E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins.

Ubiquitin-dependent proteolysis of the mitotic cyclins A and B is required for the completion of mitosis and entry into the next cell cycle. This process is catalyzed by the cyclosome, an approximately 22S particle that contains a cyclin-selective ubiquitin ligase activity, E3-C, that requires a cyclin-selective ubiquitin carrier protein (UBC) E2-C. Here we report the purification and cloning of E2-C from clam oocytes. The deduced amino acid sequence of E2-C indicates that it is a new UBC family member. Bacterially expressed recombinant E2-C is active in in vitro cyclin ubiquitination assays, where it exhibits the same substrate specificities seen with native E2-C. These results demonstrate that E2-C is not a homolog of UBC4 or UBC9, proteins previously suggested to be involved in cyclin ubiquitination, but is a new UBC family member with unique properties.

Reversible phosphorylation controls the activity of cyclosome-associated cyclin-ubiquitin ligase.

Cyclin B/cdc2 is responsible both for driving cells into mitosis and for activating the ubiquitin-dependent degradation of mitotic cyclins near the end of mitosis, an event required for the completion of mitosis and entry into interphase of the next cell cycle. Previous work with cell-free extracts of rapidly dividing clam embryos has identified two specific components required for the ubiquitination of mitotic cyclins: E2-C, a cyclin-selective ubiquitin carrier protein that is constitutively active during the cell cycle, and E3-C, a cyclin-selective ubiquitin ligase that purifies as part of a approximately 1500-kDa complex, termed the cyclosome, and which is active only near the end of mitosis. Here, we have separated the cyclosome from its ultimate upstream activator, cdc2. The mitotic, active form of the cyclosome can be inactivated by incubation with a partially purified, endogenous okadaic acid-sensitive phosphatase; addition of cdc2 restores activity to the cyclosome after a lag that reproduces that seen previously in intact cells and in crude extracts. These results demonstrate that activity of cyclin-ubiquitin ligase is controlled by reversible phosphorylation of the cyclosome complex.

Aplicación teórica del árbol de evaluación del Marine Stewardship Council, como herramienta de gestión de pesca sostenible, a la pesquería de la chirla, Chamelea gallina (Linnaeus, 1758), con draga hidráulica en el Golfo de Cádiz

La etiqueta azul del Marine Stewardship Council, pesca sostenible certificada, indica que un producto de pescado, fresco o transformado, procede de un recurso natural, salvaje, gestionado de manera respetuosa con el medio. Para obtenerla es necesario cumplir una serie de requisitos que son evaluados por una empresa certificadora (a la cual MSC ha dado el visto bueno y que es, a su vez, evaluada por otro organismo que asegura su completa imparcialidad). MSC presenta un modo de gestionar pesquerías que, según la propia organización, asegura la continuidad de la especie objetivo, de otras especies dependientes de ésta y del medio donde habitan. Sin embargo, obtener dicha eco-etiqueta azul es complejo y, sobre todo, económicamente difícil. El objetivo de este artículo es comprobar si el enfoque ecosistémico de este estándar ayudaría a paliar el impacto negativo de una pesquería que es fuente de riqueza, alimento y empleo perdurable en el Golfo de Cádiz. Es decir, aplicar los principios y criterios de MSC como herramienta de gestión de la pesquería de la chirla, Chamelea gallina (Linnaeus, 1758), con draga hidráulica.

Shell-based chronologies for the Irish Sea

We demonstrate here that the growth increment variability in the shell of the long-lived bivalve mollusc Arctica islandica can be interpreted as an indicator of marine environmental change in the climatically important North Atlantic shelf seas. Multi-centennial (up to 489-year) chronologies were constructed using five detrending techniques and their characteristics compared. The strength of the common environmental signal expressed in the chronologies was found to be fully comparable with equivalent statistics for tree-ring chronologies. The negative exponential function using truncated increment-width series from which the first thirty years have been removed was chosen as the optimal detrending technique. Chronology indices were compared with the Central England Temperature record and with seawater temperature records from stations close to the study site in the Irish Sea. Statistically significant correlations were found between the chronology indices and (a) mean air temperature for the 14-month period beginning in the January preceding the year of growth, (b) mean seawater temperatures for February-October in the year preceding the year of growth (c) late summer and autumn air temperatures and sea surface temperatures for the year of growth and (d) the timing of the autumn decline in SST. Changes through time in the correlations with air and seawater temperatures and changes towards a deeper water origin for the shells in the chronology were interpreted as an indication that shell growth may respond to stratification dynamics.

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Effects of engineering activities on the ecology of Pismo clams /

Mode of access: Internet.

