IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2−/−). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2−/− podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2−/− podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

Precision dating of the Palaeolithic: A new radiocarbon chronology for the Abri Pataud (France), a key Aurignacian sequence

This paper presents a new series of AMS dates on ultrafiltered bone gelatin extracted from identified cutmarked or humanly-modified bones and teeth from the site of Abri Pataud, in the French Dordogne. The sequence of 32 new determinations provides a coherent and reliable chronology from the site's early Upper Palaeolithic levels 5-14, excavated by Hallam Movius. The results show that there were some problems with the previous series of dates, with many underestimating the real age. The new results, when calibrated and modelled using a Bayesian statistical method, allow detailed understanding of the pace of cultural changes within the Aurignacian I and II levels of the site, something not achievable before. In the future, the sequence of dates will allow wider comparison to similarly dated contexts elsewhere in Europe. High precision dating is only possible by using large suites of AMS dates from humanly-modified material within well understood archaeological sequences modelled using a Bayesian statistical method. © 2011.

An effective key generation system using improved channel reciprocity

In physical layer security systems there is a clear need to exploit the radio link characteristics to automatically generate an encryption key between two end points. The success of the key generation depends on the channel reciprocity, which is impacted by the non-simultaneous measurements and the white nature of the noise. In this paper, an OFDM subcarriers' channel responses based key generation system with enhanced channel reciprocity is proposed. By theoretically modelling the OFDM subcarriers' channel responses, the channel reciprocity is modelled and analyzed. A low pass filter is accordingly designed to improve the channel reciprocity by suppressing the noise. This feature is essential in low SNR environments in order to reduce the risk of the failure of the information reconciliation phase during key generation. The simulation results show that the low pass filter improves the channel reciprocity, decreases the key disagreement, and effectively increases the success of the key generation.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.

RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.

CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230-42. ©2015 AACR.

The EU Clinical Trials Regulation: Key Priorities, Purposes and Aims and the Implications for Public Health

The replacement of the European Union (EU) Clinical Trials Directive by the new Clinical Trials Regulation (CTR), which entered into force on 16 June 2014 but will not apply before 28 May 2016, provides an opportunity to review the legal and political context within which this important aspect of research law and policy sits and to reflect on the implications for public health. My aim in this article is to relate the context to the key purposes and aims of EU law and policy on clinical trials in order to explain and clarify its orientation. On that basis, I argue that the CTR and the changes it introduces to the law on clinical trials are part of the EU's continued focus on market optimisation. It is this focus that orients and directs the wider pharmaceutical development pipeline, but that undermines the achievement of key public health objectives.

Secure key generation from OFDM subcarriers' channel responses

The ability to exchange keys between users is vital in any wireless based security system. A key generation technique which exploits the randomness of the wireless channel is a promising alternative to existing key distribution techniques, e.g., public key cryptography. In this paper, a secure key generation scheme based on the subcarriers' channel responses in orthogonal frequency-division multiplexing (OFDM) systems is proposed. We first implement a time-variant multipath channel with its channel impulse response modelled as a wide sense stationary (WSS) uncorrelated scattering random process and demonstrate that each subcarrier's channel response is also a WSS random process. We then define the X% coherence time as the time required to produce an X% correlation coefficient in the autocorrelation function (ACF) of each channel tap, and find that when all the channel taps have the same Doppler power spectrum, all subcarriers' channel responses has the same ACF as the channel taps. The subcarrier's channel response is then sampled every X% coherence time and quantized into key bits. All the key sequences' randomness is tested using National Institute of Standards and Technology (NIST) statistical test suite and the results indicate that the commonly used sampling interval as 50% coherence time cannot guarantee the randomness of the key sequence.

Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a 'roadmap' of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organisations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime.