Home About us Contact
|
Home About us Contact | ||
|
|
||
Quiescence
Selected AbstractsNeoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesisMOLECULAR CARCINOGENESIS, Issue 12 2006Masahiro Yamamoto Abstract Cyclin D1 overexpression is a frequent change in hepatocellular carcinomas (HCCs). Our present study demonstrated that cyclin D1 overexpression with abundant cyclin E, cdk4, cdk2, and p27Kip1 (p27) occurred in neoplastic hepatocytes from the early stage of mouse hepatocarcinogenesis. While cyclin D1 expression was mainly found in the cytoplasm of the tumor cells, it shifted to the nucleus in association with cell proliferation after the animals were subjected to a partial hepatectomy (PH), and then returned once more to the cytoplasm when the cells became quiescent. Inhibition of PI3 kinase (PI3K) by Ly294002 in mouse HCC cells in vitro suppressed the nuclear shift of cyclin D1 as well as cell proliferation, while PI3K activation by PTEN suppression failed to induce nuclear shift of cyclin D1, suggesting that PI3K activation is essential but not sufficient for the cyclin D1 nuclear shift. While MEK-ERK1/2 inhibition by PD98059 and mTOR inhibition by rapamycin affected the cyclin D1 nuclear shift and cell proliferation to a lesser extent, both these inhibitors reduced cyclin D1 levels. Finally, although p27, cdk4 and calmodulin (CaM) were detected in the cyclin D1 immunoprecipitates from both quiescent and proliferating HCC cells, Hsc70 and SSeCKS were detected only in the immunoprecipitate from quiescent cells, and p21Waf1/Cip1 (p21) was detected only in that from proliferating cells, suggesting that the cyclin D1 complex is different in quiescent and proliferating cells. These observations indicate that the nuclear/cytoplasmic localization of cyclin D1 plays an important role in the proliferation/quiescence of neoplastic hepatocytes. © 2006 Wiley-Liss, Inc. [source] A definition of and linguistic support for partial quiescenceCONCURRENCY AND COMPUTATION: PRACTICE & EXPERIENCE, Issue 8 2008Billy Yan-Kit Man Abstract The global quiescence (GQ) of a distributed computation (or distributed termination detection) is an important problem. Some concurrent programming languages and systems provide GQ detection as a built-in feature so that programmers do not need to write special synchronization code to detect quiescence. This paper introduces partial quiescence (PQ), which generalizes quiescence detection to a specified part of a distributed computation. PQ is useful, for example, when two independent concurrent computations that both rely on GQ need to be combined into a single program. The paper describes how we have designed and implemented a PQ mechanism within an experimental version of the JR concurrent programming language, and have gained experience with several representative applications. Our early results are promising qualitatively and quantitatively. Copyright © 2007 John Wiley & Sons, Ltd. [source] Cell proliferation in the developing lateral line system of zebrafish embryosDEVELOPMENTAL DYNAMICS, Issue 2 2005Laurent Laguerre Abstract The sensory organs of the embryonic lateral line system are deposited by migrating primordia that originate in the otic region. Here, we examine the pattern of cell proliferation in the posterior lateral line system. We conclude that three phases of cell proliferation are involved in the generation of this system, separated by two phases of mitotic quiescence. The first phase corresponds to generalized proliferation during gastrulation, followed by a first period of quiescence that may be related to the determination of the lateral line precursor cells. A second phase of proliferation takes place in the placode and migrating primordium. This region is organized in annuli that correspond to the expression of proneural/neurogenic genes. A second period of quiescence follows, corresponding to deposition and differentiation of the sensory organs. The third period of proliferation corresponds to continued renewal of hair cells by division of support cells within each sensory organ. Developmental Dynamics 233:466,472, 2005. © 2005 Wiley-Liss, Inc. [source] A putative role for cell cycle-related proteins in microtubule-based neuroplasticityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2009Stefanie Schmetsdorf Abstract Cyclins and cyclin-dependent kinases (Cdks) are the main components that control the orderly progression through cell cycle. In the mature nervous system, terminally differentiated neurons are permanently withdrawn from cell cycle, as mitotic quiescence is essential for the functional stability of the complexly wired neuronal system. Recently, we characterized the expression and colocalization of cyclins and Cdks in terminally differentiated pyramidal neurons. The functional impact of the expression of cell cycle-related proteins in differentiated neurons, however, has not been elucidated yet. In the present study, we show by immunoelectron microscopy and immunobiochemical methods an association of cyclins and Cdks with the microtubule network. Cyclins D, E, A and B as well as Cdks 1, 2 and 4 were also found to be associated with the microtubule-associated protein tau. Cyclin/Cdk complexes, in addition, exhibit kinase activity towards tau. In vitro, downregulation of cyclins and Cdks by a siRNA approach and by pharmacological inhibition promotes neurite extension. Taken together, these results indicate that the expression of cell cycle-related proteins in terminal differentiated neurons is associated with physiological functions beyond cell cycle control that might be involved in microtubule-based mechanisms of neuroplasticity. [source] Proliferative responses to growth factors decline rapidly during postnatal maturation of mammalian hair cell epitheliaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2007Rende Gu Abstract Millions of lives are affected by hearing and balance deficits that arise as a