A core function for p120-catenin in cadherin turnover

p120-catenin stabilizes epithelial cadherin (E-cadherin) in SW48 cells, but the mechanism has not been established. Here, we show that p120 acts at the cell surface to control cadherin turnover, thereby regulating cadherin levels. p120 knockdown by siRNA expression resulted in dose-dependent elimination of epithelial, placental, neuronal, and vascular endothelial cadherins, and complete loss of cell–cell adhesion. ARVCF and δ-catenin were functionally redundant, suggesting that proper cadherin-dependent adhesion requires the presence of at least one p120 family member. The data reveal a core function of p120 in cadherin complexes, and strongly predict a dose-dependent loss of E-cadherin in tumors that partially or completely down-regulate p120

p120-Catenin Mediates Inflammatory Responses in the Skin

SummaryAlthough p120-catenin regulates adherens junction (AJ) stability in cultured cells, genetic studies in lower eukaryotes have not revealed a role for this protein in vivo. Using conditional targeting in mice, we show that p120 null neonatal epidermis exhibits reduced intercellular AJ components but no overt disruption in barrier function or intercellular adhesion. As the mice age, however, they display epidermal hyperplasia and chronic inflammation, typified by hair degeneration and loss of body fat. Using skin engraftments and anti-inflammatory drugs, we show that these features are not attributable to reductions in junctional cadherins and catenins, but rather NFkB activation. Both in vivo and in vitro, p120 null epidermal cells activate nuclear NFkB, triggering a cascade of proinflammatory NFkB targets. Although the underlying mechanism is likely complex, we show that p120 affects NFkB activation and immune homeostasis in part through regulation of Rho GTPases. These findings provide important new insights into p120 function

Intrinsic Absorption Lines in Seyfert 1 Galaxies. I. Ultraviolet Spectra from the Hubble Space Telescope

We present a study of the intrinsic absorption lines in the ultraviolet spectra of Seyfert 1 galaxies. We find that the fraction of Seyfert 1 galaxies that show absorption associated with their active nuclei is more than one-half (10/17), which is much higher than previous estimates (3 - 10%) . There is a one-to-one correspondence between Seyferts that show intrinsic UV absorption and X-ray ``warm absorbers''. The intrinsic UV absorption is generally characterized by high ionization: C IV and N V are seen in all 10 Seyferts with detected absorption (in addition to Ly-alpha), whereas Si IV is present in only four of these Seyferts, and Mg II absorption is only detected in NGC 4151. The absorption lines are blueshifted (or in a few cases at rest) with respect to the narrow emission lines, indicating that the absorbing gas is undergoing net radial outflow. At high resolution, the absorption often splits into distinct kinematic components that show a wide range in widths (20 - 400 km/s FWHM), indicating macroscopic motions (e.g., radial velocity subcomponents or turbulence) within a component. The strong absorption components have cores that are much deeper than the continuum flux levels, indicating that the regions responsible for these components lie completely outside of the broad emission-line regions. The covering factor of the absorbing gas in the line of sight, relative to the total underlying emission, is C > 0.86, on average. The global covering factor, which is the fraction of emission intercepted by the absorber averaged over all lines of sight, is C > 0.5.Comment: 56 pages, Latex, includes 4 figures (encapsulated postscript), Fig. 1 has 2 parts and Fig. 2 has 3 parts, to appear in the Astrophysical Journa

Quantification of grazing efficacy, growth and health score of different lumpfish (Cyclopterus lumpus L.) families: possible size and gender effects

Postponed access: the file will be available after 2022-09-12To investigate the possible family influence on sea lice grazing of lumpfish on Atlantic salmon, ten families of lumpfish (N = 480) with a mean (± SD) weight of 54.8 ± 9.2 g were distributed among ten sea cages (5 × 5 × 5 m) each stocked with 400 Atlantic salmon with a mean (± SD) weight of 621.4 ± 9.2 g. All the ten cages were stocked with 48 lumpfish (12% stocking density). The stocking of cages was such that each cage consisted of two random families where full- and paternal half-sib families were randomly allocated to the different cages. There were clear differences in sea lice grazing efficacy, growth and cataract prevalence between the ten families assessed in this study. Lumpfish from families 2, 6 and 10 had the lowest mean weights but showed comparable growth rates compared to the other families throughout the study and this may be as a direct result of genetic influence. In addition, fish from these families had a significantly higher incidence of lice grazing of both L. salmonis and C. elongatus compared to the other families. Using mixed linear model to analyse the data revealed significant family and paternal effect on sea lice grazing. There was a trend for a reduction in sea lice grazing with increased size within each family. The results indicated that it was the smallest size classes of lumpfish (40–140 g) which exhibited higher sea lice grazing potential compared to the larger size classes within families. There were no clear differences in the lice grazing potential between male and female lumpfish within and between families. Overall, present findings showed that sea lice grazing of both L. salmonis and C. elongatus can be enhanced using targeted family production and if this behaviour has a genetic basis it may further enhanced through selection and targeted breeding programs.acceptedVersio

Incremental Reduction in Risk of Death Associated with Use of Guideline-Recommended Therapies in Patients with Heart Failure: A Nested Case-Control Analysis of IMPROVE HF

