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At least 163 records · Page 9Linked to original sources
PubMed1999

Unique features of SHIP, SHP-1 and SHP-2 binding to FcgammaRIIb revealed by surface plasmon resonance analysis.

A growing family of inhibitory receptors characterized by content of one or more immunoreceptor tyrosine-based inhibitor motif (ITIM), I/V xYxxL/V, has been shown to regulate activation and effector function of immune system cells. The inhibitory activity of these receptors is mediated in large part by tyrosyl phosphorylated ITIM (pITIM) interactions with cytoplasmic effectors. Interestingly, different members of the family utilize partially distinct subsets of effectors from a group that includes SHP-1, SHP-2 and SHIP, an inositol 5' phosphatase. For example, while killer inhibitory receptors bind only SHP-1 and SHP-2, FcgammaRIIB bind SHIP, SHP-1 and SHP-2. The basis of selectivity of ITIMs for effectors is unclear. In this study surface plasmon resonance has been used to characterize the binding of phosphorylated FcgammaRIIB ITIM peptides to SHP-1, SHP-2 and SHIP derived Src-homology 2 (SH2) domains. SHIP was found to bind with highest affinity with intermediate on and off rates. SHP-1 bound with lowest affinity with slow on and slow off kinetics, and only its C-terminal SH2 domain exhibited binding activity. Both C- and N-terminal SH-2 domains of SHP-2 bound the pITIM. The affinity of these interactions were similar, however, they exhibited relatively fast on fast off and slow on slow off kinetics respectively. Interestingly, removal of the Ala-Glu-Asn sequence which lies immediately N-terminal from the ITIM in FcR ablated binding to SHP-1 and SHP-2 but not to SHIP. These results reveal a previously unrecognized level of complexity of effector binding to pITIM, including dependence of optimal SHP-1 and SHP-2 binding on residues N-terminal from the ITIM.

Amino Acid Sequence↗
PubMed2002

PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells.

Expression of PTEN tumor suppressor gene has been known to dephosphorylate the phosphatidylinositol 3' kinase (PI3K) products on the 3 prime inositol ring, resulting in reduced Akt activation. Loss of PTEN expression in OPM2 and delta47 human myeloma lines led to high Akt activity toward insulin-like growth factor I (IGF-I). In contrast, mouse plasma cell tumor (PCT) lines, expressing wild type PTEN, did not respond to IGF-I for Akt activation. We demonstrated here that endogenous PTEN played a negative role in controlling Akt activity in both mouse PCT and NIH3T3 fibroblast lines by using anti-sense oligonucleotides against PTEN. To determine the role of src-homology 2-containing inositol 5' phosphatase (SHIP) in regulating the PI3K/Akt pathway, we manipulated its expression by down-regulation and overexpression in myeloma, PCT and NIH3T3 lines and analysed Akt activation. Our results showed that SHIP, unlike PTEN, did not affect Akt activity in all systems analysed, despite its ability to dephosphorylate a PI3K product. Although SHIP2 expression resulted in suppression of interleukin-6-mediated mitogen-activated protein kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt activity. Biologically, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apoptosis in OPM2 myeloma line. Together, our results have established the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and in myeloma leukemogenesis.

3T3 Cells↗
PubMed1999

The human high-affinity immunoglobulin G receptor activates SH2-containing inositol phosphatase (SHIP).

On cytokine-primed U937 cells, aggregation of the human high-affinity immunoglobulin receptor, FcgammaRI, initiates signal transduction cascades which lead to the release of calcium from intracellular stores and no significant calcium influx. In these cells, aggregation of FcgammaRI results in no significant increase in inositol trisphosphate production, but rather phospholipase D is activated. Here we show that, in interferon-gamma (IFN-gamma)-primed cells, the SH2 containing inositol 5' phosphatase, SHIP, is constitutively associated with the membrane fraction. Following aggregation of FcgammaRI, SHIP is rapidly and transiently tyrosine phosphorylated and becomes associated with the adapter molecule Shc. Shc also becomes tyrosine phosphorylated and translocates from the cytoplasm to the membrane fraction concomitant with the association between Shc and SHIP. Further, SHIP and Shc appear to be recruited to membrane-associated immune complexes following FcgammaRI aggregation. As no immunoreceptor inhibitory motif has been demonstrated to associate with FcgammaRI, these data suggest that SHIP may be recruited to the receptor through an SH2 domain interaction with Shc.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The SH2 domain-containing inositol 5'-phosphatase (SHIP) recruits the p85 subunit of phosphoinositide 3-kinase during FcgammaRIIb1-mediated inhibition of B cell receptor signaling.