consequence of sensory hair cell loss. Those deficits affect mammals permanently, but hearing and balance recover in nonmammals after epithelial supporting cells divide and produce replacement hair cells. Hair cells are not effectively replaced in mammals, but balance epithelia cultured from the ears of rodents and adult humans can respond to hair cell loss with low levels of supporting cell proliferation. We have sought to stimulate vestibular proliferation; and we report here that treatment with glial growth factor 2 (rhGGF2) yields a 20-fold increase in cell proliferation within sheets of pure utricular hair cell epithelium explanted from adult rats into long-term culture. In epithelia from neonates, substantially greater proliferation responses are evoked by rhGGF2 alone, insulin alone and to a lesser degree by serum even during short-term cultures, but all these responses progressively decline during the first 2 weeks of postnatal maturation. Thus, sheets of utricular epithelium from newborn rats average >,40% labelling when cultured for 72 h with bromo-deoxyuridine (BrdU) and either rhGGF2 or insulin. Those from 5- and 6-day-olds average 8,15%, 12-day-olds average <,1% and after 72 h there is little or no labelling in epithelia from 27- and 35-day-olds. These cells are the mammalian counterparts of the progenitors that produce replacement hair cells in nonmammals, so the postnatal quiescence described here is likely to be responsible for at least part of the mammalian ear's unique vulnerability to permanent sensory deficits. [source] A population-based model of the nonlinear dynamics of the thalamocortical feedback network displays intrinsic oscillations in the spindling (7,14 Hz) rangeEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2005Nada A. B. Yousif Abstract The thalamocortical network is modelled using the Wilson,Cowan equations for neuronal population activity. We show that this population model with biologically derived parameters possesses intrinsic nonlinear oscillatory dynamics, and that the frequency of oscillation lies within the spindle range. Spindle oscillations are an early sleep oscillation characterized by high-frequency bursts of action potentials followed by a period of quiescence, at a frequency of 7,14 Hz. Spindles are generally regarded as being generated by intrathalamic circuitry, as decorticated thalamic slices and the isolated thalamic reticular nucleus exhibit spindles. However, the role of cortical feedback has been shown to regulate and synchronize the oscillation. Previous modelling studies have mainly used conductance-based models and hence the mechanism relied upon the inclusion of ionic currents, particularly the T-type calcium current. Here we demonstrate that spindle-frequency oscillatory activity can also arise from the nonlinear dynamics of the thalamocortical circuit, and we use bifurcation analysis to examine the robustness of this oscillation in terms of the functional range of the parameters used in the model. The results suggest that the thalamocortical circuit has intrinsic nonlinear population dynamics which are capable of providing robust support for oscillatory activity within the frequency range of spindle oscillations. [source] Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell linesFEBS JOURNAL, Issue 16 2004Georgia Xouri Licensing origins for replication upon completion of mitosis ensures genomic stability in cycling cells. Cdt1 was recently discovered as an essential licensing factor, which is inhibited by geminin. Over-expression of Cdt1 was shown to predispose cells for malignant transformation. We show here that Cdt1 is down-regulated at both the protein and RNA level when primary human fibroblasts exit the cell cycle into G0, and its expression is induced as cells re-enter the cell cycle, prior to S phase onset. Cdt1's inhibitor, geminin, is similarly down-regulated upon cell cycle exit at both the protein and RNA level, and geminin protein accumulates with a 3,6 h delay over Cdt1, following serum re-addition. Similarly, mouse NIH3T3 cells down-regulate Cdt1 and geminin mRNA and protein when serum starved. Our data suggest a transcriptional control over Cdt1 and geminin at the transition from quiescence to proliferation. In situ hybridization and immunohistochemistry localize Cdt1 as well as geminin to the proliferative compartment of the developing mouse gut epithelium. Cdt1 and geminin levels were compared in primary cells vs. cancer-derived human cell lines. We show that Cdt1 is consistently over-expressed in cancer cell lines at both the protein and RNA level, and that the Cdt1 protein accumulates to higher levels in individual cancer cells. Geminin is similarly over-expressed in the majority of cancer cell lines tested. The relative ratios of Cdt1 and geminin differ significantly amongst cell lines. Our data establish that Cdt1 and geminin are regulated at cell cycle exit, and suggest that the mechanisms controlling Cdt1 and geminin levels may be altered in cancer cells. [source] Terrestrial invertebrates inhabiting lowland river floodplains of Central Amazonia and Central Europe: a reviewFRESHWATER BIOLOGY, Issue 4 2002JOACHIM ADIS 1.,Amazonian terrestrial invertebrates produce high population densities during favourable periods and may suffer a drastic decrease during occasional floods and droughts. However, the monomodal, predictable flood pulse of the larger Amazonian rivers favours the development of morphological (respiratory organs, wing-dimorphism), phenological (synchronization of life cycles, univoltine mode of life), physiological (flooding ability, gonad dormancy, alternating number of developmental stages), and behavioural adaptations (migration, temporal diving) with numerous interactions. 