Vorlesungen aus dem Gebiete der Kriegskunst; ein Handbuch für Offiziers,

Mode of access: Internet.

Letters of the Hon. C.F. Cleveland, and Hon. Henry Hubbard, Governors of Connecticut and New Hampshire, to Samuel Ward King, the charter governor of Rhode Island, refusing to deliver up Thomas Wilson Dorr, ...

Also, the letter of the Hon. Marcus Morton, and others, to the Suffrage Clam-bake.

Kleine Schriften /

1. Bd. Die Schlachten von Ligny, Quatre-Bras und Waterloo -- Briefe eines Militärs an einen andern -- Strategische Uebersicht des Feldzuges in Russland 1812 -- 2. Bd. Die Vertheidigung und der Fall von Montmedy im Jahre 1657 -- Ueber den Kosacken und dessen Brauchbarkeit im Felde -- Remarks on the organisation of the corps of artillery in the British service -- Bemerkungen bei Lesung von Jomini's Tableau analytique des principales combinaisons de la guerre -- Denkschrift über die Möglichkeit der militärischen Eroberung der europäischen Türkei durch die Russen -- 3. Bd. Der Feldzug in den Niederlanden 1793 -- 4. Bd. Biographisches. Fürst Carl von Schwarzenberg -- Fürst Joseph von Schwarzenberg -- Herzog von Reichstadt -- Wilhelm von Mayern -- Graf Johann Paar -- Graf Carl Clam-Martinitz -- 6. Bd. Gedichte -- 7. Bd. Kreig des Vizekönigs von Aegypten Mohammed Ali's gegen den Sultan in den Jahren 1831-1833.

Real-time reverse transcriptase PCR for the endogenous koala retrovirus reveals an association between plasma viral load and neoplastic disease in koalas

Koala retrovirus (KoRV) is a newly described endogenous retrovirus and is unusual in that inserts comprise a full-length replication competent genome. As koalas are known to suffer from an extremely high incidence of leukaemia/lymphoma, the association between this retrovirus and disease in koalas was examined. Using quantitative real-time reverse transcriptase PCR it was demonstrated that KoRV RNA levels in plasma are significantly increased in animals suffering from leukaemia or lymphoma when compared with healthy animals. Increased levels of KoRV were also seen for animals with clinical chlamydiosis. A significant positive association between viral RNA levels and age was also demonstrated. Real-time PCR demonstrated as much as 5 log variation in KoRV proviral DNA levels in genomic DNA extracted from whole blood from different animals. Taken together these data indicate that KoRV is an active endogenous retrovirus and suggests that it may be causally linked to neoplastic disease in koalas.

Conjunctival benign reactive lymphoid hyperplasia associated with myopic scleral thinning

Known causes of conjunctival salmon patches include lymphoma, amyloidosis, sarcoidosis, leukaemia and benign reactive lymphoid hyperplasia. The aetiology of benign reactive lymphoid hyperplasia is thought to be a localized reactive change induced by an irritative or antigenic stimulus. The case of benign reactive lymphoid hyperplasia reported herein occurred in a myopic patient with extremely thin sclera. The authors' hypothesis is that choroidal antigens are able to perfuse through thin sclera and act as chronic irritants to the overlying conjunctiva resulting in a lymphoid response and subsequent salmon patch formation.

Anti-proliferative effects of novel Glyco-lipid-arsenicals (III) on MCF-7 human breast cancer cells

Arsenic trioxide appears to be effective in the treatment of pro-myelocytic leukaemia. The substituted phenylarsen(III)oxides are highly polar, they have a high tendency to undergo oxidation to As (V) and to form oligomers, to prevent this we protected the As-(OH)2 group as cyclic dithiaarsanes. To increase the compound's biological stability and passive diffusion we conjugated the compound of interest with lipoamino acids (Laas). Alternatively, we further conjugated the dithiaarsane derivative with a carbohydrate to utilize active transport systems and to target compound. We investigated two novel glyco-lipid arsenicals (III) (compounds 9 and 11) for their ability to initiate MCF-7 breast cancer cell death and characterized the mechanism by which death was initiated. A significant decrease in MCF-7 cell proliferation was observed using 1 μM and 10 μM compound (11) and 10 μM of compound (9). Treatment with compound (11) triggered apoptosis of MFC-7 cells while compound (9) induced inhibition of cellular proliferation was not via rapid induction of apoptosis and more likely reflected necrosis and/ or alterations in the cell cycle. Differences in the anti-proliferative potency of the two compounds indicate that structural modifications influence effectiveness. © 2006 Bentham Science Publishers Ltd.