Coligation of FcgammaRIIb1 with the B cell receptor (BCR) or FcepsilonRI on mast cells inhibits B cell or mast cell activation. Activity of the inositol phosphatase SHIP is required for this negative signal. In vitro, SHIP catalyzes the conversion of the phosphoinositide 3-kinase (PI3K) product phosphatidylinositol 3,4, 5-trisphosphate (PIP3) into phosphatidylinositol 3,4-bisphosphate. Recent data demonstrate that coligation of FcgammaRIIb1 with BCR inhibits PIP3-dependent Btk (Bruton's tyrosine kinase) activation and the Btk-dependent generation of inositol trisphosphate that regulates sustained calcium influx. In this study, we provide evidence that coligation of FcgammaRIIb1 with BCR induces binding of PI3K to SHIP. This interaction is mediated by the binding of the SH2 domains of the p85 subunit of PI3K to a tyrosine-based motif in the C-terminal region of SHIP. Furthermore, the generation of phosphatidylinositol 3,4-bisphosphate was only partially reduced during coligation of BCR with FcgammaRIIb1 despite a drastic reduction in PIP3. In contrast to the complete inhibition of Tec kinase-dependent calcium signaling, activation of the serine/threonine kinase Akt was partially preserved during BCR and FcgammaRIIb1 coligation. The association of PI3K with SHIP may serve to activate PI3K and to regulate downstream events such as B cell activation-induced apoptosis.

3T3 Cells↗
PubMed2001

Activation of SHIP by NADPH oxidase-stimulated Lyn leads to enhanced apoptosis in neutrophils.

Neutrophils undergo rapid spontaneous apoptosis. Multiple antiapoptotic stimuli can inhibit this process via activation of the Akt pathway. However, despite no such effect singly, combined anti- and proapoptotic stimuli inhibit Akt activity, leaving the cells susceptible to accelerated apoptosis. The blockade of Akt activation depended on reduced phosphoinositide 3,4,5-trisphosphate levels but not decreased phosphatidylinositol 3-kinase activity, thus implicating the involvement of an inositol phosphatase. Evidence for SHIP involvement was provided by SHIP localization to membrane receptors and subsequent activation along with the observed inability of SHIP -/- neutrophils to exhibit enhanced apoptosis with the stimulus combination. Activation of SHIP was found to depend on Lyn activation, and this, in turn, required NADPH oxidase. Neutrophils from chronic granulomatous disease patients and Lyn -/- mice no longer responded to the combined stimuli. Thus, we propose a role for oxidants and Lyn in SHIP regulation and suggest a novel mechanism for regulating neutrophil apoptosis.

Apoptosis↗
PubMedDate not supplied

Stability of methylene chloride spiked passive samplers: an international shipping and transportation study.

A stability study was carried out by dynamically spiking Assay Technology Model 541 passive samplers with known amounts of methylene chloride (MeCl2) and shipping them to facilities around the world. Once arrived, these samples remained on site briefly and then were returned to the laboratory in North Chicago, III. A total of 22 sets of samples was prepared. Each sample set contained four passive samplers: blank, low (2.5 ppm), medium (25 ppm), and high (125 ppm) concentrations. Twelve of the 22 sets were separated into 4 groups of 3 sets, with each group defined as a cluster. One cluster was shipped to a pharmaceutical production facility in each country--South Africa, Pakistan, and Indonesia--and then shipped back to the lab, under normal shipping conditions. The fourth cluster was carried by one of the authors, who traveled through all three countries. The remaining 10 sets of samples were kept in the lab as controls. Each returning cluster was analyzed with two lab sets on arrival in the lab. Results obtained were evaluated using a t-test at a 95% confidence level. No significant differences were found in MeCl2 spiked passive samplers between traveled and lab controls, samples stored at room temperature and in the freezer, or analyzed right after being spiked and stored up to 7 weeks. It was concluded that MeCl2 spiked passive samplers were stable for at least 4 weeks at room temperature. There was no impact observed from international shipping and transportation on MeCl2 spiked passive samplers without temperature control.

Environmental Monitoring↗
PubMed2001

Poisoning at sea: injuries caused by chemicals aboard Danish merchant ships 1988-1996.

