G2 of the 1‐cell embryo. Thus ZGA may comprise a period of minor gene activation in the 1‐cell embryo that is followed by a period of major gene activation in the 2‐cell embryo. Following ZGA, the expression of constitutively activated genes may require an enhancer.
My favourite molecule: Polyamines, chromatin structure and transcription
Authors: Matthews Harry R. 
Published: February 2005

AbstractNucleosomes are the basic elements of chromatin structure. Polyamines, such as spermine and spermidine, are small ubiquitous molecules absolutely required for cell growth. Photoaffinity polyamines bind to specific locations in nucleosomes and can change the helical twist of DNA in nucleosomes. Acetylation of polyamines reduces their affinity for DNA and nucleosomes, thus the helical twist of DNA in nucleosomes could be regulated by cells through acetylation. I suggest that histone and polyamine acetylation act synergistically to modulate chromatin structure. On naked DNA, the photoaffinity spermine bound preferentially to a specific ‘TATA’ sequence element, suggesting that polyamines may be involved in the unusual chromatin structure in this region. Further work is needed to test whether the specificities shown by photoaffinity polyamines are also shown by cellular polyamines; such experiments are now feasible.
The fibrillin‐marfan syndrome connection
Authors: Ramirez Francesco , Pereira Lygia , Zhang Hui , Lee Brendan 
Published: February 2005

AbstractA few years ago no one would have suspected that the well‐known disorder of connective tissue, Marfan syndrome, could be caused by mutations in a recently discovered extracellular component, fibrillin. Likewise, nobody would have predicted that fibrillin represents a small family of proteins that are associated with several pheno‐typically overlapping disorders. The fibrillins are integral constituents of the non‐collagenous microfibrils, with an average diameter of 10 nm. These aggregates are distributed in the extracellular matrix of virtually every tissue. Microfibrillar bundles provide the external coating to elastin in elastic fibers, and serve an anchoring function in non‐elastic tissues. At higher resolution, individual microfibrils have a “beads‐on‐a‐string” appearance resulting from the head‐to‐tail polymerization of multiple fibrillin aggregates. Structurally, fibrillin contains a series of repeated sequences homologous to the epidermal growth factor calcium‐binding motif. Characterization of fibrillin mutations in Marfan syndrome patients, together with the elucidation of the structure of the fibrillin proteins, have provided new insights, and raised new questions, about the function of the 10 nm microfibrils. For example, it is possible that the fibrillins, in addition to serving a structural function, might also be involved in regulating cellular activities and morphogenetic programs. It is fitting that the long search for the Marfan syndrome gene has brought a novel group of proteins to the forefront of extracellular matrix biology.
Dynamics of DNA methylation during development
Authors: Brandeis Michael , Ariel Mira , Cedar Howard 
Published: February 2005

AbstractDNA methylation plays a role in the repression of gene expression in animal cells. In the mouse preimplantation embryo, most genes are unmethylated but a wave of de novo methylation prior to gastrulation generates a bimodal pattern characterized by unmethylated CpG island‐containing housekeeping genes and fully modified tissue‐specific genes. Demethylaton of individual genes then takes place during cell type specific differentiation, and this demodification may be a required step in the process of transcriptional activation. DNA modification is also involved in the maintenance of gene repression on the inactive X chromosome in female somatic cells and the marking of parental alleles at genomically imprinted gene loci.
The secretion pathway of IgA protease‐type proteins in gram‐negative bacteria
Authors: Klauser Thomas , Pohlner Johannes , Meyer Thomas F. 
Published: February 2005

AbstractThe pathogenic, Gram‐negative bacteria, Neisseria gon‐orrhoeae, Neisseria meningitidis and Haemophilus influenzae, secrete immunoglobulin A1 proteases into their extracellular surroundings. An extraordinary feature in the secretory pathway of these putative virulence factors is a self‐directed outer membrane transport step allowing the proteins to be secreted autonomously, even from foreign Gram‐negative host cells like Escherichia coli. Here we summarize recent achievements in the understanding of IgA protease outer membrane translocation.
Contact inhibition in the failure of mammalian CNS axonal regeneration
Authors: Johnson Alan R. 
Published: February 2005

