Separation of a coastal upwelling jet at Cape Blanco, Oregon, USA

The coastal upwelling region near Cape Blanco (43°N), Oregon, off the west coast of the United States, was studied using a towed conductivity-temperature-depth instrument on SeaSoar, a shipborne Acoustic DopplerCurrent Profiler, satellite sea surface temperature maps and satellite-tracked surface drifters during three cruises: August 1994, May and August 1995. Results demonstrate that the baroclinic coastal upwelling jet (and associated front), which was over the shelf poleward of Cape Blanco in all three cruises, separates from the continental shelf, providing an important mechanism for transporting material across the continental margin to the deep ocean. This flow-topography interaction mechanism is a universal phenomenon, and is likely to be important in other eastern boundary current regions of the world. The observations from the two August cruises show two different phenomena. In 1994, cyclogenesis was observed, during which the coastal jet was connected with a cyclonic eddy offshore before the connection was severed and the jet again flowed continuously around Cape Blanco but shifted eastwards. In 1995, the coastal jet meandered in the vicinity of Cape Blanco and then continued equatorward as an oceanic jet in deep water, but it was stronger and displaced farther seawards than the previous year. Drifters released early in the upwelling season (May 1995), when the strengthening longshore upwelling jet was only minimally perturbed by the Cape, were transported rapidly equatorwards and were swept through a large portion of the eastern boundary current region. Drifters released later in the upwelling season (August)were initially swept offshore and equatorwards near the Cape, but after interaction with the spatially complexmesoscale circulation, eventually returned to the continental margin with the seasonal reversal in winds andnear-surface currents. These differing flow trajectories are likely to have a significant impact on the biology ofeastern boundary currents

Intraseasonal Cross-Shelf Variability of Hypoxia along the Newport, Oregon, Hydrographic Line

AbstractObservations of hypoxia, dissolved oxygen (DO) concentrations &lt; 1.4 ml L−1, off the central Oregon coast vary in duration and spatial extent throughout each upwelling season. Underwater glider measurements along the Newport hydrographic line (NH-Line) reveal cross-shelf DO gradients at a horizontal resolution nearly 30 times greater than previous ship-based station sampling. Two prevalent hypoxic locations are identified along the NH-Line, as is a midshelf region with less severe hypoxia north of Stonewall Bank. Intraseasonal cross-shelf variability is investigated with 10 sequential glider lines and a midshelf mooring time series during the 2011 upwelling season. The cross-sectional area of hypoxia observed in the glider lines ranges from 0 to 1.41 km2. The vertical extent of hypoxia in the water column agrees well with the bottom mixed layer height. Midshelf mooring water velocities show that cross-shelf advection cannot account for the increase in outer-shelf hypoxia observed in the glider sequence. This change is attributed to an along-shelf DO gradient of −0.72 ml L−1 over 2.58 km or 0.28 ml L−1 km−1. In early July of the 2011 upwelling season, near-bottom cross-shelf currents reverse direction as an onshore flow at 30-m depth is observed. This shoaling of the return flow depth throughout the season, as the equatorward coastal jet moves offshore, results in a more retentive near-bottom environment more vulnerable to hypoxia. Slope Burger numbers calculated across the season do not reconcile this return flow depth change, providing evidence that simplified two-dimensional upwelling model assumptions do not hold in this location.</jats:p

Boron neutron capture therapy induces apoptosis of glioma cells through Bcl-2/Bax

<p>Abstract</p> <p>Background</p> <p>Boron neutron capture therapy (BNCT) is an alternative treatment modality for patients with glioma. The aim of this study was to determine whether induction of apoptosis contributes to the main therapeutic efficacy of BNCT and to compare the relative biological effect (RBE) of BNCT, γ-ray and reactor neutron irradiation.</p> <p>Methods</p> <p>The neutron beam was obtained from the Xi'an Pulsed Reactor (XAPR) and γ-rays were obtained from [⁶⁰Co] γ source of the Fourth Military Medical University (FMMU) in China. Human glioma cells (the U87, U251, and SHG44 cell lines) were irradiated by neutron beams at the XAPR or [⁶⁰Co] γ-rays at the FMMU with different protocols: Group A included control nonirradiated cells; Group B included cells treated with 4 Gy of [⁶⁰Co] γ-rays; Group C included cells treated with 8 Gy of [⁶⁰Co] γ-rays; Group D included cells treated with 4 Gy BPA (p-borono-phenylalanine)-BNCT; Group E included cells treated with 8 Gy BPA-BNCT; Group F included cells irradiated in the reactor for the same treatment period as used for Group D; Group G included cells irradiated in the reactor for the same treatment period as used for Group E; Group H included cells irradiated with 4 Gy in the reactor; and Group I included cells irradiated with 8 Gy in the reactor. Cell survival was determined using the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium (MTT) cytotoxicity assay. The morphology of cells was detected by Hoechst33342 staining and transmission electron microscope (TEM). The apoptosis rate was detected by flow cytometer (FCM). The level of Bcl-2 and Bax protein was measured by western blot analysis.</p> <p>Results</p> <p>Proliferation of U87, U251, and SHG44 cells was much more strongly inhibited by BPA-BNCT than by irradiation with [⁶⁰Co] γ-rays (<it>P </it>< 0.01). Nuclear condensation was determined using both a fluorescence technique and electron microscopy in all cell lines treated with BPA-BNCT. Furthermore, the cellular apoptotic rates in Group D and Group E treated with BPA-BNCT were significantly higher than those in Group B and Group C irradiated by [⁶⁰Co] γ-rays (<it>P </it>< 0.01). The clonogenicity of glioma cells was reduced by BPA-BNCT compared with cells treated in the reactor (Group F, G, H, I), and with the control cells (<it>P </it>< 0.01). Upon BPA-BNCT treatment, the Bax level increased in glioma cells, whereas Bcl-2 expression decreased.</p> <p>Conclusions</p> <p>Compared with ��-ray and reactor neutron irradiation, a higher RBE can be achieved upon treatment of glioma cells with BNCT. Glioma cell apoptosis induced by BNCT may be related to activation of Bax and downregulation of Bcl-2.</p

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,α)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 ± 0.02. This compares with a previously published CBE factor for BPA of 4.87 ± 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT. © 2000 Cancer Research Campaig

Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Background:Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro.Conclusions/Significance:These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001–012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16–74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi