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At least 433 records · Page 24Linked to original sources
PubMed2002

Mitotic exit network controls the localization of Cdc14 to the spindle pole body in Saccharomyces cerevisiae.

Budding yeast Cdc14 phosphatase plays essential roles in mitotic exit. Cdc14 is sequestered in the nucleolus by its inhibitor Net1/Cfi1 and is only released from the nucleolus during anaphase to inactivate mitotic CDK. It is believed that the mitotic exit network (MEN) is required for the release of Cdc14 from the nucleolus because liberation of Cdc14 by net1/cfi1 mutations bypasses the essential role of the MEN. But how the MEN residing at the spindle pole body (SPB) controls the association of Cdc14 with Net1/Cfi1 in the nucleolus is not yet understood. We found that Cdc14-5GFP was released from the nucleolus in the MEN mutants (tem1, cdc15, dbf2, and nud1), but not in the cdc5 cells during early anaphase. The Cdc14 liberation from the nucleolus was inhibited by the Mad2 checkpoint and by the Bub2 checkpoint in a different manner when microtubule organization was disrupted. We observed Cdc14-5GFP at the SPB in addition to the nucleolus. The SPB localization of Cdc14 was significantly affected by the MEN mutations and the bub2 mutation. We conclude that Cdc14 is released from the nucleolus at the onset of anaphase in a CDC5-dependent manner and that MEN factors possibly regulate Cdc14 release from the SPB.

Cell Cycle Proteins↗
PubMed2001

Timing is everything: regulation of mitotic exit and cytokinesis by the MEN and SIN.

Proper completion of mitosis requires careful coordination of numerous cellular events. It is crucial, for example, that cells do not initiate spindle disassembly and cytokinesis until chromosomes have been properly segregated. Cells have developed numerous safeguards or checkpoints to delay exit from mitosis and initiation of the next cell cycle in response to defects in late mitosis. In this review, we discuss recent work on two homologous signaling pathways in budding and fission yeast, termed the mitotic exit network (MEN) and septation initiation network (SIN), respectively, that are essential for coordinating completion of mitosis and cytokinesis with other mitotic events.

Bacterial Proteins↗
PubMed2003

The ex utero intrapartum treatment (EXIT) procedure.

The ex utero intrapartum treatment (EXIT) procedure was originally developed to reverse temporary tracheal occlusion in patients who had undergone foetal surgery for severe congenital diaphragmatic hernia (CDH). In a select group of foetuses with CDH, tracheal occlusion is used to obstruct the normal flow of foetal lung fluid and to stimulate lung expansion and growth. With the airway obstructed, airway management at birth is critical. The solution was to arrange delivery in such a way that the occlusion could be removed and the airway secured while the baby remained on placental support. If the uterus was kept relaxed and the utero-placental blood flow kept intact, the foetus could remain on a maternal 'heart-lung machine' while the airway was secured. While the technique of tracheal occlusion remains under study in clinical trials, EXIT procedures have been shown to be useful for management of other causes of foetal airway obstruction.

Airway Obstruction↗
PubMed2000

CDK inactivation is the only essential function of the APC/C and the mitotic exit network proteins for origin resetting during mitosis.

Passage through mitosis is required to reset replication origins for the subsequent S phase. During mitosis, a series of biochemical reactions involving cyclin-dependent kinases (CDKs), the anaphase promoting complex or cyclosome (APC/C), and a mitotic exit network including Cdc5, 14, and 15 coordinates the proper separation and segregation of sister chromatids. Here we show that cyclin B/CDK inactivation can drive origin resetting in either early S phase or mitosis. This origin resetting occurs efficiently in the absence of APC/C function and mitotic exit network function. We conclude that CDK inactivation is the single essential event in mitosis required to allow pre-RC assembly for the next cell cycle.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2004

Spherical aberration correction in tandem with exit-plane wave function reconstruction: interlocking tools for the atomic scale imaging of lattice defects in GaAs.