2.,In lowlands of Central Europe, the flood pulse of large rivers is less predictable than in Central Amazonia and is superimposed by the seasonal light/temperature pulse (summer/winter regime). Some terrestrial invertebrates show physiological resistance against inundation or drought, phenologies fitting the normal annual rhythm of water level fluctuation (quiescence or diapause of eggs or adult invertebrates), high dispersal ability and migration. However, most species survive simply using a `risk strategy', combining high reproduction rates, dispersal and reimmigration following catastrophic events. 3.,The diversity of species in terrestrial invertebrates is lower in lowland riverine ecosystems of Central Amazonia and Central Europe compared with the respective uplands because of flood stress in these systems. However, floodplains in Central Amazonia possess a greater number of endemic species in comparison with Central European floodplains because of long periods of fairly stable climatic conditions in comparison with large palaeoclimatic changes in Central Europe. [source] Archaeological evidence for destructive earthquakes in Sicily between 400 B.C. and A.D. 600GEOARCHAEOLOGY: AN INTERNATIONAL JOURNAL, Issue 2 2009Carla Bottari A systematic archaeoseismological study indicates that at least three earthquakes occurred between 400 B.C. and A.D. 600, causing destruction to numerous ancient monuments in Sicily. Evidence for these earthquakes comes from the collapse style of buildings (toppled walls, column drums in a domino-style arrangement, directional collapses, etc.), and the exclusion of other likely causes for such effects. Dating of inferred earthquakes is based on coins (accurate to within 5,10 years), pottery (accurate to within 50,200 years), and other artifacts. The oldest documented earthquake occurred between 370 and 300 B.C. and caused the collapse of two Greek temples in Selinunte. This otherwise poorly documented event was probably also the cause of extensive destruction in northeastern Sicily in the first century A.D. Destruction of some sites may be assigned to an earthquake that occurred between 360 and 374 and correlates with the A.D. 365 seismic sequence known from historical sources. This study covers a wider region and provides a more precise dating of earthquakes than previous studies. Although it focuses on a certain period (4th,3rd centuries B.C., 4th,7th centuries A.D.), it indicates that the period before A.D. 1000 is not a period of seismic quiescence in Sicily as was previously believed, but to a period characterized by strong and destructive earthquakes. © 2009 Wiley Periodicals, Inc. [source] Tectono-sedimentary evolution of the northernmost margin of the NE German Basin between uppermost Carboniferous and Late Permian (Rotliegend)GEOLOGICAL JOURNAL, Issue 1 2001H. Rieke Abstract The tectono-sedimentary evolution of the Rotliegend deposits of the northernmost margin of NE German Basin (NEGB) has been analysed on the basis of detailed sedimentary logs of 300,m of core material together with the re-evaluation of 600,km of seismic lines. Three distinct phases were recognized. During the initial Phase I, basin geometry was largely controlled by normal faulting related to deep-seated ductile shearing leading to a strong asymmetric shape, with a steep fault-controlled eastern margin and a gently, dipping western margin. The results of forward modelling along a cross-section fit the basin geometry in width and depth and reveal a footwall uplift of c. 1000,m. Adjacent to the steep faults, local sedimentation of Lithofacies Type I was confined to non-cohesive debris flow-dominated alluvial fans, whereas the gently dipping western margin was dominated by alluvial-cone sedimentation. During the post-extensional period (Phase II), cooling of the lithosphere generated additional accommodation space. The sediments of Lithofacies Type II, comprising mainly clast-supported conglomerates, are interpreted as braided ephemeral stream flow-surge deposits. Tectonic quiescence and an increase in flood events resulting from wetter climate led to progradation of this facies over the entire region. At the end of this period, the accommodation space was almost completely filled resulting in a level topography. Phase III was controlled by the thermal-induced subsidence of the southerly located NEGB in post-Illawarra times. The formerly isolated region tilted towards the SW, thus forming the northern margin of the NEGB during uppermost Havel and Elbe Subgroup times. The sediments of Lithofacies Type III were divided into a marginal sandstone-dominated environment and a finer-grained facies towards the SW. The former consists of poorly-sorted coarse-grained sandstones of a proximal and medial ephemeral stream floodplain facies. The latter comprise mud flat fines and fine-grained distal ephemeral stream deposits. The end of the tectono-sedimentary evolution is marked by the basinwide Zechstein transgression. Copyright © 2001 John Wiley & Sons, Ltd. [source] An improved region,time,length algorithm applied to the 1999 Chi-Chi, Taiwan earthquakeGEOPHYSICAL JOURNAL INTERNATIONAL, Issue 3 2006Chien-Chih Chen SUMMARY By means of the region,time,length (RTL) algorithm, which is widely used for investigating the precursory seismicity changes in China, Italy, Japan, Russia and Turkey, we examine the precursory seismic activity occurred prior to the 1999, Mw= 7.6, Chi-Chi earthquake around its epicentre. Based on our calculation of the RTL values, the epicentral area has been found to strongly exhibit the signature of anomalous activity, associated with the seismic quiescence and activation, before the main shock. Also proposed in this study is a helpful method for determining two important parameters used in the RTL analysis, the characteristic time and distance. Such method will largely reduce the ambiguity in the original RTL algorithm. [source] Epidermal growth factor receptor expression regulates proliferation in the postnatal rat retinaGLIA, Issue 2 2006Jennie L. Close Abstract Epidermal growth factor (EGF) is known to promote proliferation of