INTRODUCTION: Injuries involving chemicals occur aboard merchant ships, since such agents are carried commonly on board either as cargo or as needed for running the ship. In case of events involving chemicals, the crew may seek advice from the Medical First Aid Guide for Use in Accidents Involving Dangerous Goods published by the International Maritime Organization. The Guide is currently under revision. To improve knowledge of what is relevant in such a guide, a study was undertaken to identify all intoxications and corrosive incidents occurring aboard Danish merchant ships. METHODS: A retrospective study of all intoxications and corrosive incidents reported to the Danish Maritime authorities between 1988 and 1996. RESULTS: A total of 177 injuries were identified, of which 66 were systemic poisonings and 111 were due to corrosive damage to the eyes and skin. Thirteen of 66 systemic poisonings were fatal and almost three out of four corrosive injuries involved the eyes. CONCLUSIONS: This study and others show that the majority of injuries aboard merchant ships involving dangerous goods are amenable to first aid and symptomatic measures. Specific antidotes seem to have a limited role aboard merchant ships.

Denmark↗
PubMed2006

s-SHIP associates with receptor complexes essential for pluripotent stem cell growth and survival.

Embryonic stem (ES) cells are pluripotent cells that have the ability to either self-renew or differentiate into any cell type found in the mammalian body. The signaling pathways required for self-renewal of these cells are yet to be defined. Previously we identified a stem cell-specific isoform of the protein SH2 domain-containing 5'-inositol phosphatase (SHIP) that we call s-SHIP, which is expressed in both pluripotent ES cells and adult tissue-specific multipotent cells, such as hematopoietic stem cells (HSCs). s-SHIP lacks an SH2 domain but contains a 5'-inositol phosphatase domain and several protein-protein interaction domains that potentially enable its participation in many different signaling pathways. Here we show that s-SHIP associates with gp130, which forms a heterodimeric complex with the leukemia inhibitory factor receptor (LIFR). Signaling through LIFR and other receptors that heterodimerize with gp130 is critical for growth and survival of ES cells and HSCs. Our findings provide biochemical evidence that s-SHIP participates in signaling pathways important for the maintenance of pluripotent stem cell populations.

Animals↗
PubMed2004

Compound heterozygosity for Pten and SHIP augments T-dependent humoral immune responses and cytokine production by CD(4+) T cells.

Tight regulation of the phosphatidylinositiol 3-kinase (PI3K) pathway is essential not only for normal immune system development and responsiveness, but also in the prevention of immunopathology. Indeed, unchecked activation of the PI3K pathway in T cells induces lymphoproliferation and systemic autoimmunity. Evaluating the importance of threshold levels of two key PI3K pathway phosphoinositol phosphatases, we previously reported that mice heterozygous for both Pten and SHIP develop a more rapid progression of a lymphoproliferative autoimmune syndrome than do Pten(+\-) mice. Investigating the basis for this difference, we now describe a quantitative and qualitative difference in the antibody responses of C57BL\6 Pten(+\-) SHIP(+\-) mice upon challenge with a T-dependent antigen. Suspecting that this phenotypic difference might be the result, at least in part, of a T-helper cell defect, an in vitro analysis of anti-CD3/interleukin (IL)-2-expanded CD4(+) T cells was performed. After stimulation with anti-CD3, cells from mice heterozygous for both Pten and SHIP exhibited a striking increase in IL-4 secretion (> 10-fold), without a corresponding increase in T helper 2 (Th2) cell numbers being evident by intracellular staining for this cytokine. Modest increases were also seen for both IL-13 and IFN-gamma. Perhaps in keeping with this abnormal in vitro cytokine profile, IgG1 serum levels were significantly elevated in young C57BL\6 Pten(+\-) SHIP(+\-) mice. Thus, the relative levels of Pten and SHIP appear to be key variables in CD4(+) T-cell function, primarily via their ability to regulate IL-4 production.

Animals↗
PubMed2003

Evidence for a positive role of SHIP in the BCR-ABL-mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia.

Previous studies suggested that the SH2-containing inositol-5-phosphatase (SHIP) may play a tumor suppressor-like function in BCR-ABL-mediated leukemogenesis. To investigate this possibility, we first developed a new assay for quantitating transplantable multilineage leukemia-initiating cells (L-ICs) in hematopoietic stem cell (HSC)-enriched mouse bone marrow (BM) cells transduced with a BCR-ABL-GFP (green fluorescent protein) retrovirus. The frequency of L-ICs (1 of 430 Sca-1+lin- cells) was 7-fold lower than the frequency of HSCs in the Sca-1+lin- subset transduced with a control virus (1 of 65 cells). Forced BCRABL expression was also accompanied by a loss of regular HSC activity consistent with the acquisition of an increased probability of differentiation. Interestingly, the frequency and in vivo behavior of wild-type (+/+) and SHIP-/- L-ICs were indistinguishable, and in vitro, Sca-1+lin- BCR-ABL-transduced SHIP-/- cells showed a modestly reduced factor independence. Comparison of different populations of cells from patients with chronic myeloid leukemia (CML) in chronic phase and normal human BM showed that the reduced expression of full-length SHIP proteins seen in the more mature (CD34-lin+) leukemic cells is not mirrored in the more primitive (CD34+lin-) leukemic cells. Thus, SHIP expression appears to be differently altered in the early and late stages of differentiation of BCR-ABL-transformed cells, underscoring the importance of the cellular context in which its mechanistic effects are analyzed.

