Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt

Recent genome-wide association studies reveal that the FAM13A gene is associated with human lung function and a variety of lung diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and pulmonary fibrosis. The biological functions of Fam13a, however, have not been studied. In an effort to identify novel substrates of B56-containing PP2As, we found that B56-containing PP2As and Akt act antagonistically to control reversible phosphorylation of Fam13a on Ser-322. We show that Ser-322 phosphorylation acts as a molecular switch to control the subcellular distribution of Fam13a. Fam13a shuttles between the nucleus and cytoplasm. When Ser-322 is phosphorylated by Akt, the binding between Fam13a and 14-3-3 is enhanced, leading to cytoplasmic sequestration of Fam13a. B56-containing PP2As dephosphorylate phospho-Ser-322 and promote nuclear localization of Fam13a. We generated Fam13a-knockout mice. Fam13a-mutant mice are viable and healthy, indicating that Fam13a is dispensable for embryonic development and physiological functions in adult animals. Intriguingly, Fam13a has the ability to activate the Wnt pathway. Although Wnt signaling remains largely normal in Fam13a-knockout lungs, depletion of Fam13a in human lung cancer cells causes an obvious reduction in Wnt signaling activity. Our work provides important clues to elucidating the mechanism by which Fam13a may contribute to human lung diseases

Yield conditions for deformation of amorphous polymer glasses

Shear yielding of glassy polymers is usually described in terms of the pressure-dependent Tresca or von Mises yield criteria. We test these criteria against molecular dynamics simulations of deformation in amorphous polymer glasses under triaxial loading conditions that are difficult to realize in experiments. Difficulties and ambiguities in extending several standard definitions of the yield point to triaxial loads are described. Two definitions, the maximum and offset octahedral stresses, are then used to evaluate the yield stress for a wide range of model parameters. In all cases, the onset of shear is consistent with the pressure-modified von Mises criterion, and the pressure coefficient is nearly independent of many parameters. Under triaxial tensile loading, the mode of failure changes to cavitation.Comment: 9 pages, 8 figures, revte

Influence of Carbon Concentration on the Superconductivity in MgCxNi3

The influence of carbon concentration on the superconductivity (SC) in MgC$_{x}$Ni$_3$ has been investigated by measuring the low temperature specific heat combined with first principles electronic structure calculation. It is found that the specific heat coefficient $\gamma_n=C_{en}/T$ of the superconducting sample ($x\approx1$) in normal state is twice that of the non-superconducting one ($x\approx 0.85$). The comparison of measured $\gamma_n$ and the calculated electronic density of states (DOS) shows that the effective mass renormalization changes remarkably as the carbon concentration changes. The large mass renormalization for the superconducting sample and the low $T_{c}$(7K) indicate that more than one kind of boson mediated electron-electron interactions exist in MgC$_{x}$Ni$_3$.Comment: 4 pages, 4 figure

A 60GHz Wireless Access Scheme with Electrical LO Devices Free in Mobile Terminals and Base Stations

Abstract: we propose a 60GHz wireless access network scheme with centralized LO service delivered to mobile terminals and base stations from the central office. Bidirectional transmission based on the scheme has been experimentally demonstrated. OCIS codes: (060.0060) Fiber optics and optical communications; (060.2330) Fiber optics communications Introduction Due to the increasing demand for in-door, high speed wireless access networks for next generation, millimeter-wave (MM-W) wireless-over-fiber (WoF) technology has been considered as a very promising solution. However, with the increasing of the carrier frequency up to 60GHz, the diameter of the coverage area of each base station (BS) is limited within tens of meters. As a consequence, numerous electrical local oscillator (LO) devices of high frequency are required in each BS and mobile terminal (MT), incurring high system complexity and cost. Hence, cost-effective microwave photonic techniques for frequency up-conversion have been developed for system integration In this paper, we propose a new CO-BS-MT architecture to construct a bidirectional 60GHz WoF system, while providing both remote BS and MT with LO service of high-quality from the CO. For the downlink transmission, frequency up-conversion via optical beating and self-heterodyne detection techniques have been utilized to transmit and receive MM-W signals, while eliminating the use of electrical LO generators in both BS and MT. For the uplink transmission, the high-frequency LO, which is required for data up-conversion in MT and the MM-W signal downconversion in BS, is provided by the centralized LO service distributed from CO, instead of relying on electrical LO generators in MT and BS. The stability and operational parameters of LO are pre-determined and controlled in CO. A proof-of-concept experiment is carried out to demonstrate the feasibility of the proposed scheme