With the availability of resolution boosting and delocalization minimizing techniques, for example, spherical aberration correction and exit-plane wave function reconstruction, high-resolution transmission electron microscopy is drawing to a breakthrough with respect to the atomic-scale imaging of common semiconductor materials. In the present study, we apply a combination of these two state-of-the-art techniques to investigate lattice defects in GaAs-based heterostructures at atomic resolution. Focusing on the direct imaging of stacking faults as well as the core structure of edge and partial dislocations, the practical capabilities of both techniques are illustrated. For the first time, we apply the technique of bright-atom contrast imaging at negative spherical aberration together with an appropriate overfocus setting for the investigation of lattice defects in a semiconductor material. For these purposes, the elastic displacements associated with lattice defects in GaAs viewed along the 110 zone axis are measured from experimental images using reciprocal space strain map algorithms. Moreover, we demonstrate the benefits of the retrieval of the exit-plane wave function not only for the elimination of residual imaging artefacts but also for the proper on-line alignment of specimens during operation of the electron microscope--a basic prerequisite to obtain a fair agreement between simulated images and experimental micrographs.

Arsenicals↗
PubMed2001

The red blood cell glucose transporter presents multiple, nucleotide-sensitive sugar exit sites.

At any instant, the human erythrocyte sugar transporter presents at least one sugar export site but multiple sugar import sites. The present study asks whether the transporter also presents more than one sugar exit site. We approached this question by analysis of binding of [3H]cytochalasin B (an export conformer ligand) to the human erythrocyte sugar transporter and by analysis of cytochalasin B modulation of human red blood cell sugar uptake. Phloretin-inhibitable cytochalasin B binding to human red blood cells, to human red blood cell integral membrane proteins, and to purified human red blood cell glucose transport protein (GluT1) displays positive cooperativity at very low cytochalasin B levels. Cooperativity between sites and K(d(app)) for cytochalasin B binding are reduced in the presence of intracellular ATP. Red cell sugar uptake at subsaturating sugar levels is inhibited by high concentrations of cytochalasin B but is stimulated by lower (<20 nM) concentrations. Increasing concentrations of the e1 ligand forskolin also first stimulate then inhibit sugar uptake. Cytochalasin D (a cytochalasin B analogue that does not interact with GluT1) is without effect on sugar transport over the same concentration range. Cytochalasin B and ATP binding are synergistic. ATP (but not AMP) enhances [3H]cytochalasin B photoincorporation into GluT1 while cytochalasin B (but not cytochalasin D) enhances [gamma-32P]azidoATP photoincorporation into GluT1. We propose that the red blood cell glucose transporter is a cooperative tetramer of GluT1 proteins in which each protein presents a translocation pathway that alternates between uptake (e2) and export (e1) states but where, at any instant, two subunits must present uptake (e2) and two subunits must present exit (e1) states.

3-O-Methylglucose↗
PubMed2003

A role for subunit III in proton uptake into the D pathway and a possible proton exit pathway in Rhodobacter sphaeroides cytochrome c oxidase.

Protons are transferred from the inner surface of cytochrome c oxidase to the active site by the D and K pathways, as well as from the D pathway to the outer surface by a largely undefined proton exit route. Alteration of the initial proton acceptor of the D pathway, D132, to alanine has previously been shown to greatly inhibit oxidase turnover and slow proton uptake into the D pathway. Here it is shown that the removal of subunit III restores a substantial rate of O(2) reduction to D132A. Presumably an alternative proton acceptor for the D pathway becomes active in the absence of subunit III and D132. Thus, in the absence of subunit III cytochrome oxidase shows greater flexibility in terms of proton entry into the D pathway. In the presence of DeltaPsi and DeltapH, turnover of the wild-type oxidase or D132A is slower in the absence of subunit III. Comparison of the turnover rates of subunit III-depleted wild-type oxidase to those of the zinc-inhibited wild-type oxidase containing subunit III, both reconstituted into vesicles, leads to the hypothesis that the absence of subunit III inhibits the ability of the normal proton exit pathway to take up protons from the outside in the presence of DeltaPsi and DeltapH. Thus, subunit III appears to affect the transfer of protons from both the inner and outer surfaces of cytochrome oxidase, perhaps accounting for the long-observed lower efficiency of proton pumping by the subunit III-depleted oxidase.

Amino Acid Substitution↗
PubMed2007

Cytochrome c(2) Exit Strategy: Dissociation Studies and Evolutionary Implications.