Animals↗
PubMed2005

SHIP down-regulates FcepsilonR1-induced degranulation at supraoptimal IgE or antigen levels.

Cross-linking of the IgE-loaded high-affinity IgE receptor (FcepsilonR1) by multivalent Ags results in mast cell activation and subsequent release of multiple proinflammatory mediators. The dose-response curve for FcepsilonR1-mediated degranulation is bell-shaped, regardless of whether the IgE or the Ag concentration is varied. Although overall calcium influx follows this bell-shaped curve, intracellular calcium release continues to increase at supraoptimal IgE or Ag concentrations. As well, overall calcium mobilization adopts more transient kinetics when stimulations are conducted with supraoptimal instead of optimal Ag concentrations. Moreover, certain early signaling events continue to increase whereas degranulation drops under supraoptimal conditions. We identified SHIP, possibly in association with the FcepsilonR1 beta-chain, as a critical negative regulator acting within the inhibitory (supraoptimal) region of the dose-response curve that shifts the kinetics of calcium mobilization from a sustained to a transient response. Consistent with this, we found that degranulation of SHIP-deficient murine bone marrow-derived mast cells was not significantly reduced at supraoptimal Ag levels. A potential mediator of SHIP action, Bruton's tyrosine kinase, did not seem to play a role within the supraoptimal suppression of degranulation. Interestingly, SHIP was found to colocalize with the actin cytoskeleton (which has been shown previously to mediate the inhibition of degranulation at supraoptimal Ag doses). These results suggest that SHIP, together with other negative regulators, restrains bone marrow-derived mast cell activation at supraoptimal IgE or Ag concentrations in concert with the actin cytoskeleton.

Actins↗
PubMed2003

The principles of writing the medical guide for ships.

The medical training and skills of seafarers are rather limited. In Finland, the master is responsible for medical care of his crew members, having only a 5-day training in medical matters which is refreshed every year. As medical incidents are rather rare events on board ship, he has not many opportunities to increase his knowledge in this field. Highly educated and experienced medical doctors have written medical guides for ships, describing diseases and advising on their treatment. This advice is based on diagnoses made on board ship by masters. They are often incorrect, therefore the advice on treatment may also be not correct. Authors of medical guides for ships should take into consideration the limited skills and medical knowledge of persons responsible for providing health services for crews at sea. This service is usually limited to giving first aid in accidents and sudden diseases, and care of the injured or sick seafarer until he can be transported to a medical facility on shore. Long lists of possible diagnoses in the text of such a guide only cause confusion in situations on board ship. In the new edition of the guide published in Finland in 2002, the advice on treatment is based on symptoms rather than on diagnoses.

Emergency Medicine↗
PubMed1997

Diseases and work-related injuries in Polish seafarers and conditions of their work on foreign-flag ships.

A questionnaire survey was conducted in 1994-1996 among Polish seafarers employed on foreign-flag ships, in order to collect their opinions and experiences on work and life on these ships, and to estimate the morbidity and injuries incidence. The majority of 1103 respondents were satisfied with the conditions of work and life on these ships: their food, accommodation, the health and safety of work, standard of health care on board were good or satisfactory; they had no problems with living and working together on the same ship with seamen of other nationalities. But about 7.8% of respondents complained that the safety and health of work on their ship was unsatisfactory, or conditions of work "endangered their health and life". The self-reported morbidity (calculated rate 176.8 per 1000 men per year) and accidents (rate 114.5 per 1000 per year) was recorded.

Accidents, Occupational↗
PubMed2006

Organotin contamination in the Atlantic Ocean off the Iberian Peninsula in relation to shipping.

