Long-lasting transcriptional refractoriness triggered by a single exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is thought to have environmental (toxin) and genetic contributions. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) induces pathological features of PD including loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and striatal dopamine (DA) depletion. We previously described the striatal transcriptional response following acute MPTP administration in MPTP-sensitive C57BL/6J mice. We identified three distinct phases: early (5h), intermediate (24h) and late (72h) and reported that the intermediate and late responses were absent in MPTP-resistant Swiss-Webster (SWR) mice. Here we show that C57BL/6J mice pre-treated with a single 40 mg/kg dose of MPTP and treated 9 days later with 4×20 mg/kg MPTP, display a striatal transcriptional response similar to that of MPTP-resistant SWR mice, i.e. a robust acute response but no intermediate or late response. Transcriptional refractoriness is dependent upon the dose of the priming challenge with as little as 10mg/kg MPTP being effective and can persist for more than 28 days. Priming of SWR mice has no effect on their response to subsequent challenge with MPTP. We also report that paraquat, another free radical producer, also elicits striatal transcriptional alterations but these are largely distinct from those triggered by MPTP. Paraquat-induced changes are also refractory to priming with paraquat. However neither paraquat nor MPTP elicits cross-attenuation. Thus exposure to specific toxins triggers distinct transcriptional responses in striatum that are influenced by prior exposure to the same toxin. The prolonged refractory period described here for MPTP could explain at the molecular level the reported discrepancies between different MPTP administration regimens and may have implications for our understanding of the relationship between environmental toxin exposure and PD.

Factors influencing pursuit and satisfaction of academic dentistry careers: perceptions of new dental educators.

New dental educators (n = 280) with zero to five years full-time teaching experience were surveyed to ascertain their perceptions regarding salary, work environment, and workload to determine the impact of these factors on faculty recruitment and retention. Work environment was the most frequently reported factor for considering and maintaining an academic dentistry position. Educational resources, facilities, salary, and benefits were ranked as moderately important for considering an academic position. Mentoring, startup funds for research, and external private practice opportunities were also reported as moderately important for maintaining a position. Other factors of concern to new faculty included quality of administration and leadership, reputation of program, professional development opportunities, faculty autonomy, and reasonable criteria for tenure and promotion. These findings suggest that resources, strategies, and formal mentoring programs that provide direction and guidance in the areas of teaching, promotion, and tenure for new educators should be considered for implementation in our dental schools.