Inhibition of inflammatory changes in human myometrial cells by cell penetrating peptide and small molecule inhibitors of NFκB

Complications arising from Preterm Birth are the leading causes of neonatal death globally. Current therapeutic strategies to prevent Preterm Birth are yet to demonstrate success in terms of reducing this neonatal disease burden. Upregulation of intracellular inflammatory pathways in uterine cells, including those involving nuclear factor kappa-B (NFκB), have been causally linked to both human term and preterm labor, but the barrier presented by the cell membrane presents an obstacle to interventions aimed at dampening these inflammatory responses. Cell penetrating peptides (CPPs) are novel vectors that can traverse cell membranes without the need for recognition by cell surface receptors and offer the ability to deliver therapeutic cargo internal to cell membranes. Using a human uterine cell culture inflammatory model, this study aimed to test the effectiveness of CPP-cargo delivery to inhibit inflammatory responses, comparing this effect with a small molecule inhibitor (Sc514) that has a similar intracellular target of action within the NFκB pathway (the IKK complex). The CPP Penetratin, conjugated to rhodamine, was able to enter uterine cells within a 60 min timeframe as assessed by live confocal microscopy, this phenomena was not observed with the use of a rhodamine-conjugated inert control peptide (GC(GS)4). Penetratin CPP conjugated to an IKK-inhibitory peptide (Pen-NBD) demonstrated ability to inhibit both the IL1β-induced expression of the inflammatory protein COX2 and dampen the expression of a bespoke array of inflammatory genes. Truncation of the CPP vector rendered the CPP-cargo conjugate much less effective, demonstrating the importance of careful vector selection. The small molecule inhibitor Sc514 also demonstrated ability to inhibit COX2 protein responses and a broad down-regulatory effect on uterine cell inflammatory gene expression. These results support the further exploration of either CPP-based or small molecular treatment strategies to dampen gestational cell inflammatory responses in the context of preterm birth. The work underlines both the importance of careful selection of CPP vector-cargo combinations and basic testing over a broad time and concentration range to ensure effective responses. Further work should demonstrate the effectiveness of CPP-linked cargos to dampen alternative pathways of inflammation linked to Preterm Birth such as MAP Kinase or AP

Ethnopolitics Across Central and Eastern Europe in a State of Flux: Time for Updating and Upgrading?

This chapter illustrates why and how the existing theoretical models in the study of ethnopolitics need to be updated in light of the latest developments and the increasing impact of new catalysts. These are, namely, anti-immigration and the rise of the populist and radical right across Central and Eastern Europe. This chapter hints that the more systematic cooperation between academic experts in nationalism and academic experts in the populist and radical right will enable: (a) the former to assess more accurately the degree to which new variables such as Euroscepticism and anti-immigrant trends can reshape ethnopolitics, both as a living reality and a field of study, across Central and Eastern Europe; (b) the latter to formulate new interpretative models about how (right-wing) populist and Eurosceptic actors embed their agendas inside the pre-existing political cultures of nationalism and particularistic identity and memory politics. This chapter introduces and outlines the ethnosymbolic approach as well as the triadic and quadratic configurations of ethnopolitics. Then, it proceeds into a more empirical assessment of the applicability of these theoretical approaches in a series of case studies during the 1990s, as well as the more recent emergence of new catalysts and the ensuing necessity to update and upgrade the existing theoretical models

Measurement of the 18Ne(a,p_0)21Na reaction cross section in the burning energy region for X-ray bursts

The 18Ne(a,p)21Na reaction provides one of the main HCNO-breakout routes into the rp-process in X-ray bursts. The 18Ne(a,p_0)21Na reaction cross section has been determined for the first time in the Gamow energy region for peak temperatures T=2GK by measuring its time-reversal reaction 21Na(p,a)18Ne in inverse kinematics. The astrophysical rate for ground-state to ground-state transitions was found to be a factor of 2 lower than Hauser-Feshbach theoretical predictions. Our reduced rate will affect the physical conditions under which breakout from the HCNO cycles occurs via the 18Ne(a,p)21Na reaction.Comment: 5 pages, 3 figures, accepted for publication on Physical Review Letter

More and More Restrictive-But Not Always Populist: Explaining Variation in the British Conservative Party's Stance on Immigration and Asylum

This is the Author's Accepted Manuscript of an article published in the Journal of Contemporary European Studies Vol. 21, Iss. 1, copyright Taylor & Francis 2013, available online at: http://www.tandfonline.com/10.1080/14782804.2013.766474Centre-right parties are commonly inclined towards appeals and policies on immigration that are both restrictive in nature and populist in tone-in part because this is what they believe in, in part because it affords them an electoral advantage over their rivals on the centre-left. One would expect, however, that the extent to which they focus on immigration and asylum will vary according to public opinion, according to who leads them, and according to whether they are in government or in opposition. This would appear to be the case for the British Conservative Party, but the relationship is not an entirely consistent one. Moreover, while the Party has, for half a century, pursued ever more restrictive policies, the extent to which it has couched its approach in populist rhetoric varies considerably over time-and not always in line with the severity of its stance on immigration. The reason for this lies partly in the social and economic liberalism of some of its leaders (and in their related concern to act 'responsibly' on race and immigration) but also in their anxiety not to alienate key sections of the middle classes who must be persuaded to support the Party if it is to win elections. These considerations are likely to weigh heavily with other centre-right parties, too. © 2013 Copyright Taylor and Francis Group, LLC

Hematopoietic stem cell gene therapy for brain metastases using myeloid cell-specific gene promoters

Background: Brain metastases (BrM) develop in 20-40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain due to the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems. Methods: Green fluorescent protein (GFP)-transduced murine and non-transduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene expression analysis and subsequent validation of a series of promoter-GFP-reporter constructs in mice (n = 5). One of the promoters was used to deliver TNF-related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL versus control group). Results: HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (37.6% [SD = 7.2%] of all infiltrating cells for murine HSC progeny; 27.9% [SD = 4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3-53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (8.8%, SD = 7.8%). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (19.0 [SD = 3.4] versus 15.0 [SD = 2.0] days for TRAIL versus control group; two-sided p = 0.006), demonstrating therapeutic and translational potential of our approach. Conclusions: Our study establishes HSC gene therapy using a myeloid cell-specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions

Coupling of ventricular action potential duration and local strain patterns during reverse remodeling in responders and non-responders to cardiac resynchronization therapy

BACKGROUND: The high risk of ventricular arrhythmias in heart failure patients remains despite the benefit of cardiac resynchronization therapy (CRT). An electromechanical interaction between regional myocardial strain patterns and the electrophysiological substrate is thought to be important. OBJECTIVE: We investigated the in-vivo relation between left ventricular (LV) activation recovery interval (ARI), as a surrogate measure of activation potential duration (APD), and local myocardial strain patterns in responders and non-responders to CRT. METHODS: ARI were recorded from the left ventricular epicardium in 20 CRT patients 6 weeks and 6 months post implant. Two-dimensional speckle tracking echocardiography was performed at the same time to assess myocardial strains. Patients with ≥15% reduction in end-systolic volume at 6-months were classified as responders. RESULTS: ARI reduced in responders, 263±46ms vs. 246±47ms, p145ms and QRS shortening with biventricular pacing was associated with ARI shortening during CRT. CONCLUSIONS: Changes in ventricular wall mechanics predict local APD lengthening or shortening during CRT. Non-responders have a worsening of myocardial strain and local APD. Baseline QRS >145ms and QRS shortening on biventricular pacing identified patients who exhibited improvement in APD