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At least 865 records · Page 48Linked to original sources
PubMed2005

The electron-poor phosphines P{C6H3(CF3)2-3,5}3 and P(C6F5)3 do not mimic phosphites as ligands for hydroformylation. A comparison of the coordination chemistry of P{C6H3(CF3)2-3,5}3 and P(C6F5)3 and the unexpectedly low hydroformylation activity of their rhodium complexes.

The fluoroaryl phosphines P{C6H3(CF3)2-3,5}3 (La) and P(C6F5)3 (Lb) form the complexes trans-[MCl2(La)2] and trans-[MCl2(Lb)2](M = Pd or Pt) which have been isolated and fully characterised. 31P NMR studies of competition experiments show that the stability of trans-[PdCl2L2] is in the order L = Lb< La <PPh3. The crystal structure of trans-[PtCl2(La)2] is reported and reveals that the Pt-P bond lengths in trans-[PtCl2L2] are in the order L = Lb< La < PPh3. The equilibria established when [Pt(norbornene)3] is treated with or are investigated by 31P and 195Pt NMR spectroscopy and the species [PtLn(norbornene)3-n](n= 1-3) identified. Ligands and appear to have similar affinities for platinum(0). The complexes trans-[MCl(CO)(La)2] and trans-[MCl(CO)(Lb)2](M = Rh or Ir) have been synthesised and fully characterised; the values of nu(CO) are comparable with those for analogous phosphite complexes. The ligands La, Lb, P(C6H2F3-3,4,5)3 (Lc), P{C6H4(CF3)-2}3 (Ld), PPh3 and P(OPh)3 have been tested in rhodium-catalysed hydroformylation of 1-hexene and La, Lb, and PPh3 have been tested in rhodium-catalysed hydroformylation of 4-methoxystyrene. Ligands La, and Lb, have been shown to be stable under the hydroformylation catalysis conditions. For the 1-hexene reaction, the activity and selectivity for and are very similar to the PPh3 catalyst (TOF ca. 400 h(-1); n : iso 2.5-3.0) but for the sterically demanding and the activity and selectivity was much lower than with PPh3 (TOF ca. 15, n : iso ratio 0.6). Thus, the yield of heptanals obtained with the catalyst derived from La is 94% while under the same conditions with Lb only 6%. The TOF for the La/Rh catalyst was 5 times lower than for the P(OPh)3/Rh catalyst despite the superficially similar ligand electronic characteristics for La and P(OPh)3.

Journal Article↗
PubMed2004

Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes.

The process of adipogenesis involves a complex program of gene expression that includes down-regulation of the gene encoding Hes-1, a target of the Notch signaling pathway. To determine if Notch signaling affects adipogenesis, we exposed 3T3-L1 preadipocytes to the Notch ligand Jagged1 and found that differentiation was significantly reduced. This effect could be mimicked by constitutive expression of Hes-1. The block was associated with a complete loss of C/EBPalpha and peroxisome proliferator-activated receptor gamma (PPARgamma) induction and could be overcome by retroviral expression of either C/EBPalpha or PPARgamma2. Surprisingly, small interfering RNA (siRNA)-mediated reduction of Hes-1 mRNA in 3T3-L1 cells also inhibited differentiation, suggesting an additional, obligatory role for Hes-1 in adipogenesis. This role may be related to our observation that both Notch signaling and Hes-1 down-regulate transcription of the gene encoding DLK/Pref-1, a protein known to inhibit differentiation of 3T3-L1 cells. The results presented in this study establish a new target downstream of the Notch-Hes-1 pathway and suggest a dual role for Hes-1 in adipocyte development.

3T3 Cells↗
PubMed2002

Unifying themes in DNA replication: reconciling single molecule kinetic studies with structural data on DNA polymerases.