Background: Several therapies are guideline-recommended to reduce mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction, but the incremental clinical effectiveness of these therapies has not been well studied. We aimed to evaluate the individual and incremental benefits of guideline-recommended HF therapies associated with 24-month survival. Methods and results: We performed a nested case-control study of HF patients enrolled in IMPROVE HF. Cases were patients who died within 24 months and controls were patients who survived to 24 months, propensity-matched 1:2 for multiple prognostic variables. Logistic regression was performed, and the attributable mortality risk from incomplete application of each evidence-based therapy among eligible patients was calculated. A total of 1376 cases and 2752 matched controls were identified. β-Blocker and cardiac resynchronization therapy were associated with the greatest 24-month survival benefit (adjusted odds ratio for death 0.42, 95% confidence interval (CI), 0.34–0.52; and 0.44, 95% CI, 0.29–0.67, respectively). Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, implantable cardioverter-defibrillators, anticoagulation for atrial fibrillation, and HF education were also associated with benefit, whereas aldosterone antagonist use was not. Incremental benefits were observed with each successive therapy, plateauing once any 4 to 5 therapies were provided (adjusted odds ratio 0.31, 95% CI, 0.23–0.42 for 5 or more versus 0/1, P<0.0001). Conclusions: Individual, with a single exception, and incremental use of guideline-recommended therapies was associated with survival benefit, with a potential plateau at 4 to 5 therapies. These data provide further rationale to implement guideline-recommended HF therapies in the absence of contraindications to patients with HF and reduced left ventricular ejection fraction

Is expression of p120ctn in oral squamous cell carcinomas a prognostic factor?

Objectives p120ctn is a component of the catenin family. To date, there have only been two studies examining expression levels of p120ctn in oral squamous cell carcinoma (OSCC). Materials and methods Paraffined specimens of 113 OSCCs and 12 of normal mucosa were examined by immunohistochemistry. Frozen samples of 20 OSCCs and 5 of normal mucosa were examined by Western blot (WB). Results were correlated with clinicopathological parameters. Five cell lines were examined by immunofluorescence, immunocytochemistry, and WB to show immunoreactivity and cellular localization of p120ctn. Results Altered p120ctn expression was observed in 109/113 cases of OSCC. Heterogenous cytoplasmic/nuclear expression was associated with loss of membranous distribution (88/113 cases). Complete loss of expression was noted in 21/113 cases. Increased cytoplasmic expression was evident in all positive cases, without significant correlation among p120ctn staining/pattern and grading/stage. Reduction/absence of p120ctn expression was related to poor prognosis ( P Conclusion p120ctn delocalization/loss of expression could be an independent prognostic marker in OSCC

Modeling bursts and heavy tails in human dynamics

Current models of human dynamics, used from risk assessment to communications, assume that human actions are randomly distributed in time and thus well approximated by Poisson processes. We provide direct evidence that for five human activity patterns the timing of individual human actions follow non-Poisson statistics, characterized by bursts of rapidly occurring events separated by long periods of inactivity. We show that the bursty nature of human behavior is a consequence of a decision based queuing process: when individuals execute tasks based on some perceived priority, the timing of the tasks will be heavy tailed, most tasks being rapidly executed, while a few experiencing very long waiting times. We discuss two queueing models that capture human activity. The first model assumes that there are no limitations on the number of tasks an individual can hadle at any time, predicting that the waiting time of the individual tasks follow a heavy tailed distribution with exponent alpha=3/2. The second model imposes limitations on the queue length, resulting in alpha=1. We provide empirical evidence supporting the relevance of these two models to human activity patterns. Finally, we discuss possible extension of the proposed queueing models and outline some future challenges in exploring the statistical mechanisms of human dynamics.Comment: RevTex, 19 pages, 8 figure

A novel role for p120 catenin in E-cadherin function

Îndirect evidence suggests that p120-catenin (p120) can both positively and negatively affect cadherin adhesiveness. Here we show that the p120 gene is mutated in SW48 cells, and that the cadherin adhesion system is impaired as a direct consequence of p120 insufficiency. Restoring normal levels of p120 caused a striking reversion from poorly differentiated to cobblestone-like epithelial morphology, indicating a crucial role for p120 in reactivation of E-cadherin function. The rescue efficiency was enhanced by increased levels of p120, and reduced by the presence of the phosphorylation domain, a region previously postulated to confer negative regulation. Surprisingly, the rescue was associated with substantially increased levels of E-cadherin. E-cadherin mRNA levels were unaffected by p120 expression, but E-cadherin half-life was more than doubled. Direct p120–E-cadherin interaction was crucial, as p120 deletion analysis revealed a perfect correlation between E-cadherin binding and rescue of epithelial morphology. Interestingly, the epithelial morphology could also be rescued by forced expression of either WT E-cadherin or a p120-uncoupled mutant. Thus, the effects of uncoupling p120 from E-cadherin can be at least partially overcome by artificially maintaining high levels of cadherin expression. These data reveal a cooperative interaction between p120 and E-cadherin and a novel role for p120 that is likely indispensable in normal cells