Simulations of the Static Friction Due to Adsorbed Molecules

The static friction between crystalline surfaces separated by a molecularly thin layer of adsorbed molecules is calculated using molecular dynamics simulations. These molecules naturally lead to a finite static friction that is consistent with macroscopic friction laws. Crystalline alignment, sliding direction, and the number of adsorbed molecules are not controlled in most experiments and are shown to have little effect on the friction. Temperature, molecular geometry and interaction potentials can have larger effects on friction. The observed trends in friction can be understood in terms of a simple hard sphere model.Comment: 13 pages, 13 figure

Cardiac prehabilitation, rehabilitation and education in first-time atrial fibrillation (AF) ablation (CREED AF):Study protocol for a randomised controlled trial

Background: Atrial fibrillation (AF) is associated with significant morbidity/mortality. AF-ablation is an increasingly used treatment. Currently, first-time AF-ablation success is 40–80% at 1-year, depending on individual factors. There is growing evidence for improved outcomes through management of AF risk-factors/comorbidities via patient education/exercise-rehabilitation. There are no studies assessing combined prehabilitation/rehabilitation in this cohort. The aim of this randomised controlled trial is to assess efficacy of comprehensive prehabilitation/ rehabilitation and combining supervised exercise-training with AF risk-factor modification/ education compared with standard care in people undergoing first-time AF ablation. Methods: This single-centre pragmatic randomised controlled trial will recruit 106 adults with paroxysmal/persistent AF listed for first-time AF-ablation. Participants will be randomised 1:1 to cardiac prehabilitation/rehabilitation/education (CREED AF) intervention or standard care. Both groups will undergo AF-ablation at 8-weeks post-randomisation as per usual care. The CREED AF intervention will involve 6-weeks of prehabilitation (before AF-ablation) followed by 6-weeks rehabilitation (after AF-ablation) consisting of risk factor education/modification and supervised exercise training. Standard care will include a single 30-minute session of risk-factor education. Outcomes will be measured at baseline, 10-weeks and 12-months post AF-ablation, by researchers blinded to treatment allocation. The primary outcome is cardiorespiratory-fitness (peak oxygen uptake, VO 2peak) assessed using cardiopulmonary exercise testing (CPET) at 10-weeks post-ablation. Secondary outcomes include health-related quality of life, AF recurrence/burden assessed by 7-day Holter-monitor, requirement for repeat AF-ablation, study defined major adverse cardiovascular events, and cost-effectiveness (incremental cost per quality-adjusted life year (QALY)). Conclusions: This study will assess clinical-efficacy/cost-effectiveness of comprehensive prehabilitation/ rehabilitation/patient-education for people undergoing first time AF-ablation. Results will inform clinical care and design of future multi-centre clinical trials.</p

The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis

Background:To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer.Methods:Four snoRNAs, commonly used for normalisation, RNU44, RNU48, RNU43 and RNU6B, and miRNA known to be associated with pathological factors, were measured by real-time polymerase chain reaction in two patient series: 219 breast cancer and 46 head and neck squamous cell carcinoma (HNSCC). SnoRNA and miRNA were then correlated with clinicopathological features and prognosis.Results:Small-nucleolar RNA expression was as variable as miRNA expression (miR-21, miR-210, miR-10b). Normalising miRNA PCR expression data to these recommended snoRNAs introduced bias in associations between miRNA and pathology or outcome. Low snoRNA expression correlated with markers of aggressive pathology. Low levels of RNU44 were associated with a poor prognosis. RNU44 is an intronic gene in a cluster of highly conserved snoRNAs in the growth arrest specific 5 (GAS5) transcript, which is normally upregulated to arrest cell growth under stress. Low-tumour GAS5 expression was associated with a poor prognosis. RNU48 and RNU43 were also identified as intronic snoRNAs within genes that are dysregulated in cancer.Conclusion:Small-nucleolar RNAs are important in cancer prognosis, and their use as reference genes can introduce bias when determining miRNA expression. © 2011 Cancer Research UK All rights reserved

Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells

Introduction Resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies is an emerging clinical problem. The efficacy of anti-EGFR therapies can be influenced by the presence of heregulins (HRGs), which can bind erbB3/4 receptors and can activate alternative signalling pathways. In the present study we have examined whether HRG signalling can circumvent EGFR blockade in an EGFR-positive tamoxifen-resistant MCF-7 (Tam-R) breast cancer cell line. Methods Tam-R cells, incubated with the selective EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839), were exposed to HRGβ1 and the effects on erbB receptor dimerization profiles and on activation of associated downstream signalling components were assessed by immunoprecipitation, western blotting and immunocytochemistry. The effects of HRGβ1 on gefitinib-treated Tam-R cell growth and invasion were also examined, and HRGβ1 expression levels were assessed in breast cancer tissue by immunohistochemistry to address the potential clinical relevance of such a resistance mechanism. Results In Tam-R cells, HRGβ1 promoted erbB3/erbB2 and erbB3/EGFR heterodimerization, promoted ERK1/2 and AKT pathway activation and increased cell proliferation and invasion. Gefitinib prevented HRGβ1-driven erbB3/EGFR heterodimerization, ERK1/2 activation and Tam-R cell proliferation, but HRGβ1-driven erbB3/erbB2 heterodimerization, AKT activation and Tam-R cell invasion were maintained. A combination of gefitinib and the phosphatidylinositol 3-kinase inhibitor LY294002 effectively blocked HRGβ1-mediated intracellular signalling activity, growth and invasion in Tam-R cells. Similarly, targeting erbB2 with trastuzumab in combination with gefitinib in Tam-R cells reduced HRGβ1-induced erbB2 and ERK1/2 activity; however, HRGβ1-driven AKT activity and cell growth were maintained while cell invasion was significantly enhanced with this combination. In clinical tissue all samples demonstrated cytoplasmic tumour epithelial HRGβ1 protein staining, with expression correlating with EGFR positivity and activation of both AKT and ERK1/2. Conclusion HRGβ1 can overcome the inhibitory effects of gefitinib on cell growth and invasion in Tam-R cells through promotion of erbB3/erbB2 heterodimerization and activation of the phosphatidylinositol 3-kinase/AKT signalling pathway. This may have implications for the effectiveness of anti-EGFR therapies in breast cancer as HRGβ1 is enriched in many EGFR-positive breast tumours

Perceived Discrimination and Health Outcomes Among Asian Indians in the United States

Background: Perceived interpersonal discrimination while seeking healthcare services is associated with poor physical and mental health. Yet, there is a paucity of research among Asian Americans or its subgroups. This study examined the correlates of reported interpersonal discrimination when seeking health care among a large sample of Asian Indians, the 3rd largest Asian American subgroup in the US, and identify predictors of adverse self-rated physical health, a well-accepted measure of overall health status. Methods: Cross-sectional survey. Participants comprised of 1824 Asian Indian adults in six states with higher concentration of Asian Indians. Results: Mean age and years lived in the US was 45.7 ± 12.8 and 16.6 ± 11.1 years respectively. The majority of the respondents was male, immigrants, college graduates, and had access to care. Perceived interpersonal discrimination when seeking health care was reported by a relatively small proportion of the population (7.2 %). However, Asian Indians who reported poor self-rated health were approximately twice as likely to perceived discrimination when seeking care as compared to those in good or excellent health status (OR 1.88; 95 % CI 1.12–3. 14). Poor self-rated health was associated with perceived health care discrimination after controlling for all of the respondent characteristics (OR 1.93; 95 % CI: 1.17–3.19). In addition, Asian Indians who lived for more than 10 years in the U.S. (OR 3.28; 95 % CI: 1.73–6.22) and had chronic illnesses (OR 1.39; 95 % CI: 1.17–1.64) (p \u3c 0.05) were more likely to perceive discrimination when seeking health care. However, older Asian Indians, over the age of 55 years, were less likely to perceive discrimination than those aged 18–34 years Indian American. Conclusion: Results offers initial support for the hypothesis that Asian Indians experience interpersonal discrimination when seeking health care services and that these experiences may be related to poor self-rated health status