Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington's disease

Transcriptional dysfunction is a prominent hallmark of Huntington's disease (HD). Several transcription factors have been implicated in the aetiology of HD progression and one of the most prominent is repressor element 1 (RE1) silencing transcription factor (REST). REST is a global repressor of neuronal gene expression and in the presence of mutant Huntingtin increased nuclear REST levels lead to elevated RE1 occupancy and a concomitant increase in target gene repression, including brain-derived neurotrophic factor. It is of great interest to devise strategies to reverse transcriptional dysregulation caused by increased nuclear REST and determine the consequences in HD. Thus far, such strategies have involved RNAi or mutant REST constructs. Decoys are double-stranded oligodeoxynucleotides corresponding to the DNA-binding element of a transcription factor and act to sequester it, thereby abrogating its transcriptional activity. Here, we report the use of a novel decoy strategy to rescue REST target gene expression in a cellular model of HD. We show that delivery of the decoy in cells expressing mutant Huntingtin leads to its specific interaction with REST, a reduction in REST occupancy of RE1s and rescue of target gene expression, including Bdnf. These data point to an alternative strategy for rebalancing the transcriptional dysregulation in HD.

Parameterising ecological validity and integrating individual differences within second-person neuroscience

This commentary situates the second person account within a broader framework of ecological validity for experimental paradigms in social cognitive neuroscience. It then considers how individual differences at psychological and genetic levels can be integrated within the proposed framework.

Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels

Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.2 T-type Ca2+ channels in HEK293 cells raised basal [Ca2+]i and increased proliferation as compared with non-transfected cells. Proliferation and [Ca2+]i levels were reduced to levels seen in non-transfected cells either by induction of HO-1 or exposure of cells to the HO-1 product, carbon monoxide (CO) (applied as the CO releasing molecule, CORM-3). In the aortic VSMC line A7r5, proliferation was also inhibited by induction of HO-1 or by exposure of cells to CO, and patch-clamp recordings indicated that CO inhibited T-type (as well as L-type) Ca2+ currents in these cells. Finally, in human saphenous vein smooth muscle cells, proliferation was reduced by T-type channel inhibition or by HO-1 induction or CO exposure. The effects of T-type channel blockade and HO-1 induction were non-additive. Collectively, these data indicate that HO-1 regulates proliferation via CO-mediated inhibition of T-type Ca2+ channels. This signalling pathway provides a novel means by which proliferation of VSMCs (and other cells) may be regulated therapeutically.

Whatever works: proportionality as a constitutional doctrine

In The Global Model of Constitutional Rights Kai Möller claims that the proportionality test is underlain by an expansive moral right to autonomy. This putative right protects everything that advances one’s self-conception. It may of course be limited when balanced against other considerations such as the rights of others. But it always creates a duty on the state to justify the limitation. Möller further contends that the practice of proportionality can best be understood as protecting the right to autonomy. This review article summarizes the main tenets of Möller’s theory and criticizes them on two counts. First, it disputes the existence of a general right to autonomy; such a right places an unacceptably heavy burden on others. Second, it argues that we do not need to invoke a right to autonomy to explain and justify the main features of the practice of proportionality. Like other constitutional doctrines, proportionality is defensible, if it is grounded in pragmatic –mainly epistemic and institutional- considerations about how to increase overall rights compliance. These considerations are independent of any substantive theory of rights.

A Summary of the NATO ASI on Polar Cap Boundary Phenomena

The polar cap boundary is a subject of central importance to current magnetosphere-ionosphere research and its applications in “space weather” activities. The problems are that it has a number of definitions, and that the most physically meaningful definition (namely the open-closed field line boundary) is very difficult to identify in observations. New understanding of the importance of the structure and dynamics of the boundary region made the time right for a meeting reviewing our knowledge in this area. The Advanced Study Institute (ASI) on Svalbard in June 1997 discussed the boundary on both the dayside and the nightside, mapping magnetically to the dayside magnetopause and to tail plasma sheet/lobe interface, respectively. We held a “brainstorming” session, in which different ideas which arose from the presented papers were discussed and developed, and a summary session, in which session convenors gave a personal view of progress that has been made and problems which still need solving. Both were designed as ways of promoting further discussion. This paper attempts to distil some of the themes that emerged from these discussions.

