Silencing disease genes in the laboratory and the clinic

Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology

On the dependence of X-ray burst rate on accretion and spin rate

Nuclear burning and its dependence on the mass accretion rate are fundamental ingredients for describing the complicated observational phenomenology of neutron stars in binary systems. Motivated by high quality burst rate data emerging from large statistical studies, we report general calculations relating bursting rate to mass accretion rate and neutron star rotation frequency. In this first work we neglect general relativistic effects and accretion topology, though we discuss where their inclusion should play a role. The relations we derive are suitable for different burning regimes and provide a direct link between parameters predicted by theory and what is to be expected in observations. We illustrate this for analytical relations of different unstable burning regimes that operate on the surface of an accreting neutron star. We also use the observed behaviour of burst rate to suggest new constraints on burning parameters. We are able to provide an explanation for the long standing problem of the observed decrease of burst rate with increasing mass accretion that follows naturally from these calculations: when accretion rate crosses a certain threshold, ignition moves away from its initially preferential site and this can cause a net reduction of the burst rate due to the effects of local conditions that set local differences in both burst rate and stabilization criteria. We show under which conditions this can happen even if locally the burst rate keeps increasing with accretion.Comment: Accepted for publication on Ap

Evaluation of buffer-radius modelling approaches used in forest conservation and planning

Spatial modelling approaches are increasingly being used to direct forest management and conservation planning at the landscape scale. A popular approach is the use of buffer-radius methods, which create buffers around distinct forest habitat patches to assess habitat connectivity within anthropogenic landscapes. However, the effectiveness and sensitivity of such methods have rarely been evaluated. In this study, Euclidean and least-cost buffer-radius approaches were used to predict functional ecological networks within the wooded landscape of the Isle of Wight (UK). To parameterize the models, a combination of empirical evidence and expert knowledge was used relating to the dispersal ability of a model species, the wood cricket (Nemobius sylvestris Bosc.). Three scenarios were developed to assess the influence of increasing the amount of spatial and species-specific input data on the model outcomes. This revealed that the level of habitat fragmentation for the model species is likely to be underestimated when few empirical data are available. Furthermore, the least-cost buffer approach outperformed simple Euclidean buffer in predicting presence and absence for the model species. Sensitivity analyses on model performance revealed high sensitivity of the models to variation in buffer distance (i.e. maximum dispersal distance) and permeability of common landscape features such as roads, watercourses, grassland and semi-natural habitat. This indicates that when data are lacking with which to parameterize buffer-radius models, the model outcomes need to be interpreted with caution. This study also showed that if sufficient empirical data are available, least-cost buffer approaches have the potential to be a valuable tool to assist forest managers in making informed decisions. However, least-cost approaches should always be used as an indicative rather than prescriptive management tool to support forest landscape conservation and planning

Developing digital interventions: a methodological guide.

Digital interventions are becoming an increasingly popular method of delivering healthcare as they enable and promote patient self-management. This paper provides a methodological guide to the processes involved in developing effective digital interventions, detailing how to plan and develop such interventions to avoid common pitfalls. It demonstrates the need for mixed qualitative and quantitative methods in order to develop digital interventions which are effective, feasible, and acceptable to users and stakeholders

The Reflective Principal: Surviving the Journey

I recently retired from the public school system after 34 years of service in the rural West Virginia county where I was born, reared, and educated through grade 12. For 22 of those years I was an elementary principal. Those years were an exciting and challenging time for me, and I hope that sharing some of my experiences will be entertaining and useful to young principals who are just beginning their journey. It is impossible to prescribe all of the steps that will be a part of that journey, but I can’t think of any better source of guidance than those who have been down the road, met the challenges, fought the battles, and still believe it was a worthwhile and rewarding trip

Phase transitions in Ising model on a Euclidean network

A one dimensional network on which there are long range bonds at lattice distances $l>1$ with the probability $P(l) \propto l^{-\delta}$ has been taken under consideration. We investigate the critical behavior of the Ising model on such a network where spins interact with these extra neighbours apart from their nearest neighbours for $0 \leq \delta < 2$. It is observed that there is a finite temperature phase transition in the entire range. For $0 \leq \delta < 1$, finite size scaling behaviour of various quantities are consistent with mean field exponents while for $1\leq \delta\leq 2$, the exponents depend on $\delta$. The results are discussed in the context of earlier observations on the topology of the underlying network.Comment: 7 pages, revtex4, 7 figures; to appear in Physical Review E, minor changes mad

Order-disorder phase transition in a cliquey social network

We investigate the network model of community by Watts, Dodds and Newman (D. J. Watts et al., Science 296 (2002) 1302) as a hierarchy of groups, each of 5 individuals. A homophily parameter $\alpha$ controls the probability proportional to $\exp(-\alpha x)$ of selection of neighbours against distance $x$. The network nodes are endowed with spin-like variables $s_i = \pm 1$, with Ising interaction $J>0$. The Glauber dynamics is used to investigate the order-disorder transition. The transition temperature $T_c$ is close to 3.8 for $\alpha < 0.0$ and it falls down to zero above this value. The result provides a mathematical illustration of the social ability to a collective action {\it via} weak ties, as discussed by Granovetter in 1973.Comment: 10 pages, 7 figure