Small, water-soluble, type c cytochromes form a transient network connecting major bioenergetic membrane protein complexes in both photosynthesis and respiration. In the photosynthesis cycle of Rhodobacter sphaeroides, cytochrome c2 (cyt c2) docks to the reaction center (RC), undergoes electron transfer, and exits for the cytochrome bc1 complex. Translations of cyt c2 about the RC-cyt c2 docking interface and surrounding membrane reveal possible exit pathways. A pathway at a minimal elevation allowed by the architecture of the RC is analyzed using both an all-atom steered molecular dynamics simulation of the RC-cyt c2 complex and a bioinformatic analysis of the structures and sequences of cyt c. The structure-based phylogenetic analysis allows for the identification of structural elements that have evolved to satisfy the requirements of having multiple functional partners. The patterns of evolutionary variation obtained from the phylogenetic analysis of both docking partners of cyt c2 reveal conservation of key residues involved in the interaction interfaces that would be candidates for further experimental studies. Additionally, using the molecular mechanics Poisson-Boltzmann surface area method we calculate that the binding free energy of reduced cyt c2 to the RC is nearly 6 kcal/mol more favorable than with oxidized cyt c2. The redox-dependent variations lead to changes in structural flexibility, behavior of the interfacial water molecules, and eventually changes in the binding free energy of the complex.

Amino Acid Sequence↗
PubMed2001

Case report: alternating exit sites in reentry circuit of ventricular tachycardia with nonischemic cardiomyopathy - relationship between ablation site and inner loop.

We present a patient with nonischemic cardiomyopathy who had ventricular tachycardia (VT) with QRS morphology alternans. VTs of two QRS morphologies (VT1 and VT2) exhibiting a right bundle branch block pattern with inferior axis was induced by ventricular pacing. The morphology of the QRS complex during VT1 exhibited more distinctively inferior axis than those during VT2. Induced VTs had similar morphologies to clinically the documented VTs. Pacemapping at anterolateral site of the left ventricle during sinus rhythm produced the same QRS complex of VT1 in a surface 12-lead electrocardiogram. A mapping study was performed with an electrode catheter located at the same site of LV during sustained VT1. The analysis of the local electrograms and postpacing interval during concealed entrainment at the catheter mapping revealed this pacing site was at the inner loop of the reentry circuit. Radiofrequency catheter ablation was performed at this site. The morphology of VT1 changed to different QRS morphology (VT2) during the first delivery of radiofrequency energy and was terminated after 20 seconds of the application. Then VT with alternans of QRS morphology and cycle length of VT1 and VT2 was induced by ventricular pacing, and was abolished by the second application of radiofrequency energy at this same site, suggesting that this site was located in the exit site close to inner loop of the reentry circuit and the alternans of QRS morphology was linked to the change of exit site.

Cardiomyopathy, Dilated↗
PubMed2006

Following the signal sequence from ribosomal tunnel exit to signal recognition particle.

Membrane and secretory proteins can be co-translationally inserted into or translocated across the membrane. This process is dependent on signal sequence recognition on the ribosome by the signal recognition particle (SRP), which results in targeting of the ribosome-nascent-chain complex to the protein-conducting channel at the membrane. Here we present an ensemble of structures at subnanometre resolution, revealing the signal sequence both at the ribosomal tunnel exit and in the bacterial and eukaryotic ribosome-SRP complexes. Molecular details of signal sequence interaction in both prokaryotic and eukaryotic complexes were obtained by fitting high-resolution molecular models. The signal sequence is presented at the ribosomal tunnel exit in an exposed position ready for accommodation in the hydrophobic groove of the rearranged SRP54 M domain. Upon ribosome binding, the SRP54 NG domain also undergoes a conformational rearrangement, priming it for the subsequent docking reaction with the NG domain of the SRP receptor. These findings provide the structural basis for improving our understanding of the early steps of co-translational protein sorting.

Animals↗
PubMed2004

The ribosomal protein Rps15p is required for nuclear exit of the 40S subunit precursors in yeast.