Structural data suggest that DNA polymerases, from at least three different families, employ common strategies for carrying out DNA replication. Universal features include a large conformational change in the enzyme-template complex and a conserved active-site geometry that imposes a sharp kink at the 5 end of the template strand. Recent single molecule experiments have shown that stretching the DNA template markedly alters the rate of DNA synthesis catalyzed by these motor enzymes. From these data, it was previously inferred that T7 DNA polymerase and two related enzymes convert two or four (depending on the enzyme) single-stranded (ss) template bases to double helix geometry in the polymerase active site during each catalytic cycle. We discuss structural data on related DNA polymerases, which suggest that only one (ss) template base is contracted to dsDNA geometry during the rate-limiting step of each replication cycle. Previous interpretations relied upon the global stretching curves for DNA polymers alone (with no reference to the enzyme or the structure of the transition state). In contrast, we present a structurally guided model that presumes the force dependence of the replication rate is governed chiefly by local interactions in the immediate vicinity of the enzyme s active site. Our analysis reconciles single molecule kinetic studies with structural data on DNA polymerases.

Binding Sites↗
PubMed2006

A qualitative study of GPs' attitudes to self-management of chronic disease.

BACKGROUND: Improving the quality of care for patients living with a chronic illness is a key policy goal. Alongside systems to ensure care is delivered according to evidence-based guidelines, an essential component of these new models of care is the facilitation of self-management. However, changes to the way professionals deliver care is complex, and it is important to understand the key drivers and barriers that may operate in the primary care setting. AIM: To explore GPs' perspectives on their involvement in the facilitation of chronic disease self-management. DESIGN OF STUDY: Qualitative study. SETTING: General practices located in two primary care trusts in northern England. METHOD: Data were collected through in-depth, semi-structured interviews with a purposive sample of GPs. During analysis, categories of response were organised into themes that relate to Howie's theoretical model for understanding general practice consultations: content, values, context. RESULTS: The GPs' responses highlighted tensions and trade-offs regarding their role in facilitating self-management. Although GPs valued increased patient involvement in their health care, this was in conflict with other values concerning professional responsibility. Furthermore, contextual factors also limited the degree to which they could assist in encouraging self-management. CONCLUSIONS: Providing GPs with training in consultation skills is required in order to encourage the delivery of effective self-management. In addition, the context in which GPs work also needs to be modified for this to be achieved.

Adult↗
PubMed2003

Mitochondrial import receptors Tom20 and Tom22 have chaperone-like activity.

Mitochondrial preproteins are synthesized in the cytosol with N-terminal signal sequences (presequences) or internal targeting signals. Generally, preproteins with presequences are initially recognized by Tom20 (translocase of the outer membrane) and, subsequently, by Tom22, whereas hydrophobic preproteins with internal targeting signals are first recognized by Tom70. Recent studies suggest that Tom70 associates with molecular chaperones, thereby maintaining their substrate preproteins in an import-competent state. However, such a function has not been reported for other Tom component(s). Here, we investigated a role for Tom20 in preventing substrate preproteins from aggregating. In vitro binding assays showed that Tom20 binds to guanidinium chloride unfolded substrate proteins regardless of the presence or absence of presequences. This suggests that Tom20 functions as a receptor not only for presequences but also for mature portions exposed in unfolded preproteins. Aggregation suppression assays on citrate synthase showed that the cytosolic domain of Tom20 has a chaperone-like activity to prevent this protein from aggregating. This activity was inhibited by a presequence peptide, suggesting that the binding site of Tom20 for presequence is identical or close to the active site for the chaperone-like activity. The cytosolic domain of Tom22 also showed a similar activity for citrate synthase, whereas Tom70 did not. These results suggest that the cytosolic domains of Tom20 and Tom22 function to maintain their substrate preproteins unfolded and prevent them from aggregating on the mitochondrial surface.

Animals↗
PubMed2005

Free radical generation assays: new methodology for accelerated oxidation studies at low temperature in complex food matrices.

