A modular route to boron doped PAHs by combining borylative cyclisation and electrophilic C-H borylation.

Heteroatom doping into polyaromatic hydrocarbons (PAHs) is a powerful approach for modifying key physical properties, however, there are extremely few modular routes that enable facile formation of B-, B2- and B,N-(specifically not containing direct B-N bonds) doped PAHs despite the growing importance of these materials. Sequential, one pot borylative cyclisation/intramolecular electrophilic C-H borylation of naphthyl-alkynes provides a simple new route to access novel B-, B,N- and B2-doped (PAHs). The initial products, dihydronaphthalene/dihydroquinoline B-mesityl PAHs, were reacted with [Ph3C][BF4]/pyridyl base to form the oxidised B-, and B,N-doped PAHs. However, for B-triisopropylphenyl (Trip) PAH congeners oxidation has to be performed prior to Trip installation due to preferential oxidation of an isopropylaryl moiety to the styrene. This alternative sequence enables access to Trip-B-PAHs and to structurally constrained B and B2-PAHs. Analysis of the solid state structures and optoelectronic properties of these PAHs confirm that frontier orbital energies, extended packing structures, Stokes shift and quantum yields all can be rationally modified using this methodology. The simplicity of this synthetic approach makes it a powerful tool for rapidly generating novel bench stable boron doped PAHs, which is important for facilitating further structure-property relationship studies and the wider utilisation of these materials in optoelectronic applications.

Chimeric VEGFRs are activated by a small-molecule dimerizer and mediate downstream signalling cascades in endothelial cells.

Despite much interest in vascular endothelial growth factor (VEGF) and its receptors (VEGFRs -1 and -2), VEGF-induced signalling cascades remain incompletely defined. Attempts to assign individual responses to a particular receptor have used either transfected cell lines, receptor-specific growth factors or antisense oligonucleotides. Such studies have attributed the majority of VEGF-induced responses to activation of VEGFR-2. As a consequence of poor growth factor-induced VEGFR-1 autophosphorylation however, observations from these studies may instead reflect the relative activation of the two receptors. We have generated novel chimeric VEGF receptors in which the dimerization domain of the B subunit of DNA gyrase is fused to the cytoplasmic domain of VEGFRs -1 and -2. When expressed in porcine aortic endothelial cells, both chimeric VEGFR-1 and -2 autophosphorylate in response to addition of the small-molecule dimerizing agent, coumermycin. Once activated, both receptors induce downstream signalling cascades, exemplified here by the activation of MAPK, PLCgamma and PKB/Akt. Furthermore, we demonstrate that the Y1175 residue of VEGFR-2 is essential for the activation of PLCgamma mediated by this chimeric receptor. In contrast to previous reports which show a limited ability of VEGFR-1 to mediate signalling cascades, we show that once sufficiently activated, VEGFR-1 signals in a similar manner to VEGFR-2 in endothelial cells.

Activation of adenylate cyclase by human recombinant sst5 receptors expressed in CHO-K1 cells and involvement of Galphas proteins.

1. The coupling of the human somatostatin sst5 receptor recombinantly expressed in Chinese hamster ovary (CHO-K1) cells to adenylate cyclase was investigated using receptor selective ligands. 2. Forskolin (10 microM)-stimulated adenosine 3': 5'-cyclic monophosphate (cyclic AMP) accumulation was inhibited by somatostatin-14 and a number of receptor-selective agonists with a rank order of agonist potency typical of the sst5 receptor. L-362,855 and BIM-23056 behaved as full agonists. At higher somatostatin-14 concentrations there was sub-maximal inhibition resulting in a bell-shaped concentration-effect relationship. Pertussis toxin (PTx; 100 ng ml(-1), 18 h) pre-treatment abolished agonist-mediated inhibition of cyclic AMP accumulation and markedly enhanced stimulation of cyclic AMP at higher agonist concentrations. 3. The concentration of prostaglandin E2 (PGE2) in the incubation media was raised 14 fold by 1 microM somatostatin-14 but was insufficient to stimulate adenylate cyclase activity via endogenous prostanoid receptors. 4. Pre-treatment with cholera toxin (ChTx; 20 microg ml(-1), 18 h) markedly inhibited sst5 receptor-mediated increases in cyclic AMP formation in intact cells. Somatostatin-14-stimulated cyclic AMP accumulation was also observed in sst5 receptor containing CHO-K1 membranes and was inhibited by the synthetic peptide Galphasacetyl-354-372-amide (100 microM) by 65.9+/-3.5%, implicating a Galphas protein involvement in this response. 5. Activation of Galphas proteins by somatostatin-14 could be demonstrated with [35S]-guanosine 5'-[gamma-thio]triphosphate ([35S]-GTPgammaS) binding and subsequent immunoprecipitation of 35S labelled Galphas proteins with anti-Galphas serum. 6. These data show that the sst5 receptor is very efficiently coupled in a negative manner to adenylate cyclase. However, at higher agonist concentrations the receptor can also mediate activation of adenylate cyclase by a mechanism apparently involving Galphas protein activation.

