'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Never Settle for Second Best? Cy Pres Distributions in Securities Class Action Settlements

There is an old adage that one should “never settle for second best.” While this advice is arguably well taken in most areas of life, it is less useful in settlement discussions. In 2015, more federal securities class actions were filed than during the height of the financial crisis in 2008, with more of those cases settling than in any year since 2011.1Consumer class action funds often go largely unclaimed, leaving settlement funds intended to compensate injured plaintiffs unused and undistribute

Vitamin B12 measurements across neurodegenerative disorders.

Background:Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson's disease (PD) differed from those in patients with other neurodegenerative disorders. Methods:We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. Results:In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from - 17 to - 47 pg/ml/year, much greater than that reported for the elderly population. Conclusions:Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders

Trapped radiation experiment

Trapped radiation detector on Mariner IV space probe measurement of outer Van Allen belt - feasibility of detecting trapped radiation at Mar

Mutation independently affects reproductive traits and dauer larvae development in mutation accumulation lines of Caenorhabditis elegans

Developmental decisions are important in organismal fitness. For the nematode Caenorhabditis elegans, which is naturally found in the ephemeral food patches formed by rotting plant material, correctly committing to dauer or non-dauer larval development is key to genotype survival. To investigate the link between reproductive traits, which will determine how populations grow, and dauer larvae formation, we have analysed these traits in mutation accumulation lines of C. elegans. We find that reproductive traits of individual worms-the total number of progeny and the timing of progeny production-are highly correlated with the population size observed in growing populations. In contrast, we find no relationship between reproduction traits and the number of dauer larvae observed in growing populations. We also do not observe a mutational bias in dauer larvae formation. These results indicate that the control of dauer larvae formation is distinct from the control of reproduction and that differences in dauer larvae formation can evolve rapidly

Development of a fretting-fatigue mapping concept: The effect of material properties and surface treatments

Fretting-fatigue induced by combined localized cyclic contact motion and external bulk fatigue loadings may result in premature and dramatic failure of the contacting components. Depending on fretting and fatigue loading conditions, crack nucleation and possibly crack propagation can be activated. This paper proposes a procedure for estimating these two damage thresholds. The crack nucleation boundary is formalized by applying the Crossland high cycle fatigue criterion, taking into account the stress gradient and the ensuing #size##effect#. The prediction of the crack propagation condition is formalized using a short crack arrest description. Applied to an AISI 1034 steel, this methodology allows the development of an original material response fretting-fatigue map (FFM). The impact of material properties and surface treatments is investigated

Measurement of Antenna Surfaces from In- and Out-Of-Focus Beam Maps using Astronomical Sources

We present a technique for the accurate estimation of large-scale errors in an antenna surface using astronomical sources and detectors. The technique requires several out-of-focus images of a compact source and the signal-to-noise ratio needs to be good but not unreasonably high. For a given pattern of surface errors, the expected form of such images can be calculated directly. We show that it is possible to solve the inverse problem of finding the surface errors from the images in a stable manner using standard numerical techniques. To do this we describe the surface error as a linear combination of a suitable set of basis functions (we use Zernike polynomials). We present simulations illustrating the technique and in particular we investigate the effects of receiver noise and pointing errors. Measurements of the 15-m James Clerk Maxwell telescope made using this technique are presented as an example. The key result is that good measurements of errors on large spatial scales can be obtained if the input images have a signal-to-noise ratio of order 100 or more. The important advantage of this technique over transmitter-based holography is that it allows measurements at arbitrary elevation angles, so allowing one to characterise the large scale deformations in an antenna as a function of elevation.Comment: 6 pages, 5 figures (accepted by Astronomy & Astrophysics

ALMA Temporal Phase Stability and the Effectiveness of Water Vapor Radiometer

Atacama Large Millimeter/submillimeter Array (ALMA) will be the world largest mm/submm interferometer, and currently the Early Science is ongoing, together with the commissioning and science verification (CSV). Here we present a study of the temporal phase stability of the entire ALMA system from antennas to the correlator. We verified the temporal phase stability of ALMA using data, taken during the last two years of CSV activities. The data consist of integrations on strong point sources (i.e., bright quasars) at various frequency bands, and at various baseline lengths (up to 600 m). From the observations of strong quasars for a long time (from a few tens of minutes, up to an hour), we derived the 2-point Allan Standard Deviation after the atmospheric phase correction using the 183 GHz Water Vapor Radiometer (WVR) installed in each 12 m antenna, and confirmed that the phase stability of all the baselines reached the ALMA specification. Since we applied the WVR phase correction to all the data mentioned above, we also studied the effectiveness of the WVR phase correction at various frequencies, baseline lengths, and weather conditions. The phase stability often improves a factor of 2 - 3 after the correction, and sometimes a factor of 7 improvement can be obtained. However, the corrected data still displays an increasing phase fluctuation as a function of baseline length, suggesting that the dry component (e.g., N2 and O2) in the atmosphere also contributes the phase fluctuation in the data, although the imperfection of the WVR phase correction cannot be ruled out at this moment.Comment: Proc. SPIE 8444-125, in press (7 pages, 4 figures, 1 table

No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML 10 and 12 trials

Fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) are powerful adverse prognostic indicators for relapse in acute myelold leukemia (AML) but the most efficacious therapy for FLT3/ ITD+ patients is currently unknown. We evaluated outcome according to FLT3/ITD status in 1135 adult patients treated according to United Kingdom Medical Research Council (UK MRC) AML protocols: 141 received an autograft, and 170 received a matched sibling allograft in first complete remission (CR). An FLT3/ITD was detected in 25% of patients and was an independent predictor for relapse (P < .001). It remained prognostic for increased relapse in patients who received a transplant (odds ratio [OR] = 1.91; 95% confidence intervals [CIs] 1.13-3.21; P = .02), with no evidence of a difference in effect between patients who received an autograft (OR = 2.39; CIs = 1.24-4.62) and patients who received an allograft (OR = 1.31; CIs = 0.56-3.06) (test for interaction, P = .3) or between patients who did or did not receive a transplant (P = .4). These results were confirmed in an analysis of 186 patients randomized to receive or not receive an autograft in first CR and in a donor-versus-no donor analysis of 683 patients to assess the role of allograft (for latter, FLT3/ITD- OR = 0.70, CIs = 0.53-0.92; FLT3/ITD+ OR = 0.59, CIs = 0.40-0.87; test for interaction, P = .5). These results suggest that at present there is no strong evidence that FLT3 status should influence the decision to proceed to transplantation