A novel method for the rapid screening of antioxidant efficacy and oxidative stability in food and feed matrices has been developed. The analyses are described as free radical generation (FRG) assays. The new procedure combines the use of azo-initiators with analytical equipment that is widely used for antioxidant research such as the oxidative stability instrument and the oxygen bomb. The use of initiators instead of high temperatures as a driving force to increase the rate of oxidation improves the correlation between the accelerated screening of foodstuffs and real shelf life. The improved correlation can be mainly explained by the fact that food products are analyzed in their original status, maintaining all interfacial phenomena of the food matrix. Furthermore, the lower temperature of analysis reduces differences between the reaction kinetics of the assay and those of the oxidation during actual shelf life. Consequently, the correlation between the accelerated analysis and shelf life is improved, particularly when compared to accelerated oxidation at high temperatures. The FRG assays could be used successfully to evaluate the efficacy of natural antioxidants in heat-sensitive food products such as emulsions and meat products. A good correlation was observed between the accelerated tests and the oxidation parameters obtained from standard shelf-life evaluation. It was possible to successfully compare the efficacy of several antioxidants and to predict shelf life for these heat-sensitive food matrices.

Animals↗
PubMed2003

Complex vascular reconstructions in living donor liver transplantation.

We describe here the indications for and our experience with complex vascular reconstructions in living donor liver transplantation. From December 1999 to June 2002, 59 patients underwent liver transplantation, 51 receiving the right lobe, and 8 the left lateral lobe, as a graft from a living donor. The indication for interpositional grafts on the arterial side (6/59, 10%) were stenoses of the celiac trunk and after resection of the hepatic artery for oncological reasons in adults. In children, arterial interpositional grafts were performed in situations of long distances between the donor and recipient artery, or in cases of inflow release from the aorta in patients with small hepatic arteries. On the portal-venous side, one interpositional graft was performed after an oncological resection. Once the portal vein was partially arterialized because of insufficient inflow. We used veins from the recipient, and native or cryopreserved arterial homografts for these grafts. All patients were treated during the first 6 months after transplantation with aspirin only. During the follow-up we did not observe vascular complications. If required, vascular interpositional grafts in the arterial and portal-venous position can be performed without adding postoperative complications.

Anastomosis, Surgical↗
PubMed2002

Rehabilitation of executive function: facilitation of effective goal management on complex tasks using periodic auditory alerts.

The 'dysexecutive syndrome' represents a major challenge to functional recovery and adaptation following brain injury--and an important target for rehabilitation. Previous reports of everyday difficulties, and performance on complex, life-like tasks, indicate that an adequately represented goal may become neglected as patients become overly engaged in current activity. Here we examine whether the provision of brief auditory stimuli, acting to interrupt current activity and to cue patients to consider their overall goal, would improve performance in a complex task. Ten brain injured patients completed a modification of Shallice and Burgess' Six Elements task under two conditions. In the 'Hotel' test, the patients were asked to try and do some of each of five sub-tasks within 15 min. As the total time to complete all of the tasks would exceed an hour, the measure emphasises patients' ability to monitor the time, switch between the tasks and keep track of their intentions. Without the external auditory cues, the patients performed significantly more poorly than age- and IQ-matched control volunteers, a common error being to continue performing one task to the detriment of beginning or allocating sufficient time to others. When exposed to the interrupting tones, however, their performance was both significantly improved and no longer significantly different from the control group on important variables. The results have value in assessment in helping to attribute poor performance to 'goal neglect' rather than, for example, poor memory or comprehension. They also suggest that providing environmental support to one aspect of executive function may facilitate monitoring and behavioural flexibility--and therefore the useful expression of other skills that may be relatively intact.

Acoustic Stimulation↗
PubMedDate not supplied

Homocysteine oxidation and apoptosis: a potential cause of cleft palate.