Regularization of descriptor systems

Implicit dynamic-algebraic equations, known in control theory as descriptor systems, arise naturally in many applications. Such systems may not be regular (often referred to as singular). In that case the equations may not have unique solutions for consistent initial conditions and arbitrary inputs and the system may not be controllable or observable. Many control systems can be regularized by proportional and/or derivative feedback.We present an overview of mathematical theory and numerical techniques for regularizing descriptor systems using feedback controls. The aim is to provide stable numerical techniques for analyzing and constructing regular control and state estimation systems and for ensuring that these systems are robust. State and output feedback designs for regularizing linear time-invariant systems are described, including methods for disturbance decoupling and mixed output problems. Extensions of these techniques to time-varying linear and nonlinear systems are discussed in the final section.

Yield and nitrogen accumulation and partitioning in winter wheat under elevated CO2: A 3-year free-air CO2 enrichment experiment

Fossil fuel combustion and deforestation have resulted in a rapid increase in atmospheric [CO2] since the 1950’s, and it will reach about 550 μmol mol−1 in 2050. Field experiments were conducted at the Free-air CO2 Enrichment facility in Beijing, China. Winter wheat was grown to maturity under elevated [CO2] (550 ± 17 μmol mol−1) and ambient [CO2] (415 ± 16 μmol mol−1), with high nitrogen (N) supply (HN, 170 kg N ha−1) and low nitrogen supply (LN, 100 kg N ha−1) for three growing seasons from 2007 to 2010. Elevated [CO2] increased wheat grain yield by 11.4% across the three years. [CO2]-induced yield enhancements were 10.8% and 11.9% under low N and high N supply, respectively. Nitrogen accumulation under elevated [CO2] was increased by 12.9% and 9.2% at the half-way anthesis and ripening stage across three years, respectively. Winter wheat had higher nitrogen demand under elevated [CO2] than ambient [CO2], and grain yield had a stronger correlation with plant N uptake after anthesis than before anthesis at high [CO2]. Our results suggest that regulating on the N application rate and time, is likely important for sustainable grain production under future CO2 climate.

Are Good or Bad Borrowers Discouraged From Applying for Loans?

This paper takes the concept of a discouraged borrower originally formulated by Kon and Storey [Kon, Y., Storey, D.J., 2003. A theory of discouraged borrowers. Small Business Economics 21, 37–49] and examines whether discouragement is an efficient self-rationing mechanism. Using US data it finds riskier borrowers have higher probabilities of discouragement, which increase with longer financial relationships, suggesting discouragement is an efficient self-rationing mechanism. It also finds low risk borrowers are less likely to be discouraged in concentrated markets than in competitive markets and that, in concentrated markets, high risk borrowers are more likely to be discouraged the longer their financial relationships. We conclude discouragement is more efficient in concentrated, than in competitive, markets.

A five-dimensional model of attributes: some precursors of executive coach selection

The purpose of this study was to specify a set of attributes, identified as important precursors to coach selection. Executive coaching has grown exponentially, but there have been few studies as to the efficacy of coaching, including the factors that influence a manager's choice of coach. This study sought to identify these factors. The 45-item, online survey produced 267 useable responses. Results of the principal component analysis suggested a five-factor solution, with women showing a statistically significant preference over men for coaches who have the Ability to Develop Critical Thinking and Action, the Ability to Forge the Coaching Partnership and Coach Experience and Qualifications. The impact of coachee age was not significant in selecting executive coaches. The findings show a statistically significant relationship between coach attributes and the intention to continue with coaching. The implications of these findings for the selection of coaches, and for the coaching profession are discussed.