Imposex in female snails, a bioindicator of TBT contamination, and the presence of organotins in snails' tissue and sediments were studied at nine sites off the western Iberian Peninsula. The study was part of a European project (acronym HIC-TBT) co-financed by the EU-LIFE programme, intending to investigate and communicate the impact of organotins from ships in marine ecosystems. Snails and sediments were sampled during two cruises in May/June 1999 and in January 2000 in areas of high, intermediate and low-shipping density. Imposex was found in female snails from several sampling sites, some of which had an imposex incidence of 100%. Differences in sensitivity were found between species; hence comparison of imposex levels between locations where different species were collected was not straightforward. Total organotin concentrations in sediments (sum of butyl and phenyltin compounds) ranged from 21 to 185 ng Sn g(-1) with higher values for most sites sampled in the vicinity of shipping lanes. Organotin concentration in snails' tissue ranged from <5 to 196 ng Sn g(-1), which are similar to those found in snails from other offshore areas contaminated by TBT. Overall, these results give further support to the recent ban on the use of organotin based antifouling paints to all ship size.

Animals↗
PubMed2005

What shall we do with the drunken sailor? Effects of alcohol on the performance of ship operators.

The purpose of this study was to specify the effects of alcohol on the performance of ship operators as a contribution to the development of new strategies against the risks of alcohol in water traffic. The nautical performance of 21 captains before and after alcohol consumption was assessed on a ship piloting simulator. The simulated scenarios represented passages of a container vessel through the German Bight. Performance was examined by nautical instructors according to standardised protocols. Mean (S.D.) blood alcohol concentrations (BACs) of 0.100 (0.024) g/dl before and 0.100 (0.017) g/dl after the performance trial resulted in striking effects on the nautical performance. The categories most severely affected were foresight and analysis of situation (impairment in 18 of 21 cases), concentration (impairment in 16 of 21 cases), accurateness, risk disposition and navigation (impairment in 15 of 21 cases). Chart work, preparation and communication were impaired in 12, 11 and 10 of 21 cases, respectively. None of the participants were capable to operate the simulated ship with an adequate safety after ingestion of alcohol. From these findings, and in consideration of the well-established impairment of a multitude of mental and physical functions by alcohol, it can be concluded that even low BACs bear high risks in water traffic, a concentration above 0.1 g/dl will hinder a sufficiently safe performance of ship operators. This should be considered in alcohol education and legislation.

Adult↗
PubMed2006

Safety in shipping: the human element.

INTRODUCTION: There are numerous diverse papers that have addressed issues within maritime safety; to date there has been no comprehensive review of this literature to aggregate the causal factors within accidents in shipping and surmise current knowledge. METHODS: This paper reviewed the literature on safety in three key areas: common themes of accidents, the influence of human error, and interventions to make shipping safer. The review included 20 studies of seafaring across the following areas: fatigue, stress, health, situation awareness, teamwork, decision-making, communication, automation, and safety culture. RESULTS: The review identifies the relative contributions of individual and organizational factors in shipping accidents, and also presents the methodological issues with previous research. CONCLUSIONS: The paper concludes that monitoring and modifying the human factors issues presented in this paper could contribute to maritime safety performance. IMPACT ON INDUSTRY: This review illustrates which human factors issues are prevalent in incidents therefore this gives shipping practitioners a focus for interventions.

Accident Prevention↗
PubMed2006

Mediterranean fin whales at risk from fatal ship strikes.

This paper reviews and analyzes ship collision records for the relatively isolated population of fin whales in the Mediterranean Sea from 1972 to 2001. Out of 287 carcasses, 46 individuals (16.0%) were certainly killed by boats. The minimum mean annual fatal collision rate increased from 1 to 1.7 whales/year from the 1970s to the 1990s. Fatal strike events (82.2%) were reported in or adjacent to the Pelagos Sanctuary, characterized by high levels of traffic and whale concentrations. Among 383 photo-identified whales, 9 (2.4%) had marks that were attributed to a ship impact. The reported rates are unusually high for baleen whales. The high likelihood of unreported fatal strikes combined with other anthropogenic threats suggests an urgent need for a comprehensive, basin-wide conservation strategy, including ship strike mitigation requirements, like real-time monitoring of whale presence and distribution to re-locate ferry routes to areas of lower cetacean density, and reducing ship speed in high cetacean density areas.

Animals↗
PubMed2006

Intelligent ship traffic monitoring for oil spill prevention: risk based decision support building on AIS.

The paper describes a model, which estimates the risk levels of individual crude oil tankers. The intended use of the model, which is ready for trial implementation at The Norwegian Coastal Administrations new Vardø VTS (Vessel Traffic Service) centre, is to facilitate the comparison of ships and to support a risk based decision on which ships to focus attention on. For a VTS operator, tasked with monitoring hundreds of ships, this is a valuable decision support tool. The model answers the question, "Which ships are likely to produce an oil spill accident, and how much is it likely to spill?".

Decision Support Techniques↗