Cleft palate is the most common craniofacial anomaly. Affected individuals require extensive medical and psychosocial support. Although cleft palate has a complex and poorly understood etiology, low maternal folate is known to be a risk factor for craniofacial anomalies. Folate deficiency results in elevated homocysteine levels, which may disturb palatogenesis by several mechanisms, including oxidative stress and perturbation of matrix metabolism. We examined the effect of homocysteine-induced oxidative stress on human embryonic palatal mesenchyme (HEPM) cells and demonstrated that biologically relevant levels of homocysteine (20-100 microM) with copper (10 microM) resulted in dose-dependent apoptosis, which was prevented by addition of catalase but not superoxide dismutase. Incubation of murine palates in organ culture with homocysteine (100 micro) and CuSO(4) (10 microM) resulted in a decrease in palate fusion, which was not significant. Gelatin gel zymograms of HEPM cell-conditioned media and extracts of cultured murine palates, however, showed no change in the expression or activation of pro-matrix metalloproteinase-2 with homocysteine (20 microM-1 mM) with or without CuSO(4) (10 microM). We have demonstrated that biologically relevant levels of homocysteine in combination with copper can result in apoptosis as a result of oxidative stress; therefore, homocysteine has the potential to disrupt normal palate development.

Apoptosis↗
PubMed2004

Cross correlation by neurons of the medial superior olive: a reexamination.

Initial analysis of interaural temporal disparities (ITDs), a cue for sound localization, occurs in the superior olivary complex. The medial superior olive (MSO) receives excitatory input from the left and right cochlear nuclei. Its neurons are believed to be coincidence detectors, discharging when input arrives simultaneously from the two sides. Many current psychophysical models assume a strict version of coincidence, in which neurons of the MSO cross correlate their left and right inputs. However, there have been few tests of this assumption. Here we examine data derived from two earlier studies of the MSO and compare the responses to the output of a computational model. We find that the MSO is not an ideal cross correlator. Ideal cross correlation implies a strict relationship between the precision of phase-locking of the inputs and the range of ITDs to which a neuron responds. This relationship does not appear to be met. Instead, the modeling implies that a neuron responds over a wider range of ITDs than expected from the inferred precision of phase-locking of the inputs. The responses are more consistent with a scheme in which the neuron can also be activated by the input from one side alone. Such activation degrades the tuning of neurons in the MSO to ITDs.

Acoustic Stimulation↗
PubMed2002

Tom34 unlike Tom20 does not interact with the leader sequences of mitochondrial precursor proteins.

Tom20 and Tom34 are mammalian liver proteins previously identified by others to be components of the mitochondrial import translocation apparatus. It has been shown that Tom20 interacts with the leader sequence of nuclear coded matrix space precursor proteins. Here we show with recombinantly expressed Tom proteins that Tom34 binds the mature portion of the precursor and not the leader. Both these Tom proteins inhibited the import of newly translated precursor of aldehyde dehydrogenase in an in vitro assay. Only Tom20 inhibited the import of a fusion protein of the leader of aldehyde dehydrogenase attached to dihydrofolate reductase. Antibodies against Tom20 coprecipitated both the precursor of aldehyde dehydrogenase (pALDH) and of dihydrofolate reductase (pA-DHFR). Antibodies against Tom34 interacted only when the mature portion of aldehyde dehydrogenase was present. Similar import inhibition patterns were found when other precursor and chimeric constructs we investigated. When Tom34-green fluorescence protein was transfected to HeLa cells it was observed that Tom34 was found through out the cell. It is concluded from our observation that Tom34 is a cytosolic protein, whose role appeared to be to interact with mature portion of some preproteins and may keep them in an unfolded, import compatible state.

5' Untranslated Regions↗
PubMed2005

Determination of mercury evasion in a contaminated headwater stream.

Evasion from first- and second-order streams in a watershed may be a significant factor in the atmospheric recycling of volatile pollutants such as mercury; however, methods developed for the determination of Hg evasion rates from larger water bodies are not expected to provide satisfactory results in highly turbulent and morphologically complex first- and second-order streams. A new method for determining the Hg evasion rates from these streams, involving laboratory gas-indexing experiments and field tracer tests, was developed in this study to estimate the evasion rate of Hg from Gossan Creek, a first-order stream in the Upsalquitch River watershed in northern New Brunswick, Canada. Gossan Creek receives Hg-contaminated groundwater discharge from a gold mine tailings pile. Laboratory gas-indexing experiments provided the ratio of gas-exchange coefficients for zero-valent Hg to propane (tracer gas) of 0.81+/-0.16, suggesting that the evasion mechanism in highly turbulent systems can be described by the surface renewal model with an additional component of enhanced gas evasion probably related to the formation of bubbles. Deliberate field tracer tests with propane and chloride tracers were found to be a reliable and practical method for the determination of gas-exchange coefficients for small streams. Estimation of Hg evasion from the first 1 km of Gossan Creek indicates that about 6.4 kg of Hg per year is entering the atmosphere, which is a significant fraction of the regional sources of Hg to the atmosphere.