We have conducted a genetic screen in order to identify ribosomal proteins of Saccharomyces cerevisiae involved in nuclear export of the small subunit precursors. This has led us to distinguish Rps15p as a protein dispensable for maturation of the pre-40S particles, but whose assembly into the pre-ribosomes is a prerequisite to their nuclear exit. Upon depletion of Rps15p, 20S pre-rRNA is released from the nucleolus and retained in the nucleus, without alteration of the pre-rRNA early cleavages. In contrast, Rps18p, which contacts Rps15p in the small subunit, is required upstream for pre-rRNA processing at site A2. Most pre-40S specific factors are correctly associated with the intermediate particles accumulating in the nucleus upon Rps15p depletion, except the late-binding proteins Tsr1p and Rio2p. Here we show that these two proteins are dispensable for nuclear exit; instead, they participate in 20S pre-rRNA processing in the cytoplasm. We conclude that, during the final maturation steps in the nucleus, incorporation of the ribosomal protein Rps15p is specifically required to render the pre-40S particles competent for translocation to the cytoplasm.

Cell Nucleus↗
PubMed2003

De novo formation, fusion and fission of mammalian COPII-coated endoplasmic reticulum exit sites.

Transport between the endoplasmic reticulum (ER) and Golgi is mediated by the sequential action of the COPII and COPI coat complexes. COPII subunits are recruited to the ER membrane where they mediate the selection of cargo for transport to the Golgi, and also membrane deformation and vesicle formation. New ER exit sites can be generated by lateral growth and medial fission (in Pythium sp.) or by de novo formation (in Pichia pastoris) but it is not known how mammalian ER exit sites form. Here, time-lapse imaging of COPII-coated structures in live mammalian cells reveals that the number of ER export sites increases greatly during interphase by de novo formation. These results show the fusion of pre-existing ER export sites and the fission of larger structures. These three mechanisms of de novo formation, fusion and fission probably cooperate to regulate the size of these sites in mammalian cells.

Animals↗
PubMed2001

The periodic down regulation of Cyclin E gene expression from exit of mitosis to end of G(1) is controlled by a deacetylase- and E2F-associated bipartite repressor element.

The expression of cyclin E and that of a few other bona fide cell cycle regulatory genes periodically oscillates every cycle in proliferating cells. Although numerous experiments have documented the role of E2F sites and E2F activities in the control of these genes as cells exit from G(0) to move through the initial G(1)/S phase transition, almost nothing is known on the role of E2Fs during the subsequent cell cycles. Here we show that a variant E2F-site that is part of the Cyclin E Repressor Module (CERM) (Le Cam et al., 1999b) accounts for the periodic down regulation of the cyclin E promoter observed between the exit from mitosis until the mid/late G(1) phase in exponentially cycling cells. This cell cycle-dependent repression correlates with the periodic binding of an atypical G(1)-specific high molecular weight p107-E2F complex (Cyclin E Repressor Complex: CERC2) that differs in both size and DNA binding behaviors from known p107-E2F complexes. Notably, affinity purified CERC2 displays a TSA-sensitive histone deacetylase activity and, consistent with this, derepression of the cyclin E promoter by trichostatin A depends on the CERM element. Altogether, this shows that the cell cycle-dependent control of cyclin E promoter in cycling cells is embroiled in acetylation pathways via the CERM-like E2F element.

Carrier Proteins↗
PubMed2005

Essential tension and constructive destruction: the spindle checkpoint and its regulatory links with mitotic exit.

Replicated genetic material must be partitioned equally between daughter cells during cell division. The precision with which this is accomplished depends critically on the proper functioning of the mitotic spindle. The assembly, orientation and attachment of the spindle to the kinetochores are therefore constantly monitored by a surveillance mechanism termed the SCP (spindle checkpoint). In the event of malfunction, the SCP not only prevents chromosome segregation, but also inhibits subsequent mitotic events, such as cyclin destruction (mitotic exit) and cytokinesis. This concerted action helps to maintain temporal co-ordination among mitotic events. It appears that the SCP is primarily activated by either a lack of occupancy or the absence of tension at kinetochores. Once triggered, the inhibitory circuit bifurcates, where one branch restrains the sister chromatid separation by inhibiting the E3 ligase APC(Cdc20) (anaphase-promoting complex activated by Cdc20) and the other impinges on the MEN (mitotic exit network). A large body of investigations has now led to the identification of the control elements, their targets and the functional coupling among them. Here we review the emerging regulatory network and discuss the remaining gaps in our understanding of this effective mechanochemical control system.

