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

Continued strength at Tenth District banks

Commercial banks in Tenth District states continued to perform well in the first half of 1994. Profitability leveled off at a high level, asset quality improved, and loan growth accelerated. Based on these performance measures, banks in district states once again outperformed banks in the rest of the nation.Bank profits ; Federal Reserve District, 10th

State Fiscal Impact of the Succeed Scholarship Program 2016-2017

This report will address the fiscal impact of the SSP for the 2016-17 school year, the first year the program is available for students. As of February 2017 there were 22 students from 13 districts using the program to attend one of the 17 accredited private schools currently participating in the program. For 20 of the students we know which public school district he/she attended in 2015-16. All students must be attending a public school, relocating from out of state, or be members of an active duty military family in order to participate in the program. To estimate the fiscal effect of the program we compare the additional funding the local district would have received from the state if the SSP did not exist and compare it to the tuition cost covered thru the SSP. The difference is the net fiscal effect on the state

Squeezing the Public School Districts: The Fiscal Effect of Eliminating the Louisiana Scholarship Program on State Education Expenditures

Eliminating the Louisiana Scholarship Program (LSP) was proposed as a way to improve the financial situation of the Louisiana Department of Education budget in the current fiscal environment. A study released by the School Choice Demonstration Project (SCDP) found that the net fiscal impact on the Louisiana Department of Education budget would likely be an overall cost increase. In this study, we consider the effects that the removal or reduction of the program would have on individual districts. Districts would receive additional revenue from the state for affected students, but districts would also incur additional costs to educate these students. For each district, we compare the additional costs incurred to the additional funding received from the state. We conclude that the overall fiscal impact on districts will be negative; in other words, the overall additional variable costs incurred by the districts will be greater than the overall additional funding provided to the districts. In fact, we find that only 2 to 7 of the 69 school districts would benefit from the elimination of the program. For the affected districts, the average outcome would be a financial loss of about $1,500 per returning voucher student in 2016. In each scenario, we find that over 80% of student transfers would result in a financial loss for the local district. While we have framed this discussion in terms of the elimination of the LSP, the same analysis would be applicable to any situation that causes students to move from private schools to public schools in Louisiana, including the current funding cap which may force some current LSP students out of the program and has already generated a waitlist of over 400 students for next year

Consumer Attitudes toward Freshness Indicators on Perishable Food Products

Consumer/Household Economics, Food Consumption/Nutrition/Food Safety,

Functional characterization of synthetic leukotriene B and its stereochemical isomers.

Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups

Reply to "Comment on `Jamming at zero temperature and zero applied stress: The epitome of disorder' "

We answer the questions raised by Donev, Torquato, Stillinger, and Connelly in their "Comment on "Jamming at zero temperature and zero applied stress: The epitome of disorder.' " We emphasize that we follow a fundamentally different approach than they have done to reinterpret random close packing in terms of the "maximally random jammed" framework. We define the "maximally random jammed packing fraction" to be where the largest number of initial states, chosen completely randomly, have relaxed final states at the jamming threshold in the thermodynamic limit. Thus, we focus on an ensemble of states at the jamming threshold, while DTSC are interested in determining the amount of order and degree of jamming for a particular configuration. We also argue that soft-particle systems are as "clean" as those using hard spheres for studying jammed packings and point out the benefits of using soft potentials

Free Agents, Fire Sales, and Fungoes: An Econometric Examination of Team Success in Major League Baseball

This paper explores what good organizational strategies baseball teams use to put themselves into the group of those that win more often than they lose, and conversely, what poor strategies cause teams to fall into the group of those who lose more than they win