Paediatric population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in cystic fibrosis and bone marrow transplant patients

Objectives: The aim of the study was to characterise the population pharmacokinetics (popPK) properties of itraconazole (ITRA) and its active metabolite hydroxy-ITRA in a representative paediatric population of cystic fibrosis (CF) and bone marrow transplant (BMT) patients. The goals were to determine the relative bioavailability between the two oral formulations, and to explore improved dosage regimens in these patients. Methods: All paediatric patients with CF taking oral ITRA for the treatment of allergic bronchopulmonary aspergillosis and patients undergoing BMT who were taking ITRA for prophylaxis of any fungal infection were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. ITRA and hydroxy-ITRA plasma concentrations were measured by HPLC[1]. A nonlinear mixed-effect modelling approach (NONMEM 5.1.1) was used to describe the PK of ITRA and hydroxy-ITRA simultaneously. Simulations were used to assess dosing strategies in these patients. Results: Forty-nine patients (29CF, 20 BMT) were recruited to the study who provided 227 blood samples for the population analysis. A 1-compartment model with 1st order absorption and elimination best described ITRA kinetics, with 1st order conversion to hydroxy-ITRA. For ITRA, the apparent clearance (ClItra/F) and volume of distribution (Vitra/F) was 35.5L/h and 672L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h-1 and for the oral solution formulation it was 0.959 h-1. The capsule comparative bioavailability (vs. solution) was 0.55. For hydroxy-ITRA, the apparent volume of distribution and clearance were 10.6 L and 5.28 L/h, respectively. Of several screened covariates only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. Conclusion: The developed popPK model adequately described the pharmacokinetics of ITRA and hydroxy-ITRA in paediatric patients with CF and patients undergoing BMT. High inter-patient variability confirmed previous data in CF[2], leukaemia and BMT[3] patients. From the population model, simulations showed the standard dose (5 mg/kg/day) needs to be doubled for the solution formulation and even 4 times more given of the capsules to achieve an adequate target therapeutic trough plasma concentration of 0.5 mg/L[4] in these patients.

AIDS: structure, replication and spread of the AIDS virus

AIDS (Acquired Immune Deficiency Syndrome)was first, described as a new disease of humans in 1981. The origins of the disease are controversial. AIDS is caused by a retrovirus, a type of virus which rarely attacks human cells. The first virus of this type recorded in humans is reponsible for a type of leukaemia and was identified in 1978. AIDS is thus the third type of human retrovirus to be discovered and hence, is referred to as T-lymphotrophic virus III (HTLV-III). For viruses to replicate, they have to invade a host cell which in this case is a T4-lymphocyte, a type of white blood cell that regulates the immune system. The problems of the disease result directly from the death of these cells. As a consequence, the immune system is compromised leading to a number of opportunistic secondary infections and other disorders.

Chemical synthesis of DNA and RNA containing thio-substituted bases and their post-synthetic modifications

Modified oligonucleotides containing sulphur group have been useful tools for studies of carcinogenesis, protein or nucleic acid structures and functions, protein-nucleic acid interactions, and for antisense modulation of gene expression. One successful example has been the synthesis and study of oligodeoxynucleotides containing 6-thio-2'-deoxyguanine. 6-Thio-2-deoxyguanosine was first discovered as metabolic compound of 6- mercaptopurine (6-MP). Later, it was applied as drug to cure leukaemia. During the research of its toxicity, a method was developed to use the sulphur group as a versatile position for post-synthetic modification. The advantage of application of post-synthetic modification lies in its convenience. Synthesis of oligomers with normal sequences has become routine work in most laboratories. However, design and synthesis of a proper phosphoramidite monomer for a new modified nucleoside are always difficult tasks even for a skilful chemist. Thus an alternative method (post-synthetic method) has been invented to overcome the difficulties. This was achieved by incorporation of versatile nucleotides into oligomers which contain a leaving group, that is sufficiently stable to withstand the conditions of synthesis but can be substituted by nucleophiles after synthesis, to produce, a series of oligomers each containing a different modified base. In the current project, a phosphoramidite monomer with 6-thioguanine has been successfully synthesised and incorporated into RNA. A deprotection procedure, which is specific for RNA was designed for oligomers containing 6-thioguanosine. The results were validated by various methods (UV, HPLC, enzymatic digestion). Pioneer work in utilization of the versatile sulphur group for post-synthetic modification was also tested. Post-synthetic modification was also carried out on DNA with 6- deoxythioguanosine. Electrophilic reagents with various functional groups (alphatic, aromatic, fluorescent) and bi-functional groups have been attached with the oligomers.