Anaphase↗
PubMed2001

Transient exit block of a DDD pacemaker with unipolar leads in subcutaneous emphysema following pneumothorax.

This case report describes a transient pacemaker exit block due to subcutaneous emphysema following pneumothorax. Pneumothorax after pacemaker implantation is rare, but development of subcutaneous emphysema under such circumstances is even more uncommon. Exit block develops only with the use of unipolar leads; with implantation of bipolar leads, this complication cannot occur.

Aged↗
PubMed2000

The mechanism of killing and exiting the protozoan host Acanthamoeba polyphaga by Legionella pneumophila.

The ability of Legionella pneumophila to cause legionnaires' disease is dependent on its capacity to replicate within cells in the alveolar spaces. The bacteria kill mammalian cells in two phases: induction of apoptosis during the early stages of infection, followed by an independent and rapid necrosis during later stages of the infection, mediated by a pore-forming activity. In the environment, L. pneumophila is a parasite of protozoa. The molecular mechanisms by which L. pneumophila kills the protozoan cells, after their exploitation for intracellular proliferation, are not known. In an effort to decipher these mechanisms, we have examined induction of both apoptosis and necrosis in the protozoan Acanthamoeba polyphaga upon infection by L. pneumophila. Our data show that, although A. polyphaga undergoes apoptosis following treatment with actinomycin D, L. pneumophila does not induce apoptosis in these cells. Instead, intracellular L. pneumophila induces necrotic death in A. polyphaga, which is mediated by the pore-forming activity. Mutants of L. pneumophila defective in expression of the pore-forming activity are indistinguishable from the parental strain in intracellular replication within A. polyphaga. The parental strain bacteria cause necrosis-mediated lysis of all the A. polyphaga cells within 48 h after infection, and all the intracellular bacteria are released into the tissue culture medium. In contrast, all cells infected by the mutants remain intact, and the intracellular bacteria are 'trapped' within A. polyphaga after the termination of intracellular replication. Failure to exit the host cell after termination of intracellular replication results in a gradual decline in the viability of the mutant strain bacteria within A. polyphaga starting 48h after infection. Our data show that the pore-forming activity of L. pneumophila is not required for intracellular bacterial replication within A. polyphaga but is required for killing and exiting the protozoan host upon termination of intracellular replication.

Acanthamoeba↗
PubMed2003

Ultrasonographic guidance for location of the trachea during the EXIT procedure for cervical teratoma.

Cervical teratomas are rare tumors of infancy that are associated with a high mortality rate caused by compression and distortion of the infant's airway. Recent attempts at managing the fetal airway before delivery have focused on the EXIT (ex-utero intrapartum treatment) procedure, in which time to secure an airway is provided while preserving uteroplacental gas exchange. The authors report the use of intraoperative ultrasound guidance during an EXIT procedure for an infant with massive cervical teratoma to aid in identification of the trachea.

Airway Obstruction↗
PubMed2002

Student nurse attrition: use of an exit-interview procedure to determine students' leaving reasons.

This study is part of a research programme at the University of Glamorgan aimed at reducing student nurse discontinuation. A number of methodological limitations in previous studies on attrition have been identified and are addressed in this study. A preliminary picture of attrition within this school is established and the validity of the data examined. The average attrition rate for the school over an 8-year period was 19%, which compares favourably with national rates. Data on students' leaving reasons were obtained through an exit-interview procedure; this achieved high response rates which for exceed those represented in previous studies. Academic difficulties and wrong career choice were among the most commonly reported leaving reasons; this is similar to findings from previous research. However family, health and financial difficulties emerge as equally important categories. The exit form facilitated the recording of multiple leaving reasons for each student, an innovative approach in attrition research. Almost half the students discontinued for at least two reasons; the interrelationships between leaving reasons and possible explanations for the findings are considered. The complexity of factors contributing to attrition are discussed and will be tackled in subsequent stages of the research programme.

Attitude of Health Personnel↗