Air↗
PubMed2004

Interactions of TOM1L1 with the multivesicular body sorting machinery.

Tom1L1 (Tom1-like1) and related proteins Tom1 (Target of Myb1) and Tom1L2 (Tom1-like2) constitute a new protein family characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. Recently it was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVBs). Here we report a novel interaction between Tom1L1 and members of the MVB sorting machinery. Specifically, we found that the VHS domain of Tom1L1 interacts with Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domain of Tom1L1, is responsible for binding to TSG101 (tumor susceptibility gene 101). Myc epitope-tagged Tom1L1 showed a cytosolic distribution but was recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signaling proteins such as Grb2 and p85. We showed that a fraction of Fyn kinase localizes at endosomes and that this distribution becomes more evident after epidermal growth factor internalization. Moreover, expression of a constitutive active form of Fyn also promoted the recruitment of Tom1L1 to enlarged endosomes. Taken together, we propose that Tom1L1 could act as an intermediary between signaling and degradative pathways.

Endosomal Sorting Complexes Required for Transport↗
PubMed2003

HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q.

BACKGROUND: Despite strong evidence for a genetic component to variation in high-density lipoprotein cholesterol levels (HDL-C), specific polymorphisms associated with normal variation in HDL-C have not been identified. It is known, however, that HDL-C levels are influenced in complex ways by factors related to age and sex. In this paper, we examined the evidence for age- and sex-specific linkage of HDL-C in a longitudinal sample of participants from the Framingham Heart Study. To determine if aging could influence our ability to detect linkage, we explored the evidence for linkage of HDL-C at three time points, t1, t2, and t3, spaced approximately 8 years apart and corresponding respectively to visits 11, 15, and 20 for the original cohort and 1, 2, and 4 for the offspring and spouses. Additionally, to examine the effects of sex on linkage at each time point, we estimated the heritability and genetic correlation of HDL-C, performed linkage analysis of HDL-C, tested for genotype-by-sex interaction at a QTL, and performed linkage analysis of HDL-C in males and females separately. RESULTS AND CONCLUSION: In women, we found evidence for a QTL on chromosome 2q influencing HDL-C variation. Although the QTL could be detected in the combined sample of males and females at the first time point, the linkage was not significant at subsequent time points.

Adult↗
PubMed2006

HLA and RA revisited: citrullinated food for the SE hypothesis, the DR6 effect, and NIMA.

An obvious way to unravel the apparently complex association between human leukocyte antigen (HLA) and rheumatoid arthritis (RA) is to reduce the heterogeneity of this multifactorial disease. Recently we have discovered that shared epitope (SE)-positive HLA-DRB1 alleles are exclusively associated with a subgroup of RA patients that test positive for auto-antibodies against cyclic citrullinated peptides. Further studies suggested that SE-positive alleles are classical immune response genes for the development of these antibodies. On the basis of these and other data we formulated a two-hit model for the pathogenesis of RA which incorporates a novel "citrullinated" SE hypothesis. About 5 years ago Zanelli et al. reported that HLA-DR6 (*1301 and *1302) and some other DR alleles that share the DERAA-sequence on amino acids 70-74 of their third hypervariable region are associated with protection from (severe) RA. Recently we corroborated these data in a large prospective cohort study and demonstrated that protection was observed both in the presence and in the absence of a SE susceptibility allele on the other haplotype. Finally we review the state of the art of the association of noninherited maternal HLA antigens with both susceptibility to and protection from RA.

