No Observed Adverse Effects: Developing Neurons, Organophosphate Insecticides, and the 1996 Food Quality Protection Act

Physicians are familiar with organophosphates (OPs) as a classic, though obscure, cause of cholinergic poisoning. Many opportunities for human exposure existsixty million pounds of OPs are applied as insecticides to sixty million acres of U.S. land each year, and, until recently, over one-fifth of Americans used these chemicals in their homes. Most physicians, however, still know little about the dangers that these pesticides pose to the developing nervous system. By the late 1980s, toxicologists increasingly recognized that toxicants such as lead and mercury, even at doses well-below the level required to cause symptomatic poisoning, could induce subtle, yet permanent, neurological deficits if the exposure occurred during critical periods of brain development. In the early 1990s, scientists and regulators began to realize that developmental neurotoxicity (DNT), as this phenomenon was called, could also result from OPs. In 1996 Congress passed the Food Quality Protection Act (FQPA), marking a major turning point in the regulation of hazardous chemicals. Prior to the FQPA, the Environmental Protection Agency (EPA) based its calculations of pesticide risk on adults and largely neglected the increased susceptibility of infants and children. The new law took a precautionary stance, protecting the vulnerable neural and physical development of the fetus and child with the inclusion of a 10-X safety factor, and shifting the burden of proof from health advocates to the pesticide manufacturers. The ensuing ten-year battle between health groups, pesticide manufacturers, and the EPA over the laws enforcement now provides an instructive lesson into the complex scientific, political, and economic world of environmental health, and serves as a relatively successful example of effective policy improving public health

C-SAW---contextual semantic alignment of ontologies: using negative semantic reinforcement

Understanding the meaning of each term in an ontology is essential for successfully integrating and aligning ontologies. Much ontology integration research to date is focused on syntactic, structural and semantic matching where the actual meaning of the concepts is disregarded. The C-SAW approach to ontology alignment is based on the Contextualizing the concepts by using a set of Semantic Alignment Words (C-SAW). The C-SAW approach is enhanced by Negative Semantic Reinforcement (NSR), where additional semantic meaning can be added to the set of Semantic Alignment Words, by considering words which are unrelated to the concept

Contextual Semantic Integration For Ontologies

Information integration in organisations has been hindered by differences in the software applications used and by the structure and semantic differences of the different data sources (de Bruijn, 2003). This is a common problem in the area of Enterprise Application Integration (EAI) where numerous ah-hoc programs have typically been created to perform the integration process. More recently ontologies have been introduced into this area as a possible solution to these problems, but most of the current approaches to ontology integration only address platform, syntactic and structural differences and do not address the semantic differences between the data sources (de Bruijn, 2003). For ontology semantic integration the underlying meaning of each element is needed. An approach based on introducing the contextualisation of the terms used in an ontology is proposed. This approach is called Contextual Semantic Integration for Ontologies

Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis

ddab314Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogeneous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.Peer reviewe