Ligand conjugate SAR and enhanced delivery in NHP.

N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.

Glycosyl iodides. History and recent advances.

The use of glycosyl iodides as an effective method for the preparation of glycosides has had a recent resurgence in carbohydrate chemistry, despite its early roots in which these species were believed to be of limited use. Renewed interest in these species as glycosylating agents has been spurred by their demonstrated utility in the stereoselective preparation of O-glycosides, and other glycosylic compounds. This review provides a brief historical account followed by an examination of the use of glycosyl iodides in the synthesis of oligosaccharides and other glycomimetics, including C-glycosylic compounds, glycosyl azides and N-glycosides.

Waist-to-hip ratio and adipose tissue distribution: contribution of subcutaneous adiposity.

The waist-to-hip ratio (WHR) reflects the relative distribution of adipose tissue in the human body. However, whether this is due to the musculoskeletal structures of the waist and hip or the overlying subcutaneous adipose tissue has been disputed. We measured waist and hip girths in 11 male and 11 female cadavers, aged 55-94 years, before and after complete removal of skin and subcutaneous adipose tissue. Girths measured following removal of subcutaneous adipose tissue were termed "waist gx" and "hip gx", and their ratio "WHRx". Masses of regional adipose tissue segments were obtained by complete dissection, and the adipose mass ratios "trunk/arm-plus-leg", "trunk/leg", "internal/arm-plus-leg", and "internal/leg" were derived. As assessed by analysis of variance, WHR accounted for significant (P < 0.05) portions of the variance in all adipose mass ratios; adjustment for internal adipose mass increased the significance of all these relationships (P < 0.005). The ratio WHRx was not related to any ratio of regional adipose masses. Waist girth was related to trunk (P < 0.001) and internal (P < 0.05) adipose masses, and hip girth was related to arm-plus-leg adipose mass (P < 0.0001) and leg adipose mass (P < 0.0001), but waist gx and hip gx were not related to dependent variables. The results indicate that the ability of WHR and waist and hip girths to reflect the regional distribution of adipose tissue in the body is dependent upon the subcutaneous adipose tissue mass of the waist hip area, not its musculoskeletal constituency.

The relationship of the heart rate deflection point to the ventilatory threshold in trained cyclists.

The purpose of this study was to assess the relationship of the heart rate deflection point (HRDP) to the ventilatory threshold (VT) in trained cyclists. Twenty-one endurance-trained cyclists (mean +/- SD: Vo(2)max = 67.6 +/- 4.7 ml x kg x min(-1)) completed a maximal cycle ergometer test of volitional fatigue using a ramped protocol. Ventilatory variables (Ve, Vo(2), Vco(2)) and power were measured online with averages reported every 20 seconds. Heart rate (HR) was recorded every 20 seconds using a Polar monitor. VT was calculated using the excess CO(2) elimination curve. The first derivative of a logistic growth curve fit to the HR-power data produced the HRDP. No significant differences (p > 0.01) existed between HR values at HRDP (171.7 +/- 9.6 b x min(-1)) and VT (169.8 +/- 9.9 b x min(-1)) or between Vo(2) values at HRDP (53.6 +/- 4.2 ml x kg x min(-1)) and VT (52.2 +/- 4.8 ml x kg x min(-1)). But power values at HRDP (318.7 +/- 30.7 W) were significantly different (p < 0.01) from those at VT (334.8 +/- 36.7 W). There were significant relationships between HRDP and VT for the physiological variables of HR (r = 0.92, p < 0.001), Vo(2) (r = 0.72, p < 0.001), and power (r = 0.77, p < 0.001). These findings indicate that HR and Vo(2) at HRDP are not significantly different from the values at VT in trained cyclists. HR values derived from HRDP may be used to set parameters for training intensity. Variability in the speed/power-HRDP relationship across detrained/trained states may be used to evaluate training programs.

Human body composition: A review of adult dissection data.

Although body composition analysis is popular, dissection data are sparse and sometimes difficult to access. Published data that include the weights of skin, adipose tissue, muscle, and bone, along with body weight, are reviewed. The 31 men and 20 women include 34 cadavers from three separate dissection studies in Brussels, 12 from 19th century reports, and 5 from the United States. The age range was 16-94y. Men differed from women in that they had less adipose tissue and more muscle in both absolute and relative terms. The body mass index (BMI) did not differ between the sexes, because lower weights of muscle and bone compensated for the greater adiposity in women. The relationship between the BMI and relative adiposity was significant, but the BMI explained only about one-third of the variance in adiposity, indicating that in this sample it is a poor predictor of fatness. The composition of the fat-free weight (FFW) and adipose tissue free weight (ATFW), though less variable than body weight, showed enough variability that the assumption of constancy of the fat-free body required for densitometry and other indirect methods of fat estimation, could not be supported. In the few dissections that did fat extraction, essential on non-adipose fat, varied from 4-14% of the FFW, thus undermining the concept of lean body weight. More dissection data are needed, especially in children and adolescents, and especially in conjunction with in vivo body composition methods to help in their validation. Am. J. Hum. Biol. 11:167-174, 1999. Copyright 1999 Wiley-Liss, Inc.