'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

Assessment worlds colliding? Negotiating between discourses of assessment on an online open course

Using the badged open course, Taking your first steps into Higher Education, this case study examines how assessment on online open courses draws on concepts of assessment used within formal and informal learning. Our experience was that assessment used within open courses, such as massive open online courses, is primarily determined by the requirements of quality assurance processes to award a digital badge or statement of participation as well as what is technologically possible. However, this disregards much recent work in universities that use assessment in support of learning. We suggest that designers of online open courses should pay greater attention to the relationship of assessment and learning to improve participant course completion

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

Voice and Exit as Accountability Mechanisms: Can Foot-Voting Be Made Safe for the Chinese Communist Party?

According to Albert O. Hirschman’s famous dichotomy, citizens can express their preferences with their “voice” (by voting with ballots to elect better representatives) and “exit” (by voting with their feet to choose better places to live). Suppose, however, that ballot-voting is ineffective: Can exit not merely aid but also replace voice? Using as a case study the People’s Republic of China, a party state without elective democracy, we argue that exit is not a substitute for, but rather a complement to, voice. China’s bureaucratic promotion system plays the role of local elections in the United States, promoting or replacing local officials based on their performance in office. In either regime, however, it is costly for local voters (in the United States) or the Chinese Communist Party (in China) to monitor and assess local officials. Attention to foot-voting in the legal design of local government can help reduce these costs. By evaluating cadres who run the lower levels of China’s local governments on the basis of how successfully they attract mobile households, the central CCP authorities could reduce the costs of monitoring these local officials and thereby reproduce, by bureaucratic means, some of the benefits of electoral democracy. Success in attracting foot-voters can be most cheaply measured by the Party’s evaluating cadres primarily on the basis of local land values which, because they are a product of foot-voters’ decisions about where to live, function like ballots insofar as they reflect the popularity of local cadres’ policy decisions with mobile Chinese households. For foot-voting to improve governmental accountability, however, the Chinese system of local government law requires some basic but politically feasible reforms ― in particular, the introduction of a local property tax system, the creation of a federated city system that grants power and autonomy to sub-city units, and the liberalization of China’s household registration system to make the population fully mobile across different jurisdictions.postprin