Human metabolism of aluminium-26 and gallium-67 injected as citrates.

1. 26Al and 67Ga were given as citrates to a healthy male volunteer by intravenous injection. The retention of both tracers was studied by body radioactivity measurement. Levels in blood and excreta were determined by gamma-ray spectrometry and/or accelerator mass spectrometry. 2. More than half of the 26Al had left the blood after 15 min and the decline continued, leaving < 1% in blood after 2 d; the losses occurred both to renal excretion and through uptake by other compartments. Estimated excretion up to 13 d was 83% (urine) and 1.8% (faeces). Whole-body retention of 15% at 13 d declined to approximately 4% at 1178 d, when the daily reduction corresponded to a biological half-life of 7 y, suggesting that sustained intake of dietary aluminium may lead to a progressively increasing internal deposit. 3. The metabolism of 67Ga differed markedly from that of 26Al in all aspects studied.

Metabolism of injected plutonium in two healthy men.

The metabolism of plutonium has been studied following intravenous injection of 237Pu as Pu (IV) citrate into two healthy male volunteers. Measurements of the tracer in samples of blood and excreta were made by gamma-ray spectrometry, and patterns of organ uptake were investigated through serial measurements with a scintillation counter viewing the liver and selected skeletal sites. Excretion in urine and feces measured during the first 3 wk accorded closely with the patterns deduced by Durbin from the report of Langham et al. on patients injected with 239Pu. However, concentrations in blood were roughly twice those suggested by Durbin during most of the 14 d covered by our measurements. In one subject, the liver deposit increased to a plateau after about 21 d, at roughly 55% of the injection; in the other, the increase was prolonged, reaching about 70% after several months.

Metabolism of injected barium in six healthy men.

Data are presented on the early metabolism and long-term retention of 133Ba (half-life 10.74 y) injected into six healthy male volunteers at ages 25-81 y. The tracer appeared to be mainly skeletal within several days, much earlier than predicted by the ICRP's model of alkaline earth metabolism. Excretion was mainly fecal, the relative fecal:urinary clearance up to 14 d ranging from 6 to 15 in the six subjects. The whole-body retention at 50 d (mean 8%, range 4.5 to 12%) was similar to that inferred from published data on the retention of injected Ra in man (mean 7%, range 3-13%). For about 1 y thereafter, the retention of Ba could be represented by simple power functions of time, with the rate of loss correlating with the excretory plasma clearance rate inferred over the first 4 d. In the subject aged 81 y, the pattern differed from that established following an earlier injection at age 60, but the differences were not necessarily related to advancing age.

Metabolism of Ca and Sr in late adult life.

Data are presented on the metabolism of Ca and Sr in a healthy male volunteer who, in a series of investigations conducted between the ages of 53 and 82 y, received controlled intakes of 45Ca, 47Ca, or 85Sr. No age-related trends were established, either in factors affecting the skeletal deposition of the tracers or in their subsequent retention studied for up to 462 d after intake. The data thus lend support to an important working postulate in the ICRP's model of alkaline earth metabolism.

Human uptake of 137Cs in mutton.

The uptake of radiocesium from mutton contaminated by fallout from the Chernobyl reactor accident has been studied in eight healthy male volunteers. Each subject consumed, on adjacent days, two meals prepared from the mutton containing a total of 0.8 kBq 137Cs. The elevation and subsequent decline in whole-body content were determined from body radioactivity measurements prior to the meals and at intervals up to 15 wk afterwards. Clearance of 137Cs between 1 and 15 wk showed a biological half-time of 102 +/- 24 (SD) d, (range 84-154 d). The fraction cleared with this half-time was 80 +/- 4% (range 72-85%). No attempt was made to determine the early retention and excretion but, if the ICRP's assumption of 10% clearance with a 2-d half-life were valid, the data would indicate an average uptake (f1) of 89%, i.e., marginally lower than the value of 100% assumed in setting limits on intake.

