Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes

Prevalence of electronegative electroretinograms in a healthy adult cohort

Objective: An electronegative electroretinogram (ERG) can indicate important ocular or systemic disease. This study explored the prevalence of electronegative responses to dark-adapted stimuli in a largely healthy cohort. Methods: and Analysis 211 participants recruited from the TwinsUK cohort underwent ERG testing incorporating international standard (International Society for Clinical Electrophysiology of Vision (ISCEV)) protocols and additional stimuli. Responses were recorded using conductive fibre electrodes, following pupil dilation and 20 min dark adaptation. Responses analysed were to the ISCEV standard and strong flashes (3.0 and 10 cd/m2 s), and to additional white flashes (0.67–67 cd/m2 s). A-wave and b-wave amplitudes were extracted; b:a ratios were calculated and proportions of eyes with ratios<1 were noted. Results: Mean (SD) age was 62.4 (11.4) years (median, 64.3; range 23–86 years). 93% were female. Mean (SD) b:a ratios for right and left eyes, respectively, were 1.86 (0.33) and 1.81 (0.29) for the standard flash, and 1.62 (0.25) and 1.58 (0.23) for the stronger flash; average b:a ratio was lower for the stronger flash (p<0.0001). No waveforms were electronegative. For additional flashes, b:a ratio decreased with increasing flash strength. No electronegative waveforms were seen except in three eyes (0.7%) for the strongest flash; in some cases, drift in the waveform may have artefactually reduced the b:a ratio. Conclusion: For standard dark-adapted stimuli, no participants had electronegative waveforms. The findings support the notion that electronegative waveforms (in response to standard flash strengths) are unusual, and should prompt further investigation

GRB 090417B and its Host Galaxy: A Step Towards an Understanding of Optically-Dark Gamma-Ray Bursts

GRB 090417B was an unusually long burst with a T_90 duration of at least 2130 s and a multi-peaked light curve at energies of 15-150 keV. It was optically dark and has been associated with a bright star-forming galaxy at a redshift of 0.345 that is broadly similar to the Milky Way. This is one of the few cases where a host galaxy has been clearly identified for a dark gamma-ray burst and thus an ideal candidate for studying the origin of dark bursts. We find that the dark nature of GRB 090417B cannot be explained by high redshift, incomplete observations, or unusual physics in the production of the afterglow. Assuming the standard relativistic fireball model for the afterglow we find that the optical flux is at least 2.5 mag fainter than predicted by the X-ray flux. The Swift/XRT X -ray data are consistent with the afterglow being obscured by a dense, localized sheet of dust approximately 30-80 pc from the burst along the line of sight. Our results suggest that this dust sheet imparts an extinction of A_V >~ 12 mag, which is sufficient to explain the missing optical flux. GRB 090417B is an example of a gamma-ray burst that is dark due to the localized dust structure in its host galaxy.Comment: Accepted for publication in Ap

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6–12 mg m−2) and docetaxel (50–75 mg m−2). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m−2 with docetaxel 60 mg m−2. Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (⩾18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel

The Star-Forming Galaxy Contribution to the Cosmic MeV and GeV Gamma-Ray Background

While star-forming galaxies could be major contributors to the cosmic GeV $\gamma$-ray background, they are expected to be MeV-dim because of the "pion bump" falling off below ~100 MeV. However, there are very few observations of galaxies in the MeV range, and other emission processes could be present. We investigate the MeV background from star-forming galaxies by running one-zone models of cosmic ray populations, including Inverse Compton and bremsstrahlung, as well as nuclear lines (including $^{26}$Al), emission from core-collapse supernovae, and positron annihilation emission, in addition to the pionic emission. We use the Milky Way and M82 as templates of normal and starburst galaxies, and compare our models to radio and GeV--TeV $\gamma$-ray data. We find that (1) higher gas densities in high-z normal galaxies lead to a strong pion bump, (2) starbursts may have significant MeV emission if their magnetic field strengths are low, and (3) cascades can contribute to the MeV emission of starbursts if they emit mainly hadronic $\gamma$-rays. Our fiducial model predicts that most of the unresolved GeV background is from star-forming galaxies, but this prediction is uncertain by an order of magnitude. About ~2% of the claimed 1 MeV background is diffuse emission from star-forming galaxies; we place a firm upper limit of <~10% based on the spectral shape of the background. The star-formation contribution is constrained to be small, because its spectrum is peaked, while the observed background is steeply falling with energy through the MeV-GeV range.Comment: Published in ApJ, 27 pages, emulateapj format. Readers may be interested in the concurrent paper by Chakraborty and Fields (arXiv:1206.0770), a calculation of the Inverse Compton background from star-forming galaxie

Scintillation in (C6H5CH2NH3)2SnBr4: Green-Emitting Lead-Free Perovskite Halide Materials

