Semi-Quantitative Models for Identifying Potent and Selective Transthyretin Amyloidogenesis Inhibitors

Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration

Which comforting messages really work best? A different perspective on Lemieux and Tighe’s “receiver perspective”

Abstract OnlyThis article responds critically to a recent article by Lemieux and Tighe (Communication Research Reports, 21, 144–153, 2004) in which the authors conclude that recipients of comforting efforts prefer messages that exhibit a moderate rather than high level of person centeredness. It is argued that an erroneous assumption made by Lemieux and Tighe about the status of “receiver perspective” research on the comforting process led to faulty interpretations of the data and unwarranted conclusions about recipient preferences regarding comforting messages. Alternative interpretations of Lemieux and Tighe's data are presented; these are guided by the extensive previous research that has assessed evaluations and outcomes of comforting messages

Ethnicity and Emotional Support in Same-Sex Friendship: A Comparison of Asian-American, African-Americans, and Euro-Americans

Emotional support is a central feature around which white, middle-class adults organize their same-sex friendships. The purpose of this study was to examine whether emotional support is accorded the same significance in the friendships of Asian- and African-Americans. Participants included 199 students (60 Euro-American men and women, 80 Asian-American men and women, and 59 African-American men and women) attending either a state or private university in California

Which Comforting Messages Really Work Best? A Different Perspective on Lemieux and Tighe\u27s Reciever Perspective

This article responds critically to a recent article by Lemieux and Tighe (Communication Research Reports, 21 , 144–153, 2004 ) in which the authors conclude that recipients of comforting efforts prefer messages that exhibit a moderate rather than high level of person centeredness. It is argued that an erroneous assumption made by Lemieux and Tighe about the status of “receiver perspective” research on the comforting process led to faulty interpretations of the data and unwarranted conclusions about recipient preferences regarding comforting messages. Alternative interpretations of Lemieux and Tighe\u27s data are presented; these are guided by the extensive previous research that has assessed evaluations and outcomes of comforting messages