both retinal progenitors and Muller glia in vitro, but several questions remain concerning an in vivo role for this factor. In this study, we investigated whether the EGF receptor (EGFR) is necessary for the maintenance of normal levels of progenitor and Muller glial proliferation in vivo. Here, we show that (1) mice with homozygous deletion of the Egfr gene have reduced proliferation in late stages of retinal histogenesis, (2) EGF is mitogenic for Müller glia in vivo during the first two postnatal weeks in the rodent retina, (3) the effectiveness of EGF as a Müller glial mitogen declines in parallel with the decline in EGFR expression as the retina matures, and (4) following damage to the retina from continuous light exposure, EGFR expression is up-regulated in Müller glia to levels close to those in the neonatal retina, resulting in a renewed mitotic response to EGF. Together with previous results from other studies, these data indicate that the downregulation of a growth factor receptor is one mechanism by which glial cells maintain mitotic quiescence in the mature nervous system. © 2006 Wiley-Liss, Inc. [source] Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferationGLIA, Issue 1 2005Jaime Struve Abstract Astrocyte proliferation is tightly controlled during development and in the adult nervous system. In the present study, we find that a high-molecular-weight (MW) form of the glycosaminoglycan hyaluronan (HA) is found in rat spinal cord tissue and becomes degraded soon after traumatic spinal cord injury. Newly synthesized HA accumulates in injured spinal cord as gliosis proceeds, such that high-MW HA becomes overabundant in the extracellular matrix surrounding glial scars after 1 month. Injection of hyaluronidase, which degrades HA, into normal spinal cord tissue results in increased numbers of glial fibrillary acidic protein (GFAP)-positive cells that also express the nuclear proliferation marker Ki-67, suggesting that HA degradation promotes astrocyte proliferation. In agreement with this observation, adding high- but not low-MW HA to proliferating astrocytes in vitro inhibits cell growth, while treating confluent, quiescent astrocyte cultures with hyaluronidase induces astrocyte proliferation. Collectively, these data indicate that high-MW HA maintains astrocytes in a state of quiescence, and that degradation of HA following CNS injury relieves growth inhibition, resulting in increased astrocyte proliferation. © 2005 Wiley-Liss, Inc. [source] Copepod life cycle adaptations and success in response to phytoplankton spring bloom phenologyGLOBAL CHANGE BIOLOGY, Issue 6 2009HANNO SEEBENS Abstract In a seasonal environment, the timing of reproduction is usually scheduled to maximize the survival of offspring. Within deep water bodies, the phytoplankton spring bloom provides a short time window of high food quantity and quality for herbivores. The onset of algal bloom development, however, varies strongly from year to year due to interannual variability in meteorological conditions. Furthermore, the onset is predicted to change with global warming. Here, we use a long-term dataset to study (a) how a cyclopoid copepod, Cyclops vicinus, is dealing with the large variability in phytoplankton bloom phenology, and (b) if bloom phenology has an influence on offspring numbers. C. vicinus performed a two-phase dormancy, that is, the actual diapause of fourth copepodid stages at the lake bottom is followed by a delay in maturation, that is, a quiescence, within the fifth copepodid stage until the start of the spring bloom. This strategy seems to guarantee a high temporal match of the food requirements for successful offspring development, especially through the highly vulnerable naupliar stages, with the phytoplankton spring bloom. However, despite this match with food availability in all study years, offspring numbers, that is, offspring survival rates were higher in years with an early start of the phytoplankton bloom. In addition, the phenology of copepod development suggested that also within study years, early offspring seems to have lower mortality rates than late produced offspring. We suggest that this is due to a longer predator-free time period and/or reduced time stress for development. Hence, within the present climate variability, the copepod benefited from warmer spring temperatures resulting in an earlier phytoplankton spring bloom. Time will show if the copepod's strategy is flexible enough to cope with future warming. [source] Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytes in vivo,HEPATOLOGY, Issue 1 2006Nils-Holger Zschemisch Cyclin E1 controls G1/S phase transition of the eukaryotic cell cycle. We report the impact of alternative spliced cyclin E1 isoforms on cell cycle regulation in hepatocytes. We show that expression of new cyclin E1 mRNA variants IN3, ,4, and ,5 is associated with retarded proliferation in murine hepatocellular carcinoma. Additionally, we demonstrate that a new cyclin E1 isoform ,3/8 lacking the central part of wild-type mRNA is expressed predominantly in nonproliferating murine hepatocytes. Following partial hepatectomy, ,3/8 is downregulated when hepatocytes enter the cell cycle from quiescence. The ,3/8 protein does not exhibit any cyclin box motif but binds cyclin-dependent kinase 2 without stimulating kinase activity. We demonstrate that ,3/8 lacks any nuclear localization signal and is exclusively located in the cytoplasm. Overexpression of ,3/8 in cultured cells leads to a delayed G0-G1 transition, indicating that this splice variant helps to maintain a quiescent state of hepatocytes. In conclusion, we identified an isoform of cyclin E1 involved in G0 maintenance and suggest an additional mechanism for cell cycle control. (HEPATOLOGY 2006;44:164,173.) [source] Developing a post-fire flood chronology and recurrence probability from alluvial stratigraphy in the Buffalo Creek watershed, Colorado, USA,HYDROLOGICAL