AbstractAnamniote animals, such as fish and amphibians, are able to regenerate damaged CNS nerves following injury, but regeneration in the mammalian CNS tracts, such as the optic nerve, does not occur. However, severed adult mammalian retinal axons can regenerate into peripheral nerve segments grafted into the brain and this finding has emphasized the importance of the environment in explaining regenerative failure in the adult mammalian CNS. Following lesions, regenerating axons encounter the glial cells, oligodendrocytes and astro‐cytes, and their derivatives, respectively myelin and the astrocytic scar. Experiments to investigate the influence of these components on axon growth in culture have revealed cell‐surface and extracellular matrix molecules that inhibit axon extension and growth cone motility. Structural and functional characterization of these ligands and their receptors is underway, and may solve the interesting neurobiological conundrum posed by the failure of mammalian CNS regeneration. Simultaneously, this might allow new possibilities for treatment of the severe clinical disabilities resulting from injury to the brain and spinal cord.
Paxillin: A cytoskeletal target for tyrosine kinases
Authors: Turner Christopher E. 
Published: February 2005

AbstractPaxillin is a recently identified member of the complex of cytoskeletal proteins that is found concentrated in cultured cells and in vivo at the cytoplasmic face of regions of cell attachment to the extracellular matrix. These sites, in view of their close proximity to the extracellular matrix, are well positioned to act as signal‐transducing centers to ‘report on’ changes in the cells, immediate environment. Recent findings indicate that such signals are in part mediated through the activation of tyrosine kinases concentrated at the sites of adhesion. Changes in the phosphotyrosine content of paxillin accompanying this elevation in kinase activity suggest that paxillin may be an important intermediary in these pathways.
How meiotic cells deal with non‐exchange chromosomes
Authors: Wolf Klaus Werner 
Published: February 2005

AbstractThe chromosomes which segregate in anaphase I of meiosis are usually physically bound together through chiasmata. This association is necessary for proper segregation, since univalents sort independently from one another in the first meiotic division and this frequently leads to genetically unbalanced offspring. There are, however, a number of species where genetic exchanges in the form of meiotic cross‐overs, the prerequisite of the formation of chiasmata, are routinely missing in one sex or between specific chromosomes. These species nevertheless manage to segregate these non‐exchange chromosomes. There are four direct modes for associating achiasmatic chromosomes: (a) modified SC, (b) adhesion of chromatids comparable to somatic pairing, (c) ‘stickiness’ of heterochromatin or (d) specific ‘segregation bodies’, consisting of material structurally different from chromatin. There is also the possibility that the spindlepossibly joining forces with the kinetochores‐carries out the faithful segregation of univalents which are not directly physically attached to one another. Finally, amphitelic orientation of univalents in metaphase I and pairing of the chromatids in meiosis II appear to ensure correct segregation as well.
The flavonoid biosynthetic pathway in plants: Function and evolution
Authors: Koes Ronald E. , Quattrocchio Francesca , Mol Joseph N. M. 
Published: February 2005

AbstractFlavonoids are a class of low molecular weight phenolic compounds that is widely distributed in the plant kingdom. They exhibit a diverse spectrum of biological functions and play an important role in the interaction between plants and their environment. Flavonoids not only protect the plant from the harmful effects of UV irradiation but also play a crucial role in the sexual reproduction process. A special class of flavonoid polymers, the tannins, plays a structural role in the plant. Yet other classes of flavonoids, flavonols and anthocyanins, have been implicated in the attraction of pollinators. Certain flavonoids participate in the interaction between plants and other organisms such as symbiotic bacteria and parasites. This raises the intriguing question as to how these different compounds arose and evolved. Based on taxonomy and molecular analysis of gene expression patterns it is possible to deduce a putative sequence of acquisition of the different branches of the biosynthetic pathway and their regulators.
Signaling mechanisms in induction of the R7 photoreceptor in the developing Drosophila retina
Authors: Yamamoto Daisuke 
Published: February 2005

AbstractThe Drosophila compound eye is an excellent experimental system for analysing fate induction of identifiable single cells. Each ommatidium, a unit eye, contains eight photoreceptors (R1‐R8), and the differentiation of these photoreceptors occurs in the larval eye imaginal disc in discrete steps: first R8 is determined, then R2/R5, R3/R4, R1/R6 and finally R7. Induction of R7, in particular, has been extensively studied at the molecular level. The R8 photoreceptor presents on its surface a ligand, Bride of Sevenless, that binds and activates Sevenless receptor tyrosine kinase in the R7 precursor. Autophosphorylated Sevenless initiates a Ras1‐mediated cascade, which eventually activates transcription factors in the nucleus via Raf1 and MAP kinases, resulting in R7 development. However, recent studies indicate that Sevenless (Sev) functions just to neuralize the cell and has no role in R7 fate determination per se. It appears that the R7 fate may represent the lowest rung of a ‘neuronal ground state’, which is attained without any specific inductive cue. It is plausible that the R7 precursor is actively prevented from taking on the neuronal fate and this inhibition is removed by activation of Sev.
Trinucleotide repeat expansions and human genetic disease
Authors: Bates Gillian , Lehrach Hans 
Published: February 2005

