RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

LOGISTICS SCHEDULING： ANALYSIS OFTWO-STAGE PROBLEMS

This paper studies the coordination effects between stages for scheduling problems where decision-making is a two-stage process. Two stages are considered as one system. The system can be a supply chain that links two stages, one stage representing a manufacturer; and the other, a distributor It also can represent a single manufacturer, while each stage represents a different department responsible for a part of operations. A problem that jointly considers both stages in order to achieve ideal overall system performance is defined as a system problem. In practice, at times, it might not be feasible for the two stages to make coordinated decisions due to (i) the lack of channels that allow decision makers at the two stages to cooperate, and/or (ii) the optimal solution to the system problem is too difficult (or costly) to achieve.Two practical approaches are applied to solve a variant of two-stage logistic scheduling problems. The Forward Approach is defined as a solution procedure by which the first sta     

A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

Cellular and Molecular Life Sciences - Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations...     

Evaluation and control of miRNA-like off-target repression for RNA interference

RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.     

Intrinsic forces alone are sufficient to cause closure of the neural tube in the chick

Summary An isolated neural plate or a postnodal piece of early chick embryos, when cultured under appropriate experimental conditions, can undergo morphogenetic movements and form tubular structures closely resembling neural tubes of early chick embryos.This work was supported by grants from the NIH (NS 23200 and NS 21730) and the Busch Fund of Rutgers University.     

Comparison of classifications using measures intermediate between metric dissimilarity and consensus similarity

Two fundamental approaches to the comparison of classifications (e g, partitions on the same finite set of objects) can be distinguished One approach is based upon measures of metric dissimilarity while the other is based upon measures of similarity, or consensus These approaches are not necessarily simple complements of each other Instead, each captures different, limited views of comparison of two classifications The properties of these measures are clarified by their relationships to Day's complexity models and to association measures of numerical taxonomy The two approaches to comparison are equated with the use of separation and minimum value sensitive measures, suggesting the potential application of an intermediate sensitive measure to the problem of comparison of classifications Such a measure is a linear combination of separation sensitive and minimum value sensitive components The application of these intermediate measures is contrasted with the two extremes The intermediate measure for the comparison of classifications is applied to a problem of character weighting arising in the analysis of Australian stream basinsWe thank Bill Day, Mike Austin, Peter Minchin and two anonymous referees for many helpful comments We also thank P Arabie for useful discussion of consensus methods and character weighting     

强度G对听者包围感的影响

在音乐厅中，空间印象被认为是由视在声源宽度（ASW）以及听者包围感（LEV）所描述的音质．许多研究者曾对此能影响观众厅空间印象的声学参量得出过一些结论．然而，LEV与声压级的关系尚未充分被认识．因此，文中对SPL和IACC等声学参量从频域和时域等方面加以研究，开在新的Sejong室内乐厅（476座）采用哚青作为声源进行主观评价，探讨听者的判断与受早、后期声能影响的客观参量之间的关系，并确定能产生听者包围感的最低声强（G）值．     

Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo

Cutting the axons of the cholinergic neurons that project to the hippocampal formation results in death of most of these cells. Previous studies have shown that administration of nerve growth factor before or at the same time as the lesion will prevent this cell death. Here we demonstrate that basic fibroblast growth factor (FGF) administered into the brain reduces the death of cholinergic neurons in the medial septum and diagonal band of Broca after transection of their axons, in both young adult and aged rats. Moreover, FGF can partially protect against death of cholinergic neurons even when administered two days after axonal transection. These results indicate a possible function for FGF in the normal support of basal forebrain cholinergic neurons, but its range of activity could be wider, for FGF also supports noncholinergic neurons in vitro, it is localized in many of the central nervous system neurons, and it is found in relatively high concentrations in the brain.     

The effects of acute and chronic morphine on regional distribution of cardiac output in brain

Both acute and chronic administration of morphine resulted in an increase in the percent cardiac output received by brain. However, various brain regions were affected differently by the drug treatments. The greatest increases in percent cardiac output received after chronic administration of morphine occurred in pons and cerebellum, while the greatest increases after acute administration occurred in cortex and midbrain. The changes found are in contrast with earlier studies which suggest that morphine has no effect on cerebral blood flow.     

Population coding of saccadic eye movements by neurons in the superior colliculus

The deeper layers of the superior colliculus are involved in the initiation and execution of saccadic (high velocity) eye movements. A large population of coarsely tuned collicular neurons is active before each saccade. The mechanisms by which the signals that precisely control the direction and amplitude of a saccade are extracted from the activity of the population are unknown. It has been assumed that the exact trajectory of a saccade is determined by the activity of the entire population and that information is not extracted from only the most active cells in the population at a subsequent stage of neural processing. The trajectory of a saccade could be based on vector summation of the movement tendencies provided by each member of the population of active neurons or be determined by a weighted average of the vector contributions of each neuron in the active population. Here we present the results of experiments in which a small subset of the active population was reversibly deactivated with lidocaine. These results are consistent with the predictions of the latter population-averaging hypothesis and support the general idea that the direction, amplitude and velocity of saccadic eye movements are based on the responses of the entire population of cells active before a saccadic eye movement.