PROCESSES, Issue 15 2001John G. Elliott Abstract Stratigraphic and geomorphic evidence indicate floods that occur soon after forest fires have been intermittent but common events in many mountainous areas during the past several thousand years. The magnitude and recurrence of these post-fire flood events reflects the joint probability between the recurrence of fires and the recurrence of subsequent rainfall events of varying magnitude and intensity. Following the May 1996 Buffalo Creek, Colorado, forest fire, precipitation amounts and intensities that generated very little surface runoff outside of the burned area resulted in severe hillslope erosion, floods, and streambed sediment entrainment in the rugged, severely burned, 48 km2 area. These floods added sediment to many existing alluvial fans, while simultaneously incising other fans and alluvial deposits. Incision of older fans revealed multiple sequences of fluvially transported sandy gravel that grade upward into charcoal-rich, loamy horizons. We interpret these sequences to represent periods of high sediment transport and aggradation during floods, followed by intervals of quiescence and relative stability in the watershed until a subsequent fire occurred. An alluvial sequence near the mouth of a tributary draining a 0·82 km2 area indicated several previous post-fire flood cycles in the watershed. Dendrochronologic and radiocarbon ages of material in this deposit span approximately 2900 years, and define three aggradational periods. The three general aggradational periods are separated by intervals of approximately nine to ten centuries and reflect a ,millennium-scale' geomorphic response to a closely timed sequence of events: severe and intense, watershed-scale, stand-replacing fires and subsequent rainstorms and flooding. Millennium-scale aggradational units at the study site may have resulted from a scenario in which the initial runoff from the burned watershed transported and deposited large volumes of sediment on downstream alluvial surfaces and tributary fans. Subsequent storm runoff may have produced localized incision and channelization, preventing additional vertical aggradation on the sampled alluvial deposit for several centuries. Two of the millennium-scale aggradational periods at the study site consist of multiple gravel and loam sequences with similar radiocarbon ages. These closely dated sequences may reflect a ,multidecade-scale' geomorphic response to more frequent, but aerially limited and less severe fires, followed by rainstorms of relatively common recurrence. Published in 2001 John Wiley & Sons, Ltd. [source] Gene positional changes relative to the nuclear substructure during carbon tetrachloride-induced hepatic fibrosis in ratsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2004Apolinar Maya-Mendoza Abstract In the interphase nucleus the DNA of higher eukaryotes is organized in loops anchored to a substructure known as the nuclear matrix (NM). The topological relationship between gene sequences located in the DNA loops and the NM appears to be very important for nuclear physiology because processes such as replication, transcription, and processing of primary transcripts occur at macromolecular complexes located at discrete sites upon the NM. Mammalian hepatocytes rarely divide but preserve a proliferating capacity that is displayed in vivo after specific stimulus. We have previously shown that transient changes in the relative position of specific genes to the NM occur during the process of liver regeneration after partial ablation of the liver, but also that such changes correlate with the replicating status of the cells. Moreover, since chronic exposure to carbon tetrachloride (CCl4) leads to bouts of hepatocyte damage and regeneration, and eventually to non-reversible liver fibrosis in the rat, we used this animal model in order to explore if genes that show differential activity in the liver change or modify their relative position to the NM during the process of liver fibrosis induction. We found that changes in the relative position of specific genes to the NM occur during the chronic administration of CCl4, but also that such changes correlate with the proliferating status of the hepatocytes that goes from quiescence to regeneration to replicative senescence along the course of CCl4 -induced liver fibrosis, indicating that specific configurations in the higher-order DNA structure underlie the stages of progression towards liver fibrosis. © 2004 Wiley-Liss, Inc. [source] Anti-aging activity of the Ink4/Arf locusAGING CELL, Issue 2 2009Ander Matheu Summary The proteins encoded by the Ink4/Arf locus, p16Ink4a, p19Arf and p15Ink4b are major tumour suppressors that oppose aberrant mitogenic signals. The expression levels of the locus are progressively increased during aging and genome-wide association studies have linked the locus to a number of aging-associated diseases and frailty in humans. However, direct measurement of the global impact of the Ink4/Arf locus on organismal aging and longevity was lacking. In this work, we have examined the fertility, cancer susceptibility, aging and longevity of mice genetically modified to carry one (Ink4/Arf -tg) or two (Ink4/Arf -tg/tg) intact additional copies of the locus. First, increased gene dosage of Ink4/Arf impairs the production of male germ cells, and in the case of Ink4/Arf -tg/tg mice results in a Sertoli cell-only-like syndrome and a complete absence of sperm. Regarding cancer, there is a lower incidence of aging-associated cancer proportional to the Ink4/Arf gene dosage. Interestingly, increased Ink4/Arf gene dosage resulted in lower scores in aging markers and in extended median longevity. The increased survival was also observed in cancer-free mice indicating that cancer protection and delayed aging are separable activities of the Ink4/Arf locus. In contrast to these results, mice carrying one or two additional copies of the