Arthritis, Rheumatoid↗
PubMed2004

A synthetic superoxide dismutase/catalase mimetic (EUK-134) inhibits membrane-damage-induced activation of mitogen-activated protein kinase pathways and reduces p53 accumulation in ultraviolet B-exposed primary human keratinocytes.

Salen-manganese complexes exhibit powerful superoxide dismutase and catalase activity, with pharmacologic efficacy in several oxidative-stress-associated disease models. Ultraviolet (UV) B not only induces direct DNA damage, but also generates oxidative stress. EUK-134, a salen-manganese complex, might therefore confer a direct protection against UVB-induced oxidative stress and consequently alleviate UVB-damage-induced signal transduction. We investigated the effect of EUK-134 on the UVB-induced accumulation and stabilization of the p53 protein. p53 plays a central role in the UVB response, both as sensor of UVB damage and as a mediator of a protective response. Cells treated with EUK-134 before UVB irradiation showed a significantly lower accumulation of the p53 protein in a concentration-dependent fashion. Furthermore, EUK-134 severely reduced N-terminal phosphorylation of p53. The extracellular signal-regulated kinase ERK and the stress-activated kinases JNK and p38 have been implicated in the UVB-induced N-terminal phosphorylation and accumulation of p53. Pre-treatment with EUK-134 inhibited the UVB-induced activation of these mitogen-activated protein kinase (MAPK) pathways. We hypothesize that EUK-134, by direct protection of the membrane from UVB-induced oxidative damage, reduces oxidative stress induced MAPK signaling and consequently lowers the level of p53 induction. The protection conferred by EUK-134 resulted in a significant increase in cell survival following UVB irradiation.

Cell Survival↗
PubMed2004

Crystal structure of the actin binding domain of the cyclase-associated protein.

Cyclase-associated protein (CAP or Srv2p) is a modular actin monomer binding protein that directly regulates filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localization and the establishment of cell polarity. The crystal structure of the C-terminal dimerization and actin monomer binding domain (C-CAP) reveals a highly unusual dimer, composed of monomers possessing six coils of right-handed beta-helix flanked by antiparallel beta-strands. Domain swapping, involving the last two strands of each monomer, results in the formation of an extended dimer with an extensive interface. This structural and biochemical characterization provides new insights into the organization and potential mechanistic properties of the multiprotein assemblies that integrate dynamic actin processes into the overall physiology of the cell. An unanticipated finding is that the unique tertiary structure of the C-CAP monomer provides a structural model for a wide range of molecules, including RP2 and cofactor C, proteins involved in X-linked retinitis pigmentosa and tubulin maturation, respectively, as well as several uncharacterized proteins that exhibit very diverse domain organizations. Thus, the unusual right-handed beta-helical fold present in C-CAP appears to support a wide range of biological functions.

Actins↗
PubMed2005

Effects of hydrogen bonding on the acidity of adenine, guanine, and their 8-oxo derivatives.

Complexes between ammonia, water, or hydrogen fluoride and adenine, guanine, or their 8-oxo derivatives are investigated using density-functional theory. The binding strengths of the neutral and (N9) anionic complexes are considered for a variety of purine binding sites. The effects of hydrogen-bonding interactions on the (N9) acidity of the purine derivatives are considered as a function of the molecule bound and the binding site. It is found that hydrogen-bonding interactions with one molecule can increase the acidity of purine derivatives by up to 60 kJ mol(-1). The (calculated) simultaneous effects of up to four molecules on the acidity of the purine derivatives are also considered. Our data suggest that the effects of more than one molecule on the acidity of the purines are generally less than the sum of the individual (additive) effects, where the magnitude of the deviation from additivity increases with the number, as well as the acidity, of molecules bound. Nevertheless, the increase in the acidity due to additional hydrogen-bonding interactions is significant, where the effect of two, three, or four hydrogen-bonding interactions can be as large as approximately 95, 115, and 130 kJ mol(-1), respectively. The present study provides a greater fundamental understanding of hydrogen-bonding interactions involving the natural purines, as well as those generated through oxidative DNA damage, which may aid the understanding of important biological processes.

Acids↗