Trajectory of primordial follicle depletion is accelerated in obese mice in response to 7,12-dimethylbenz[a]anthracene exposure†.

Both obesity and exposure to environmental genotoxicants, such as 7,12-dimethylbenz[a]anthracene, negatively impair female reproductive health. Hyperphagic lean KK.Cg-a/a (n = 8) and obese KK.

Biological sex differences in hepatic response to in utero dimethylbenz(a)anthracene exposure.

Fetal hepatic dimethylbenz(a)anthracene (DMBA) biotransformation is not defined, thus, this study investigated whether the fetal liver metabolizes DMBA and differs with biological sex. KK.Cg-a/a (lean; n = 20) or KK.

Altered histone abundance as a mode of ovotoxicity during 7,12-dimethylbenz[a]anthracene exposure with additive influence of obesity†.

Histones are slowly evolving chromatin components and chromatin remodeling can incorporate histone variants differing from canonical histones as an epigenetic modification. Several identified histone variants are involved with the environmental stress-induced DNA damage response (DDR). Mechanisms of DDR in transcriptionally inactive, prophase-arrested oocytes and epigenetic regulation are under-explored in ovarian toxicology.

Mutability of druggable kinases and pro-inflammatory cytokines by their proximity to telomeres and A+T content.

Mutations of protein kinases and cytokines are common and can cause cancer and other diseases. However, our understanding of the mutability in these genes remains rudimentary. Therefore, given previously known factors which are associated with high mutation rates, we analyzed how many genes encoding druggable kinases match (i) proximity to telomeres or (ii) high A+T content.

Obesity partially potentiates dimethylbenz[a]anthracene-exposed ovotoxicity by altering the DNA damage repair response in mice†.

Obesity adversely affects reproduction, impairing oocyte quality, fecundity, conception, and implantation. The ovotoxicant, dimethylbenz[a]anthracene, is biotransformed into a genotoxic metabolite to which the ovary responds by activating the ataxia telangiectasia mutated DNA repair pathway. Basal ovarian DNA damage coupled with a blunted response to genotoxicant exposure occurs in obese females, leading to the hypothesis that obesity potentiates ovotoxicity through ineffective DNA damage repair.

TRPV4 mRNA is elevated in the caudate nucleus with NPH but not in Alzheimer's disease.

Symptoms of normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD) are somewhat similar, and it is common to misdiagnose these two conditions. Although there are fluid markers detectable in humans with NPH and AD, determining which biomarker is optimal in representing genetic characteristics consistent throughout species is poorly understood. Here, we hypothesize that NPH can be differentiated from AD with mRNA biomarkers of unvaried proximity to telomeres.

Drug-Targeted Genomes: Mutability of Ion Channels and GPCRs.

Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) high adenine and thymine (A+T) content. We extracted genomic information using the genome data viewer and examined the mutability of 118 ion channel and 143 GPCR genes based on their association with factors (i) and (ii).

Use of Lean Methodologies in Outpatient Urology Clinic.

Introduction: Our objective was to apply lean methodologies to identify and improve processes in the urology clinic.

Methods: A total of 85 appointments in provider and procedure clinics were observed and analyzed using time studies, spaghetti diagrams and process mapping tools. The team determined wait times and rework as areas for quality improvement.

Evaluation of an 11.2% spinetoram topical spot-on solution for the control of experimental and natural flea (Ctenocephalides felis) infestations on cats in Europe.

Spinetoram is the newest member the spinosyn-class of natural products to be commercialized for flea control on cats in the United States under the tradename Cheristin for cats. This report describes results from two laboratory studies and a multi-center clinical field trial designed to confirm the efficacy of a topical spot-on solution containing spinetoram (11.2% w/w, 130 mg/mL) against European strains of the cat flea, Ctenocephalides felis.

Into the Wild: Parallel Transcriptomics of the Tsetse-Wigglesworthia Mutualism within Kenyan Populations.

Tsetse flies (Diptera: Glossinidae) have medical significance as the obligate vectors of African trypanosomes. In addition, tsetse harbor a simple gut microbiota. A predominant gut microbiota member, the Gammaproteobacterium Wigglesworthia spp.

Initial evaluations of the effectiveness of spinetoram as a long-acting, oral systemic pulicide for controlling cat flea (Ctenocephalides felis) infestations on dogs.

Spinetoram is a semi-synthetic, spinosyn class natural product derived from fermentation by the actinomycete, Saccharopolyspora spinosa. Based on LD (50% lethal dose) values against adult cat fleas (Ctenocephalides felis) using an in vitro contact assay, spinetoram was approximately 4-fold more potent than spinosad. Subsequently, two parallel-arm, randomized block design laboratory studies were conducted to evaluate the effectiveness of orally administered spinetoram against experimental C.