p53 gene (p53 -tg and p53 -tg/tg) had a normal longevity despite their increased cancer protection. We conclude that the Ink4/Arf locus has a global anti-aging effect, probably by favouring quiescence and preventing unnecessary proliferation. [source] Inhibitory effect of osmotic concentration, potassium and pH on motility of the sperm of the North American burbot Lota lota maculosaJOURNAL OF FISH BIOLOGY, Issue 1 2007M. D. Zuccarelli Seminal plasma factors maintaining North American (NA) burbot Lota lota maculosa sperm quiescent were examined. Sperm were diluted into buffered saline solutions of various compositions and motility assessed. After 1 h in these solutions at 10° C, aliquots of the suspension were diluted with tap water and motility again assessed. Dilution of sperm in an incubation solution containing Ca2+ in the absence of K+ initiated sperm motility resulting in low motility when sperm were subsequently diluted in tap water. Incubation solutions with osmolalities >200 mOsm kg,1 and containing 12·5 mM K+ prevented the onset of sperm motility and were associated with maximal sperm motility upon dilution in tap water. Sperm maintained at lower osmolalities exhibited limited motility upon dilution in tap water indicating interdependence between K+ and osmolality in maintaining sperm quiescent in the presence of Ca2+. Sperm kept in incubation solution at pH values < c. 7·5 for 1 h demonstrated reduced motility when subsequently diluted in tap water. That motility of sperm was pH sensitive was further indicated by CO2 inhibition of motility. Therefore, NA burbot sperm are probably maintained in an immotile state, yet with potential for motility, by combination of high K+, osmolality and possibly pH. The results from this study differ from published information on sperm quiescence in the temporally and geographically distinct Eurasian burbot Lota lota lota. [source] Testicular activity is restored by melatonin replacement after suprachiasmatic nucleus lesion or superior cervical ganglionectomy in minkJOURNAL OF PINEAL RESEARCH, Issue 1 2002Daniel L Maurel Subcutaneous melatonin implants were inserted in mink subjected to natural (autumn) or experimental gonadostimulatory short-days (4L:20D), after lesion of the suprachiasmatic nucleus (SCNx) or after superior cervical ganglionectomy (SCGx). Gonad stimulation was assessed by measuring testicular volume and plasma testosterone level. In SCNx and SCGx animals, all measurements were indicative of sexual quiescence. In contrast, both SCNx and SCGx animals with melatonin, maintained in natural or experimental gonadostimulating short-days, showed an increase in testicular activity 2 months after melatonin implantation. Thus, melatonin (and pineal activity) is a prerequisite for the photoperiodic stimulation of reproductive activity, and the SCN is not necessarily the target site for melatonin action on the renewal of reproduction in the mink. [source] Adipogenic Phenotype of Hepatic Stellate CellsALCOHOLISM, Issue 2005Hide Tsukamoto Abstract: Transdifferentiation of hepatic stellate cells (HSC) constitutes a major cellular event in the genesis of alcoholic liver fibrosis and cirrhosis and molecular mechanisms underlying this process is incompletely understood. Our laboratory proposed several years ago that HSC quiescence requires the transcriptional program known to be integral to preadipocyte to adipocyte differentiation. In support of the hypothesis, our research demonstrates the expression of adipogenic transcription factors (C/EBPs, PPAR,, SREBP-1c, LXR,) and adipocyte-specific genes (adipsin, resistin) are high in quiescent HSC and depleted in activated HSC. Three gain-of-function approaches have been taken to test this notion: the treatment of activated HSC with the adipocyte differentiation cocktail; ectopic expression of PPAR, or SREBP-1c. All three treatments coordinately upregulate a panel of putative adipogenic transcrition factors and cause morphologic and biochemical reversal of activated HSC to quiescent cells. These findings establish a new conceptual framework for the treatment of liver fibrosis and propose an intriguing notion concerning the plasticity of HSC. [source] Close dependence of fibroblast proliferation on collagen scaffold matrix stiffnessJOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Issue 2 2009E. Hadjipanayi Abstract Human dermal fibroblasts (HDFs) in free-floating collagen matrices show minimal proliferation, although this may increase when the matrix is ,under tension'. We have investigated the detailed mechanics underlying one of the possible controls of this important cell behaviour, in particular the hypothesis that this is a response to substrate stiffness. Hyperhydrated collagen gels were plastic-compressed (PC) to give a predetermined collagen density and stiffness. Mechanical properties were tested using a dynamic mechanical analyser; cell number by Alamar blue assay. In the stiffest PC matrices, cell proliferation was rapid and seeding density-dependent, with a population doubling time of 2 days. In contrast, compliant attached matrices showed a 4 day lag period and a doubling time of 6 days. HDF growth was directly related to matrix stiffness, such that increasing stiffness using a range of compression levels (0,75% fluid removal) supported increasing proliferation rate, doubling times and matrix elastic modulus. HDF quiescence in compliant matrices was reversible, such that increasing stiffness in situ by compression at 1 and 5 days initiated proliferation. We conclude that collagen matrix stiffness regulates proliferation of fibroblasts (a duro-response), with important implications for understanding fibroblast,matrix feedback controls during wound healing and the design and regulation of engineered connective tissues based on collagen and other hydrogel-based scaffolds. Copyright © 2008 John Wiley & Sons, Ltd. [source] Overexpression of cyclin D2 is associated