A comparison of techniques in the assessment of chest wall thickness and composition.

The thickness and composition of defined regions of the anterior chest wall are important factors in the assessment of pulmonary plutonium by low-energy x ray counting. Estimates of these quantities are reported for seven male subjects investigated by three laboratories using ultrasonic methods and by a fourth laboratory using magnetic resonance imaging. No important bias was found in any one laboratory's estimates of chest wall thickness relative to those of the others, but differences of up to 6 mm were noted for individual subjects. The discrepancies are believed principally to reflect the different sampling regimes adopted to reach a representative mean chest wall thickness over the region of interest from measurements at selected points. The adipose-tissue component was consistently found to be lower when assessed by magnetic resonance imaging compared with estimates by ultrasound, but the differences were unimportant in the context of plutonium assessment.

Relationships between Root Temperature and the Transport of Ammonium and Nitrate Ions by Italian and Perennial Ryegrass (Lolium multiflorum and Lolium perenne).

At root temperature below 14 C the absorption of (15)N from NH(4) (+) greatly exceeded that from NO(2) (-) by tillers of Lolium multiflorum and Lolium perenne under conditions where pH, external concentration, plant N status, and pretreatment temperature were varied. There was a marked increase in the temperature sensitivity of NO(3) (-) transport below 14 C, irrespective of the temperature at which plants were grown previously. A marked increase in the temperature sensitivity was also seen for NH(4) (+) transport, but this occurred at the lower temperature of 10 C. Pretreatment of roots at 8 C lowered this still further to 5 C. Above and below these transition temperatures the Q(10) values for NO(3) (-) and NH(4) (+) transport were similar. Thus, the increased absorption of NH(4) (+) relative to NO(3) (-) at low temperatures seems to be related primarily to the difference in transition temperatures.It seems possible that NO(3) (-) and NH(4) (+) are absorbed through separate regions of the cell membrane differing in lipid composition and phase transition temperatures.

Postoperative bladder distention: measurement with bladder ultrasonography.

Bladder distention is a common postoperative occurrence. A process improvement project was conducted at a Midwestern Veteran Affairs Medical Center to determine whether a new method for detecting bladder distention, bladder ultrasonography, was more effective than manual palpation in the perianesthesia setting. Data were collected on 494 men over a 9-month period using bladder ultrasonography. Of those patients, 19.4% had postoperative bladder distention with greater than 400 mL of urine. This compared with 1.4% of patients who had bladder distention detected during the previous year using manual palpation. Data from the project supported the use of bladder ultrasonography as being more effective than manual palpation in the assessment of postoperative bladder distention in the PACU.

The Shc-related adaptor protein, Sck, forms a complex with the vascular-endothelial-growth-factor receptor KDR in transfected cells.

Despite much progress in recent years, the precise signalling events triggered by the vascular-endothelial-growth-factor (VEGF) receptors, fms-like tyrosine kinase (Flt1) and kinase insert domain-containing receptor (KDR), are incompletely defined. Results obtained when Flt1 and KDR are individually expressed in fibroblasts or porcine aortic endothelial cells have not been entirely consistent with those observed in other endothelial cells expressing both receptors endogenously. It has also been difficult to demonstrate VEGF-induced phosphorylation of Flt1, which has led to speculation that KDR may be the more important receptor for the mitogenic action of VEGF on endothelial cells. In an attempt to identify physiologically important effectors which bind to KDR, we have screened a yeast two-hybrid mouse embryo library with the cytoplasmic domain of KDR. Here we describe the identification of the adaptor protein, Shc-like protein (Sck), as a binding partner for KDR. We demonstrate that this interaction requires phosphorylation of KDR, and identify the binding site for the Src-homology 2 (SH2) domain as tyrosine-1175 of KDR. We have also shown that the SH2 domain of Sck, but not that of Src-homology collagen protein (Shc), can precipitate phosphorylated KDR from VEGF-stimulated porcine aortic endothelial cells expressing KDR, and that an N-terminally truncated Sck protein can associate with KDR, in a phosphorylation-dependent fashion, when co-expressed in human embryonic kidney 293 cells. Furthermore, we demonstrate that in the two-hybrid assay, both Shc and Sck SH2 domains can associate with the related receptor Flt1.