Optimization of isoxazoline amide benzoxaboroles for identification of a development candidate as an oral long acting animal ectoparasiticide.

Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, (S)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (23), with a favorable pharmacodynamics profile in dogs (Cmax=7.42ng/mL; Tmax=26.

Discovery of an orally bioavailable isoxazoline benzoxaborole (AN8030) as a long acting animal ectoparasiticide.

A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.

Efficacy of spinosad against acaricide-resistant and -susceptible Rhipicephalus (Boophilus) microplus and acaricide-susceptible Amblyomma americanum and Dermacentor variabilis.

Various acaricide-resistant strains of Rhipicephalus (Boophilus) microplus, representative of the major resistance mechanisms found in Mexico and Brazil, were exposed to spinosad using the Food and Agriculture Organization of the United Nations larval packet test and adult immersion test (AIT). Larvae of all strains tested were found to be susceptible to spinosad. Conversely, spinosad did not show toxic activity toward engorged females used in the AIT.

A comparison of three bioassay techniques to determine amitraz susceptibility in Boophilus microplus (Acari: Ixodidae).

The ability of the Miller, Soberanes, and White bioassay techniques to describe amitraz susceptibility in three different strains of Boophilus microplus (Canestrini) (Acari: Ixodidae) was compared. For a susceptible strain, all techniques adequately described amitraz susceptibility by producing a full range of mortality that corresponded with increasing concentration of amitraz. However, when resistant strains were evaluated, only the Miller and the Soberanes techniques adequately estimated the dose-response relationship.

In vitro and in vivo characterization of p-amino-phenethyl-m-trifluoromethylphenyl piperazine (PAPP), a novel serotonergic agonist with anthelmintic activity against Haemonchus contortus, Teladorsagia circumcincta and Trichostrongylus colubriformis.

The neurotransmitter serotonin (5-hydroxy tryptamine or 5HT) regulates key physiological processes in nematodes such as locomotion and feeding. PAPP (p-amino-phenethyl-m-trifluoromethylphenyl piperazine) is a known agonist of the 5-HT(1Hc) receptor of the barber pole worm, Haemonchus contortus. In this study, PAPP was highly active against L3-stage larvae of H.

Knockdown and mortality comparisons among spinosad-, imidacloprid-, and methomyl-containing baits against susceptible Musca domestica (Diptera: Muscidae) under laboratory conditions.

The activity of spinosad, imidacloprid, and methomyl baits and technical actives were assessed against susceptible house flies, Musca domestica L. (Diptera: Muscidae). In a feeding assay, imidacloprid affected flies more rapidly than methomyl or spinosad, but spinosad was 2.

Therapeutic and persistent efficacy of spinosad applied as a pour-on or a topical spray against natural infestations of chewing and sucking lice on cattle.

Studies were conducted in Wisconsin and Illinois, USA, to assess and compare the therapeutic and persistent efficacy of spinosad when applied as either a pour-on or topical spray and compared with cyfluthrin pour-on and coumaphos topical spray for controlling natural infestations of chewing (Bovicola bovis) and sucking (Linognathus vituli, Solenopotes capillatus and Haematopinus eurysternus) lice on cattle. Thirty-five animals at each trial site were blocked according to pre-treatment lice counts and randomly allocated to one of five treatment groups: single treatments of spinosad (25 g/L), diluted with water to 0.04% active ingredient and applied as a whole-body topical spray; spinosad (25 g/L) applied as a neat pour-on at 2 mg/kg body weight; Co-Ral Emulsifiable Livestock Insecticide (5.

An in vivo rodent model for identifying and characterizing acaricides.

Evaluation of candidate acaricides in livestock or companion animals is expensive, time-consuming, and usually requires large quantities of test material. To identify promising substances at the earliest possible stage of the development process, robust and predictive surrogate animal models, capable of rapidly characterizing potency with minimal compound requirements, are necessary. The objective of this study was to generate an in vivo surrogate animal bioassay capable of rapidly and accurately predicting the topical activity of acaricides emerging from in vitro acaricide bioassays.

Comparison of in vitro and in vivo ectoparasiticide activity of experimental benzimidazole-carbamate with permethrin and amitraz.

A series of in vitro and in vivo bioassays were conducted to assess the ectoparasiticide activity of isopropyl-4-nitro-2,6-bis(trifluoromethyl)-1-benzimidazole-carbamate, an experimental benzimidazole-carbamate class compound. This compound was less potent than permethrin against ectoparasiticide-susceptible larvae of the lone star tick, Amblyomma americanum (L.) (Acari: Ixodidae); larvae of the southern cattle tick, Boophilus microplus (Canestrini); and adult stable fly, Stomoxys calcitrans (L.