with increased in vivo invasiveness of human squamous carcinoma cellsMOLECULAR CARCINOGENESIS, Issue 3 2002Shao Chen Liu Abstract Overexpression of cyclin D2 was studied in 10 human squamous cell carcinoma lines, to establish whether this gene plays a role in tumor progression. We found that those cell lines that overexpressed cyclin D2 (CCND2) had the most invasive in vivo behavior. The invasive ability of the cell lines was determined by evaluating the penetration of carcinoma cells into the tracheal wall in an in vivo assay with de-epithelialized tracheas transplanted into the subcutaneous tissue of nude mice. From five cell lines that exhibited low invasive ability, we selected two that had very little CCND2 expression (SCC9 and SCC15), to evaluate whether CCND2 gene transfer would increase the invasive behavior. After confirming the successful transfer of CCND2 by Northern, Western, and kinase-activity assays, we assessed the in vivo invasive behavior of the CCND2 -transfected cells and their respective vector alone,transfected controls. The cell lines containing the transferred CCND2 gene had a significantly higher invasive ability than respective controls. This was accompanied by a moderate increase in gelatinase activity. In addition, the in vitro proliferative abilities, under normal culture conditions, of the parental CCND2 - transfected and vector alone,transfected cells were found to be similar, as was the in vivo labeling index of Ki-67 in the tracheal transplants. These results indicated that the overexpression of CCND2 in squamous cell carcinoma lines modulates cell proliferation after induced quiescence and also has a powerful enhancing effect on in vivo aggressive growth behavior. © 2002 Wiley-Liss, Inc. [source] Living on the edge: demographic and phylogeographical patterns in the woodlouse-hunter spider Dysdera lancerotensis Simon, 1907 on the eastern volcanic ridge of the Canary IslandsMOLECULAR ECOLOGY, Issue 15 2007LETICIA BIDEGARAY-BATISTA Abstract The Eastern Canary Islands are the emerged tips of a continuous volcanic ridge running parallel to the northeastern African coast, originated by episodic volcanic eruptions that can be traced back to the Miocene and that, following a major period of quiescence and erosion, continued from the Pliocene to the present day. The islands have been periodically connected by eustatic sea-level changes resulting from Pleistocene glacial cycles. The ground-dwelling spider Dysdera lancerotensis Simon, 1907 occurs along the entire ridge, except on recent barren lavas and sand dunes, and is therefore an ideal model for studying the effect of episodic geological processes on terrestrial organisms. Nested clade and population genetic analyses using 39 haplotypes from 605 base pairs of mitochondrial DNA cytochrome c oxidase I sequence data, along with phylogenetic analyses including two additional mitochondrial genes, uncover complex phylogeographical and demographic patterns. Our results indicate that D. lancerotensis colonized the ridge from north to south, in contrast to what had been expected given the SSW-NNE trend of volcanism and to what had been reported for other terrestrial arthropods. The occurrence of several episodes of extinction, recolonization and expansion are hypothesized for this species, and areas that act as refugia during volcanic cycles are identified. Relaxed molecular clock methods reveal divergence times between main haplotype lineages that suggest an older origin of the northern islets than anticipated based on geological evidence. This study supports the key role of volcanism in shaping the distribution of terrestrial organisms on oceanic islands and generates phylogeographical predictions that warrant further research into other terrestrial endemisms of this fascinating region. [source] Proteasome- and SCF-dependent degradation of yeast adenine deaminase upon transition from proliferation to quiescence requires a new F-box protein named Saf1pMOLECULAR MICROBIOLOGY, Issue 4 2006Stéphanie Escusa Summary In response to nutrient limitation, Saccharomyces cerevisiae cells enter into a non-proliferating state termed quiescence. This transition is associated with profound changes in gene expression patterns. The adenine deaminase encoding gene AAH1 is among the most precociously and tightly downregulated gene upon entry into quiescence. We show that AAH1 downregulation is not specifically due to glucose exhaustion but is a more general response to nutrient limitation. We also found that Aah1p level is tightly correlated to RAS activity indicating thus an important role for the protein kinase A pathway in this regulation process. We have isolated three deletion mutants, srb10, srb11 and saf1 (ybr280c) affecting AAH1 expression during post-diauxic growth and in early stationary phase. We show that the Srb10p cyclin-dependent kinase and its cyclin, Srb11p, regulate AAH1 expression at the transcriptional level. By contrast, Saf1p, a previously uncharacterized F-box protein, acts at a post-transcriptional level by promoting degradation of Aah1p. This post-transcriptional regulation is abolished by mutations affecting the proteasome or constant subunits of the SCF (Skp1,Cullin,F -box) complex. We propose that Saf1p targets Aah1p for proteasome-dependent degradation upon entry into quiescence. This work provides the first direct evidence for active degradation of proteins in quiescent yeast cells. [source] UBVRI observations of the flickering of RS Ophiuchi at quiescence,MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 1 2010R. K. Zamanov ABSTRACT We report observations of the flickering variability of the recurrent nova RS Oph at quiescence on the basis of simultaneous observations in five bands (UBVRI). RS Oph has a flickering source with (U,B)0=,0.62 ± 0.07, (B,V)0= 0.15 ± 0.10 and (V,R)0= 0.25 ± 0.05. We find for the flickering source a temperature Tfl, 9500 ± 500 K, and luminosity Lfl, 