Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis

Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype. © 2013 Donthamsetty et al

Detection of an Optical Counterpart to the ALFALFA Ultra-compact High Velocity Cloud AGC 249525

We report on the detection at $>$98% confidence of an optical counterpart to AGC 249525, an Ultra-Compact High Velocity Cloud (UCHVC) discovered by the ALFALFA blind neutral hydrogen survey. UCHVCs are compact, isolated HI clouds with properties consistent with their being nearby low-mass galaxies, but without identified counterparts in extant optical surveys. Analysis of the resolved stellar sources in deep $g$- and $i$-band imaging from the WIYN pODI camera reveals a clustering of possible Red Giant Branch stars associated with AGC 249525 at a distance of 1.64$\pm$0.45 Mpc. Matching our optical detection with the HI synthesis map of AGC 249525 from Adams et al. (2016) shows that the stellar overdensity is exactly coincident with the highest-density HI contour from that study. Combining our optical photometry and the HI properties of this object yields an absolute magnitude of $-7.1 \leq M_V \leq -4.5$, a stellar mass between $2.2\pm0.6\times10^4 M_{\odot}$ and $3.6\pm1.0\times10^5 M_{\odot}$, and an HI to stellar mass ratio between 9 and 144. This object has stellar properties within the observed range of gas-poor Ultra-Faint Dwarfs in the Local Group, but is gas-dominated.Comment: 9 pages, 4 figures; accepted to ApJ

Factors Associated with the Prescribing of Olanzapine, Quetiapine, and Risperidone in Patients with Bipolar and Related Affective Disorders

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90038/1/phco.31.8.806.pd

Conventional and Genetic Evidence on the Association between Adiposity and CKD

Background The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. Methods Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). Results Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. Conclusions Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.</p

Tech-Savvy Beef Cattle? How Heifers Respond to Moving Virtual Fence Lines

Global Positioning System (GPS)-based virtual fences offer the potential to improve the management of grazing animals. Prototype collar devices utilising patented virtual fencing algorithms were placed on six Angus heifers in a 6.15 hectare paddock. After a "no fence" period, sequential, shifting virtual fences restricted the animals to 40%, 60%, and 80% of the paddock area widthways and 50% lengthways across 22 days. Audio cues signaled the virtual boundary, and were paired with electrical stimuli if the animals continued forward into the boundary. Within approximately 48 h, the cattle learned the 40% fence and were henceforth restricted to the subsequent inclusion zones a minimum of 96.70% (±standard error 0.01%) of the time. Over time, the animals increasingly stayed within the inclusion zones using audio cues alone, and on average, approached the new fence within 4.25 h. The animals were thus attentive to the audio cue, not the fence location. The time spent standing and lying and the number of steps were similar between inclusion zones (all p ≥ 0.42). More lying bouts occurred at the 80% and lengthways inclusion zones relative to "no fence" (p = 0.04). Further research should test different cattle groups in variable paddock settings and measure physiological welfare responses to the virtual fencing stimuli

Temporary Exclusion of Cattle from a Riparian Zone Using Virtual Fencing Technology

Grazing cattle can both negatively and positively impact riparian zones, dependent on controlled grazing management. Virtual fencing technology, using collar devices that operate via GPS can provide audio cues and electrical stimuli to temporarily exclude cattle from specified areas as desired. An early experimental prototype automated virtual fencing system was tested in excluding ten cattle from a riparian zone in Australia. Animals were given free access to an 11.33-hectare area for three weeks, excluded from river access by a virtual fence for ten days (2.86-hectare inclusion zone), followed by free access again for six days. Animals were almost exclusively contained by the virtual fence. All animals received audio cues and electrical stimuli with daily fence interactions, but there was high individual variation with some animals first approaching the fence more often than others. Overall, there was an approximately 25% probability that animals would receive an electrical stimulus following an audio cue. Individual associative learning may have been socially-facilitated by the group’s behaviour. Following fence deactivation, all animals re-entered the previously excluded area. Further research with more groups and longer periods of exclusion using updated collar devices would determine the scope of virtual fencing technology for cattle grazing control

The transcription factor PPARα is overexpressed and is associated with a favourable prognosis in IDH-wildtype primary glioblastoma

© 2016 John Wiley & Sons Ltd Aims: PPARα agonists are in current clinical use as hypolipidaemic agents and show significant antineoplastic effects in human glioblastoma models. To date however, the expression of PPARα in large-scale glioblastoma datasets has not been examined. We aimed to investigate the expression of the transcription factor PPARα in primary glioblastoma, the relationship between PPARα expression and patients’ clinicopathological features and other molecular markers associated with gliomagenesis. Methods and results: With protein immunoblotting techniques and reverse transcription quantitative real-time PCR, PPARα was found to be significantly overexpressed in glioblastoma compared with control brain tissue (P = 0.032 and P = 0.005). PPARA gene expression was found to be enriched in the classical glioblastoma subtype within The Cancer Genome Atlas (TCGA) dataset. Although not associated with overall survival when assessed by immunohistochemistry, cross-validation with the TCGA dataset and multivariate analyses identified PPARA gene expression as an independent prognostic marker for overall survival (P = 0.042). Finally, hierarchical clustering revealed novel, significant associations between high PPARA expression and a putative set of glioblastoma molecular mediators including EMX2, AQP4, and NTRK2. Conclusions: PPARα is overexpressed in primary glioblastoma and high PPARA expression functions as an independent prognostic marker in the glioblastoma TCGA dataset. Further studies are required to explore genetic associations with high PPARA expression and to analyse the predictive role of PPARα expression in glioblastoma models in response to PPARα agonists

High-Power, High-Frequency, Annular-Beam Free-Electron Maser

The authors have developed a 15--17 GHz free electron maser (FEM) capable of producing high power pulses with a phase stability appropriate for linear collider applications. The electron beam source is a 1 {micro}s, 800 kV, 5 kA, 6-cm-dia annular electron beam machine called BANSHEE. The beam interacts with the TM{sub 02} mode Raman FEM amplifier in a corrugated cylindrical waveguide where the beam runs close to the interaction device walls to reduce the power density in the fields. They studied the phase stability by analyzing the dispersion relation for an axial FEL, in which the rf field was transversely wiggled and the electron trajectories were purely longitudinal. Detailed particle-in-cell simulations demonstrated the transverse wiggling of the rf mode and the axial FEL interaction and explicit calculations of the growing root of the dispersion relation are included to verify the phase stability