Tectonics and Magmatism in the Basin and Range Province of the Western United States

The nature and geochemistiy of Miocene magmatism coeval to major extension is studied in detail along the Colorado River between 34-36°N. A tectonomagmatic model is proposed and developed into a general model for the Basin and Range. Mafic magmas are divided into three groups on the basis of geochemistry: group 1 (most recent) magmas have [Nb/La] >1, and Sr and Pb isotope ratios indistinguishable from OIB, these basalts are thought to derive by <10% melting of an asthenospheric source; group 2 & 3 magmas have [Nb/La] <1 and elevated Sr and Pb isotope ratios suggesting a subcontinental lithospheric mantle (SCLM) source. Group 3 magma geochemistry is rather variable, but consistent with an increasing degree of partial melting (1-14%) of a trace element enriched garnet Iherzolite source with time. Group 2 magmas have HREE, Y and Sc enriched relative to groups 1 & 3, although relatively depleted LILE and LREE. It is argued that the group 2 & 3 sources are related by depth and that melting in the SCLM progressed to shallower, less enriched, levels with time. Intermediate to high silica magmas display a positive 87Sr/86Sr vs. Si02 correlation and evolution to moderately alkaline compositions. Fractionation and AFC processes are insufficient to replicate the observed geochemical variations, instead these magmas are modelled by binary mixing between mafic and silicic endmember melts. The distribution and volume of these ‘hybrid’ magmas suggests that a ductile melting zone developed in the middle crust, which dominated the Miocene crustal extension. Geophysical evidence, combined with plate tectonic reconstructions and the changes in magma geochemistry with time, indicate that plate tectonics was the driving force behind extension and magmatism. The influence of a mantle plume is thought to be unnecessary, rather SCLM melting was initiated by heat input from the asthenosphere as it re-equilibrated to fill the ‘void’ left by the northward migration of the Farallon Plate beneath the W. USA

Porphyrin Derivatives and Photodynamic Therapy Effects on Triple Negative Breast Cancer

There are limited effective options for treatment of triple negative breast cancer (TNBC) due to its lack of the three receptors typically used to target breast cancer. The use of photodynamic therapy (PDT) to kill cells that take up light-absorbing compounds (PDT agents) may be an effective option to treat TNBC. We tested the efficacy of modified porphyrins as PDT agents against cells from TNBC. We compared these to Foscan, which is similar in structure to porphyrins and has been approved for use in Europe. Our 1st goal was to measure which porphyrins were taken up best by TNBC cells. Measuring the uptake of some of our compounds had been problematic due to their hydrophobic nature. We optimized the uptake protocol and showed that TNBC cells take up the compounds to different extents. One of the primary side effects of PDT is skin toxicity for up to 4-6 weeks after treatment due to exposure to sunlight. Our 2nd goal was to compare the toxicity in the light and in the dark of PipOH, H2TPPC, and Foscan. In previous experiments, Foscan showed dark toxicity at low concentrations, but in these experiments there was variability in our results with Foscan so no clear comparison could be drawn. Our 3rd goal was to find combinations of PDT agent and concentration that are effective on TNBC cells at high light energy but minimize killing cells with ambient light. We measured the effect on cell killing by varying both the light dose and the concentration of 3 compounds to find concentrations that are effective at high doses of light but minimize toxicity at moderate doses. All 3 compounds show promise, but the dose must be carefully selected

Azithromycin Failure in Mycoplasma genitalium Urethritis

We report significant failure rates (28%, 95% confidence interval 15%–45%) after administering 1 g azithromycin to men with Mycoplasma genitalium–positive nongonococcal urethritis. In vitro evidence supported reduced susceptibility of M. genitalium to macrolides. Moxifloxacin administration resulted in rapid symptom resolution and eradication of infection in all cases. These findings have implications for management of urethritis

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

In T cells, the Tec kinases IL-2-inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4(+) T cells from Itk(-/-) and Itk(-/-)Rlk(-/-) mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-gamma production by colitogenic CD4(+) T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases

Acoustic emission as an aid to understanding raceway damage in rolling element bearings [Abstract]

Acoustic Emission (AE) sensors were used to detect signals arising from a cylindrical roller bearing with artificial defects seeded onto the outer raceway. High frequency analysis indicated the condition of the bearings through the determination of an increase in the structural resonances of the system as the size of an artificial defect was increased. As higher loads were applied, frequencies around 100kHz were excited, indicating the release of AE possibly attributed to friction and the plastic deformation as peaks, induced through engraving of the raceway, were over-rolled and worn down. Sensitivity of AE to this level in bearings indicates that detection of subsurface cracking may be possible in future work, providing early indication of incipient failure

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations

BACKGROUND Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. METHODS We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. RESULTS A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. CONCLUSIONS In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965.

Juvenile root vigour improves phosphorus use efficiency of potato

Aims Potato (Solanum tuberosum L.) has a large phosphorus (P)-fertiliser requirement. This is thought to be due to its inability to acquire P effectively from the soil. This work tested the hypothesis that early proliferation of its root system would enhance P acquisition, accelerate canopy development, and enable greater yields. Methods Six years of field experiments characterised the relationships between (1) leaf P concentration ([P]leaf), tuber yield, and tuber P concentration ([P]tuber) among 27 Tuberosum, 35 Phureja and 4 Diploid Hybrid genotypes and (2) juvenile root vigour, P acquisition and tuber yield among eight Tuberosum genotypes selected for contrasting responses to P-fertiliser. Results Substantial genetic variation was observed in tuber yield, [P]leaf and [P]tuber. There was a strong positive relationship between tuber yields and P acquisition among genotypes, whether grown with or without P-fertiliser. Juvenile root vigour was correlated with accelerated canopy development and both greater P acquisition and tuber biomass accumulation early in the season. However, the latter relationships became weaker during the season. Conclusions Increased juvenile root vigour accelerated P acquisition and initial canopy cover and, thereby, increased tuber yields. Juvenile root vigour is a heritable trait and can be selected to improve P-fertiliser use efficiency of potato