AbstractTrinucleotide repeat expansions are now a well‐established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar musclar atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG‐rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3′ untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed.
Membrane ruffling and signal transduction
Authors: Ridley Anne J. 
Published: February 2005

AbstractOne of the earliest structural changes observed in cells in response to many extracellular factors is membrane ruffling: the formation of motile cell surface protrusions containing a meshwork of newly polymerized actin filaments. It is becoming clear that actin reorganization is an integral part of early signal transduction pathways, and that many signalling molecules interact with the actin cytoskeleton. The small GTP‐binding protein Rac is a key regulator of membrane ruffling, and proteins that can regulate Rac activity, such as Bcr, are likely to act on this signalling pathway. In addition, several previously characterized signal transducing molecules are implicated in the membrane‐ruffling response, including Ras, the adaptor protein Grb2, phosphatidyl inositol 3‐kinase, phospholipase A2 and phorbol ester‐responsive proteins. Changes in polyphosphoinositide metabolism and intracellular Ca2+ levels may also play a role. A number of actin‐binding and organizing proteins localize to membrane ruffles and are potential targets for these signal transducing molecules.
From embryonal carcinoma cells to neurons: The P19 pathway
Authors: Bain Gerard , Ray William J. , Yao Min , Gottlieb David I. 
Published: February 2005

AbstractThe differentiation of mammalian neurons during development is a highly complex process involving regulation and coordination of gene expression at multiple steps. The P19 mouse embryonal carcinoma cell line is a suitable model system with which to analyze regulation of neuronal differentiation. These multipotential cells can be maintained and propagated in tissue culture in an undifferentiated state. Exposure of aggregated P19 cells to retinoic acid results in the differentiation of cells with many fundamental phenotypes of mammalian neurons. Undifferentiated P19 cells are amenable to genetic manipulations such as transfection and establishment of stable clonal cell lines expressing introduced genes. Proteins that play a key role in the neuronal differentiation of P19 cells are beginning to be identified. These include retinoic acid receptors, the epidermal growth factor receptor and the transcription factors Oct‐3 and Brn‐2. The biological and technical advantages of this system should facilitate deeper analysis of the activities of proteins that play a role in neuronal differentiation.
Roots: Mutation frequency decline revisited
Authors: Witkin Evelyn M. 
Published: February 2005

Abstract‘Mutation frequency decline’ (MFD) was discovered about forty years ago, and described as the disappearance of a particular class of ultraviolet light‐induced mutations in Escherichia coli that occurred whenever protein synthesis was briefly inhibited immediately after irradiation. Later, MFD was interpreted as an excision repair anomaly uniquely affecting nonsense suppressor mutations induced in certain tRNA genes. Never fully understood, MFD has recently been linked to the newly discovered transcription‐coupled rapid repair of ultraviolet damage on the templat strand of active genes. This article recalls the emergence and development of the MFD story, and offers a new way to explain it and its relation to strand‐specific excision repair.
Arrested development: Understanding v‐abl
Authors: Kerr Lawrence D. 
Published: February 2005

AbstractThe protein tyrosine kinase activity of the v‐abl oncogene has been demonstrated to subvert the normal second messenger systems used by lymphoid cells for growth and differentiation. Transformation of bone marrow with the Abelson murine leukemia virus results in the appearance of B cell lineage cells arrested at the pre‐B cell stage. Recent reports have characterized these cells expressing high v‐abl kinase activity as deficient in detectable NF‐kB DNA binding activity and low level RAG gene expression. These observations suggest that v‐abl may be inhibiting the differentiation of B cells by blocking these two crucial elements in the maturation pathway.
Profilin: At the crossroads of signal transduction and the actin cytoskeleton
Authors: Sohn Richard H. , Goldschmidt‐Clermont Pascal J. 
Published: February 2005

AbstractDespite its small size, profilin is an amazingly diverse and sophisticated protein whose precise role in cells continues to elude the understanding of researchers 15 years after its discovery. Its ubiquity, abundance and necessity for life in more evolved organisms certainly speaks for its exterme importance in cell function. So far, three ligands for profilin have been well‐characterized in vitro: actin monomers, membrane polyphosphoinositides and poly‐L‐proline. In the years following its discovery, profilin's role in vivo progressed from that of a simple actin‐binding protein which inhibits actin polymerization, to one which, as an important regulator of the cytoskeleton, can even promote actin polymerization under the appropriate circumstances. In addition, interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways.
Beta thymosins as actin binding peptides
Authors: Safer Daniel , Nachmias Vivianne T. 
Published: February 2005

AbstractThe beta thymosins are a highly conserved family of strongly polar 5 kDa polypeptides that are widely distributed among vertebrate classes; most are now known to bind to monomeric actin and inhibit its polymerization. One beta thymosin, beta four, (Tβ4) is the predominant form in mammalian cells, present at up to 0.5 mM. Many species are known to produce at least two beta thymosin isoforms, in some cases in the same cell. Their expression can be separately regulated. When present outside the cell, the N‐terminal tetrapeptide of beta four appears to affect cell cycle regulation; beta thymosins or smaller fragments derived from them may have additional regulatory functions. We suggest that many developmental changes in beta thymosin levels within cells and tissues may be related to changes in G‐actin pool size.
Transcription factors and the regulation of haemopoiesis: Lessons from GATA and SCL proteins
Authors: Bockamp E.‐O. , McLaughlin F. , Murrell A. , Green A. R. 
Published: February 2005

AbstractOne of the central issue of developmental biology concerns the molecular mechanisms whereby a multipotent cell gives rise to distinct differentiated progeny. Differences between specialised cell types reflect variations in their patterns of gene expression. The regulation of transcription initiation is an important control point for gene expression and it is, therefore, not surprising that transcription factors play a pivotal role in mammalian development and differentiation.Haemopoiesis offers a uniquely tractable system for the study of lineage commitment and differentiation. The importance of transcription factor in the normal regulation of haemopoiesis is underlined by the frequency with which transcription factors are targeted by leukaemogenic mutations. Studies of the function and regulation of haemopoietic transcription factors, especially those expressed in lineage‐restricted patterns, should greatly increase our understanding of the molecular control of haemopoiesis. In this review we have focused on insights provided by recent studies of the GATA and SCL proteins.
Regulation of the ras signalling network
Authors: Maruta Hiroshi , Burgess Antony W. 
Published: February 2005

AbstractThe mitogenic action of cytokines such as epidermal growth factor (EGF)d̊ or platelet dericed growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor‐induced and oncogenic activation of Ras involve the conversion of Ras from the GDP‐bound (D‐Ras) to the GTP‐bound (T‐Ras) forms. T‐Ras activates a network of protein kinases including c‐Mos, c‐Raf‐1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c‐Jun, c‐Myc and c‐Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the coversion of T‐Ras to D‐Ras. A series of small NF1 fragments, which bind T‐Ras, as well as truncated forms or derivatives of c‐Raf‐1, c‐Jun and c‐Myc, are capable of blocking the T‐Ras‐activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T‐Ras‐associated tumors, which represent more than 30% of total human carcinomas.
Roots: The thymus: Maestro of the immune system
Authors: Miller Jacques F. A. P. 
Published: February 2005

AbstractThe thymus has been an enigmatic organ for centuries. Its true function was revealed only in 1961 when it was shown to be responsible for the proper development of the immune system. This finding has revolutionized the science of immunology and has led to a better understanding of the mechanisms involved in resistance to infections and of the pathogenesis of autoimmune and immunodeficiency diseases.
White gene expression, repressive chromatin domains and homeotic gene regulation in Drosophila
Authors: Pirrotta Vincenzo , Rastelli Luca 
Published: February 2005

AbstractThe use of Drosophila chromosomal rearrangements and transposon constructs involving the white gene reveals the existence of repressive chromatin domains that can spread over considerable genomic distances. One such type of domain is found in heterochromatin and is responsible for classical position‐effect variegation. Another type of repressive domain is established, beginning at specific sequences, by complexes of Polycomb Group proteins. Such complexes, which normally regulate the expression of many genes, including the homeotic loci, are responsible for silencing, white gene variegation, pairing‐dependent effects and insertional targeting.
Recent advances in drug design methods: Where will they lead?
Authors: Dean Philip M. 
Published: February 2005

AbstractDrug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so‐called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has no general analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non‐peptide scaffolds.