Phytoestrogens

Collectively, plants contain several different families of natural products among which are compounds with weak estrogenic or antiestrogenic activity toward mammals. These compounds, termed phytoestrogens, include certain isoflavonoids, flavonoids, stilbenes, and lignans. The best-studied dietary phytoestrogens are the soy isoflavones and the flaxseed lignans. Their perceived health beneficial properties extend beyond hormone-dependent breast and prostate cancers and osteoporosis to include cognitive function, cardiovascular disease, immunity and inflammation, and reproduction and fertility. In the future, metabolic engineering of plants could generate novel and exquisitely controlled dietary sources with which to better assess the potential health beneficial effects of phytoestrogens

A double-bounded risk-risk trade-off analysis of heatwave-related mortality risk: Evidence from India

As climate variability is increasing, extreme events such as temperature fluctuations are expected to become more frequent. Low- and middle-income countries (LMICs) are especially vulnerable to heat-related variability and its ensuing impacts on mortality. Therefore, there is an urgent need to understand how citizens in LMICs trade-off climate-related mortality risks with other risks such as traffic accidents, and what values they place on reducing such risks. As populations in LMICs are income-constrained, we adopt a non-monetary, Risk-Risk Trade-Off (RRTO) valuation method instead of the standard willingness-to-pay stated preference-based approach. We estimate the resulting risk premium for heatwave-related mortality risks through an adapted double-bounded, dichotomous choice approach to establish whether, on average, people value avoiding these risks more compared to reducing traffic risks. Using a sample of over 2,300 individuals from across 7 states in India, a country with one of the highest heat-related mortality globally, we estimate the heatwave risk mortality premium to be between 2.2 – 2.9, indicating that on average, individuals weigh reducing heatwave-related mortality risks more than two times that of reducing traffic accident mortality risks. Based on a standard benefit transfer methodology for LMICs, this premium translates to a Value of Statistical Life (VSL) of USD 0.37 – 2.61 million for India

The unsialylated subpopulation of recombinant activated factor VII binds to the asialo-glycoprotein receptor (ASGPR) on primary rat hepatocytes

SummaryRecombinant activated factor VII (rFVIIa; NovoSeven®) is a heterogeneously glycosylated serine protease used for treatment of haemophiliacs with inhibitors. The drug substance contains a subpopulation consisting of ~20% of rFVIIa molecules which are unsialylated and consists of carbohydrate moieties with terminally exposed galactose and N-acetyl-D-galactosamine (GalNAc). Recently, data from an in situ per-fused liver model showed that a subpopulation of rFVIIa, appearing to be unsialylated rFVIIa, was cleared by the liver, thus suggesting a carbohydrate-moiety mediated mechanism. The parenchymal cells of the liver, hepatocytes, are known to abundantly express functional carbohydrate-specific receptors and in this study we therefore used primary rat hepatocytes to study binding and intracellular fate of rFVIIa at a cellular level. Immunofluorescence microscopy showed that rFVIIa was distributed into distinct intracellular vesicles and electron microscopic autoradiography revealed that radioiodinated rFVIIa distributed only into cytoplasmic free vesicles resembling endosomes and lysosomes. These findings suggest that endocytosis of rFVIIa in hepatocytes could be partly mediated via initial membrane binding to a receptor. Quantitative binding studies showed that the presence of excess unlabelled asialo-orosomucoid, asialo-rFVIIa and GalNAc significantly decreased binding of 125I-rFVIIa. An antibody which specifically binds to the carbohydrate recognition domain of the asialoglycoprotein receptor (ASGPR) significantly decreased binding of asialo-rFVIIa by ~36% and rFVIIa by ~19%. Together our data showed that a receptor-mediated mechanism involving the ASGPR is able to bind a subpopulation of unsialylated rFVIIa, while a hepatic mechanism for binding and clearing sialylated rFVIIa is still unknown.</jats:p