ABSTRACT
Electricity generation from wind energy has proliferated throughout North America and will continue to grow. Given Canada's expected increase in wind energy capacity, consideration of the potential adverse impacts to bird and bat populations is prudent given their sensitivity to these projects. The province of Ontario, Canada is currently the leading jurisdiction for wind energy development, and for provincial guidance on pre- and post-construction monitoring. With uniform monitoring guidance in Ontario, wind energy proponents, and third-party consultants, have developed post-construction monitoring protocols that meet provincial guidance, while also providing standardized reporting. In Atlantic Canada, post-construction guidelines vary between provinces, depending mostly on guidance from the Environment Canada Canadian Wildlife Service and relevant provincial agencies. To ensure quality post-construction monitoring results in Atlantic Canada and other provinces, it is imperative that all Canadian provinces adopt similar approaches to those employed in Ontario. This paper reviews major causes of bird and bat mortalities; reviews Canadian federal and Ontario provincial bird and bat monitoring guidelines to elucidate gaps between environmental assessment (EA) theory and application; summarizes post-construction monitoring protocols from eight bird and bat post-construction monitoring programs used in Ontario; and, proposes recommendations to support future wind development opportunities across Canada and specifically in Atlantic Canada.
Subject(s)
Chiroptera , Energy-Generating Resources , Wind , Animals , Birds , Canada , Environmental Policy , North America , OntarioABSTRACT
A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, CCR1/antagonists & inhibitors , Calcium/metabolism , Cell Line , Cell Movement/drug effects , Chemokine CCL3/metabolism , Chemotaxis/drug effects , Humans , Molecular Structure , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , Piperidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.
Subject(s)
Arthritis, Experimental/drug therapy , Benzyl Compounds/pharmacology , Cyclobutanes/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Administration, Oral , Animals , Arthritis, Experimental/chemically induced , Benzyl Compounds/chemistry , Binding Sites , Collagen , Cyclobutanes/chemistry , Disease Models, Animal , Drug Design , Male , Mice , Mice, Inbred BALB C , Receptors, CCR1 , Structure-Activity RelationshipABSTRACT
Transcription of snRNA genes by either RNA polymerase II (U1 to U5) or RNA polymerase III (U6) is dependent upon a proximal sequence element (PSE) located approximately 40 to 60 bp upstream of the transcription start site. In Drosophila melanogaster, RNA polymerase specificity is determined by as few as three nucleotide differences within the otherwise well-conserved 21-bp PSE. Previous photo-cross-linking studies revealed that the D. melanogaster PSE-binding protein, DmPBP, contains three subunits (DmPBP45, DmPBP49, and DmPBP95) that associate with the DNA to form complexes that are conformationally distinct depending upon whether the protein is bound to a U1 or a U6 PSE. We have identified and cloned the genes that code for these subunits of DmPBP by virtue of their similarity to three of the five subunits of SNAP(c), the human PBP. When expressed in S2 cells, each of the three cloned gene products is incorporated into a protein complex that functionally binds to a PSE. We also find that the conformational difference referred to above is particularly pronounced for DmPBP45, herein identified as the ortholog of human SNAP43. DmPBP45 cross-linked strongly to DNA for two turns of the DNA helix downstream of the U1 PSE, but it cross-linked strongly for only a half turn of the helix downstream of a U6 PSE. These substantial differences in the cross-linking pattern are consistent with those of a model in which conformational differences in DmPBP-DNA complexes lead to selective RNA polymerase recruitment to U1 and U6 promoters.