10.1039/d1ra01123eRSC Advances113420635-2064

Discovery of the optical counterpart and early optical observations of GRB990712

We present the discovery observations of the optical counterpart of the gamma-ray burster GRB990712 taken 4.16 hours after the outburst and discuss its light curve observed in the V, R and I bands during the first ~35 days after the outburst. The observed light curves were fitted with a power-law decay for the optical transient (OT), plus an additional component which was treated in two different ways. First, the additional component was assumed to be an underlying galaxy of constant brightness. The resulting slope of the decay is 0.97+/-0.05 and the magnitudes of the underlying galaxy are: V = 22.3 +/- 0.05, R = 21.75 +/- 0.05 and I = 21.35 +/- 0.05. Second, the additional component was assumed to be a galaxy plus an underlying supernova with a time-variable brightness identical to that of GRB980425, appropriately scaled to the redshift of GRB990712. The resulting slope of the decay is similar, but the goodness-of-fit is worse which would imply that either this GRB is not associated with an underlying supernova or the underlying supernova is much fainter than the supernova associated with GRB980425. The galaxy in this case is fainter: V = 22.7 +/- 0.05, R = 22.25 +/- 0.05 and I = 22.15 +/- 0.05; and the OT plus the underlying supernova at a given time is brighter. Measurements of the brightnesses of the OT and the galaxy by late-time HST observation and ground-based observations can thus assess the presence of an underlying supernova.Comment: To appear in Ap

Prevalence of electronegative electroretinograms in a healthy adult cohort.

Funder: Fight for Sight UK, Birdshot Uveitis Society, Thomas Pocklington TrustFunder: NIHROBJECTIVE: An electronegative electroretinogram (ERG) can indicate important ocular or systemic disease. This study explored the prevalence of electronegative responses to dark-adapted stimuli in a largely healthy cohort. METHODS AND ANALYSIS: 211 participants recruited from the TwinsUK cohort underwent ERG testing incorporating international standard (International Society for Clinical Electrophysiology of Vision (ISCEV)) protocols and additional stimuli. Responses were recorded using conductive fibre electrodes, following pupil dilation and 20 min dark adaptation. Responses analysed were to the ISCEV standard and strong flashes (3.0 and 10 cd/m2 s), and to additional white flashes (0.67-67 cd/m2 s). A-wave and b-wave amplitudes were extracted; b:a ratios were calculated and proportions of eyes with ratios<1 were noted. RESULTS: Mean (SD) age was 62.4 (11.4) years (median, 64.3; range 23-86 years). 93% were female. Mean (SD) b:a ratios for right and left eyes, respectively, were 1.86 (0.33) and 1.81 (0.29) for the standard flash, and 1.62 (0.25) and 1.58 (0.23) for the stronger flash; average b:a ratio was lower for the stronger flash (p<0.0001). No waveforms were electronegative. For additional flashes, b:a ratio decreased with increasing flash strength. No electronegative waveforms were seen except in three eyes (0.7%) for the strongest flash; in some cases, drift in the waveform may have artefactually reduced the b:a ratio. CONCLUSION: For standard dark-adapted stimuli, no participants had electronegative waveforms. The findings support the notion that electronegative waveforms (in response to standard flash strengths) are unusual, and should prompt further investigation

Seasonal and species‐level water‐use strategies and groundwater dependence in dryland riparian woodlands during extreme drought

Drought‐induced groundwater decline and warming associated with climate change are primary threats to dryland riparian woodlands. We used the extreme 2012–2019 drought in southern California as a natural experiment to assess how differences in water‐use strategies and groundwater dependence may influence the drought susceptibility of dryland riparian tree species with overlapping distributions. We analyzed tree‐ring stable carbon and oxygen isotopes collected from two cottonwood species (Populus trichocarpa and P. fremontii) along the semi‐arid Santa Clara River. We also modeled tree source water δ18O composition to compare with observed source water δ18O within the floodplain to infer patterns of groundwater reliance. Our results suggest that both species functioned as facultative phreatophytes that used shallow soil moisture when available but ultimately relied on groundwater to maintain physiological function during drought. We also observed apparent species differences in water‐use strategies and groundwater dependence related to their regional distributions. P. fremontii was constrained to more arid river segments and ostensibly used a greater proportion of groundwater to satisfy higher evaporative demand. P. fremontii maintained ∆13C at pre‐drought levels up until the peak of the drought, when trees experienced a precipitous decline in ∆13C. This response pattern suggests that trees prioritized maintaining photosynthetic processes over hydraulic safety, until a critical point. In contrast, P. trichocarpa showed a more gradual and sustained reduction in ∆13C, indicating that drought conditions induced stomatal closure and higher water use efficiency. This strategy may confer drought avoidance for P. trichocarpa while increasing its susceptibility to anticipated climate warming