50,150 L, (using a distance of d= 1.6 kpc). We also find that on a (U,B) versus (B,V) diagram, the flickering of the symbiotic stars differs from that of the cataclysmic variables. The possible source of the flickering is discussed. The data are available upon request from the authors. [source] Dwarf nova oscillations and quasi-periodic oscillations in cataclysmic variables , VII.MONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 2 2009OY Carinae, oscillations in dwarf novae in quiescence ABSTRACT We have observed dwarf nova oscillations (DNOs) in OY Car during outburst, down through decline and beyond; its behaviour is similar to what we have previously seen in VW Hyi, making it only the second dwarf nova to have DNOs late in outburst that continue well into quiescence. There are also occasional examples of DNOs in deep quiescence, well away from outburst , they have properties similar to those during outburst, indicating similar physical causes and structures. We discuss the occurrence of DNOs in other dwarf novae and conclude that DNOs during quiescence are more common than often supposed and exhibit properties similar to those seen in outburst. [source] A thousand and one nova outburstsMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2007Noya Epelstain ABSTRACT A full nova cycle includes mass accretion, thermonuclear runaway resulting in outburst and mass-loss, and finally, decline. Resumed accretion starts a new cycle, leading to another outburst. Multicycle nova evolution models have been calculated over the past twenty years, the number being limited by numerical constraints. Here we present a long-term evolution code that enables a continuous calculation through an unlimited number of nova cycles for an unlimited evolution time, even up to 1.5 × 1010 yr. Starting with two sets of the three independent nova parameters , the white dwarf (WD) mass, the temperature of its isothermal core, and the rate of mass transfer on to it , we have followed the evolution of two models, with initial masses of 1 M, and 0.65 M, through over 1000 and over 3000 cycles, respectively. The accretion rate was assumed constant throughout each calculation: 10,11 M, yr,1 for the 1 M, WD, and 10,9 M, yr,1 for the 0.65 M, one. The initial temperatures were taken to be relatively high: 30 × 106 and 50 × 106 K, respectively, as they are likely to be at the onset of the outburst phase. The results show that although on the short-term consecutive outbursts are almost identical, on the long-term scale the characteristics change. This is mainly due to the changing core temperature, which decreases very similarly to that of a cooling WD for a time, but at a slower rate thereafter. As the WD's mass continually decreases, since both models lose more mass than they accrete, the central pressure decreases accordingly. The outbursts on the massive WD change gradually from fast to moderately fast, and the other characteristics (velocity, abundance ratios, isotopic ratios) change, too. Very slowly, a steady state is reached, where all characteristics, both in quiescence and in outburst, remain almost constant. For the less massive WD accreting at a high rate, outbursts are similar throughout the evolution. [source] Keck infrared observations of GRO J0422+32 in quiescenceMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 2 2007Mark T. Reynolds ABSTRACT We present Keck K -band photometry and low-resolution H - and K -band spectroscopy of the X-ray nova GRO J0422+32 obtained while the system was in the quiescent state. No clear ellipsoidal modulation is present in the light curve, which is instead dominated by a strong flickering component. In the K band, we observe strong Br, emission, with an equivalent width of 38 ± 5 Å. From this, we conclude that the accretion disc is the most likely source of the observed photometric contamination, and that previous infrared-based attempts to constrain the mass of the putative black hole in this system are prone to considerable uncertainty. We finally proceed to show how it is possible to place meaningful constraints on some of the binary parameters of this system, even in the presence of a relatively high level of contamination from the disc. [source] VW Hyi: optical spectroscopy and Doppler tomographyMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2006Amanda J. Smith ABSTRACT We present high-quality optical spectroscopy of the SU UMa-subtype dwarf nova, VW Hyi taken while the system was in quiescence. An S-wave is executed by the emission cores of the hydrogen Balmer lines and by the emission lines of He i, Ca ii, Fe ii and He ii. Using Doppler tomography, we show it originates in the accretion stream,disc impact region. The He ii emission is strongly phase-dependent, suggesting it originates exclusively within a hot cavity at the initial impact. We map the ionization structure of the stream,disc interaction region. One possible interpretation of this is that the Balmer hotspot lies downstream of the He ii hotspot in the outer accretion disc, with the He i and Ca ii hotspots at intermediate locations between the two. This suggests that Balmer emission is suppressed until material has cooled somewhat downstream of the impact site and is able to recombine. We favour a phase offset of 0.15 ± 0.04 between the photometric ephemeris and inferior conjunction of the mass donor. The white dwarf contributes significantly to the optical continuum, with broad Balmer absorption and narrow Mg ii ,4481 absorption clearly apparent. This latter feature yields the gravitational redshift: vgrav= 38 ± 21 km s ,1, so M1= 0.71+0.18,0.26 M,. This implies M2= 0.11 ± 0.03 M, and hence the donor is not a brown dwarf. A prominent Balmer jump is also observed. We note that the previously accepted system parameters for both VW Hyi and WX Hyi incorporate an algebraic error, and we provide a recalculated M1(q) plane for WX Hyi. [source] | ||||||||||||||||||||||||||||||||||