Estimation of the parameters of a type I geometric distribution from truncated observations on conception delays

In connection with the estimation of the average fecundability of a group of women, it has been assumed in the past that the waiting time for a conception follows a type I geometric distribution, and its two parameters have been estimated by the method of moments and the method of maximum likelihood. In a follow-up study, starting with a group of women, there is always the possibility that some women will remain nonpregnant in the limited period of time they are observed, and the problem arises as to how to estimate the same parameters if the follow-up experiment is terminated after a fixed period of time. The present paper deals with this truncation problem, and provides three different methods for estimating the parameters, which are applied to data from the Menstrual and Reproductive History Study at the University of Minnesota. In the last section, an extended model is presented which incorporates the possibility of dropout cases.     

Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer’s disease

The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.     

Changes in forest understory associated with Juniperus encroachment in Oklahoma,USA

Question: Does understory vegetation cover and richness decline along a gradient of increasing Juniperus virginiana midstory canopy cover and is that decline best correlated with litter accumulation? Location: Cross Timbers Forest in Payne County, OK, USA. Methods: We measured vegetation in forest gaps as well as forest areas without J. virginiana, at the inner and outer edge of J. virginiana canopies and near J. virginiana trunks (200 plots) and compared vegetation differences among location to light, litter, soil and microclimate variables. Results: Species richness (11 spp m^?2 to 6 spp m^?2) and summer vegetation cover (53.3% to 12.7%) declined with proximity to trunks. Regression indicated that richness declines (R²=0.08) and cover (R²=0.18) were best correlated with J. virginiana litter accumulation. Partial canonical correspondence analysis (pCCA) revealed two strong canonical axes, one related to litter/light and another to cover of Quercus spp. versus J. virginiana. Tree seedlings and woody vines dominated near J. virginiana. Forbs, graminoids and Quercus spp. seedlings were more common in areas without J. virginiana. Conclusions: Increasing J. virginiana and consequent litter additions alter understory biomass and composition and, through inhibiting Quercus spp. recruitment, may lead to changes in overstory composition. Decreases in herbaceous litter, which historically contributed to fuel accumulation, may have positive feedback effects on midstory encroachment by reducing the potential for prescribed burning.     

5-Heteroatom-substituted pyrazoles as canine COX-2 inhibitors: Part 2. Structure-activity relationship studies of 5-alkylethers and 5-thioethers

Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.     

5-heteroatom substituted pyrazoles as canine COX-2 inhibitors. Part 1: Structure-activity relationship studies of 5-alkylamino pyrazoles and discovery of a potent, selective, and orally active analog

Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.     

A New Target for Amyloid Beta Toxicity Validated by Standard and High-Throughput Electrophysiology

Background

Soluble oligomers of amyloid beta (Aβ) are considered to be one of the major contributing factors to the development of Alzheimer''s disease. Most therapeutic development studies have focused on toxicity directly at the synapse.

Methodology/Principal Findings

Patch clamp studies detailed here have demonstrated that soluble Aβ can also cause functional toxicity, namely it inhibits spontaneous firing of hippocampal neurons without significant cell death at low concentrations. This toxicity will eventually lead to the loss of the synapse as well, but may precede this loss by a considerable amount of time. In a key technological advance we have reproduced these results utilizing a fast and simple method based on extracellular electrophysiological recording of the temporal electrical activity of cultured hippocampal neurons using multielectrode arrays (MEAs) at low concentrations of Aβ (1–42). We have also shown that this functional deficit can be reversed through use of curcumin, an inhibitor of Aβ oligomerization, using both analysis methods.

Conclusions/Significance

The MEA recording method utilized here is non-invasive, thus long term chronic measurements are possible and it does not require precise positioning of electrodes, thus it is ideal for functional screens. Even more significantly, we believe we have now identified a new target for drug development for AD based on functional toxicity of hippocampal neurons that could treat neurodegenerative diseases prior to the development of mild cognitive impairment.