BackgroundThe striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo.Methods1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (MA), two commonly used neurotoxins in rodent models of Parkinson’s disease, were administered to wild-type (Dyn+/+) and prodynorphin-deficient mice (Dyn−/−). We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR).ResultsTreatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn-l- than in Dyn+/+. Dyn−/− showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn+/+. Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn−/− than in Dyn+/+. Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn−/− than in Dyn+/+. Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP.ConclusionsThe in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects.
At the time of the 1918–1919 ‘Spanish’ influenza pandemic, influenza researchers did not just relate this disease to the human population, despite the focus of historians of medicine on its human aspects and meanings. In line with the use of historical reports of animals with influenza in present-day microbiological studies on influenza among different animal species, this article investigates understandings of animal influenza in the Netherlands during the 1918–1919 pandemic. The article adds to microbiological uses of the historical record by putting observations of animals with influenza in historical contexts, in particular the context of military dealings with influenza at the end of the First World War, and the social position of veterinary medicine. The case of the Dutch military horse veterinarian Emile Bemelmans, who argued that human and horse influenza were identical, illustrates that knowledge of these contexts is important to critically use historical sources reporting animals with influenza in present-day biological influenza research.
We present the dynamically typed A-calculus, an extension of the statically typed I-calculus with a special type Dyn and explicit dynamic type coercions corresponding to run-time type tagging and type check-and-untag operations. Programs in run-time typed languages can be interpreted in the dynamically typed L-calculus via a nondeterministic completion process that inserts explicit coercions and type declarations such that a well-typed term results. We characterize when two different completions of the same run-time typed program are coherent with an equational theory that is independent of an underlying I-theory. This theory is refined by orienting some equations to define safety and minimality of completions. Intuitively, a safe completion is one that does not produce an error at run-time which another completion would have avoided, and a minimal completion is a safe completion that executes fewest tagging and check-and-untag operations amongst all safe completions. We show that every untyped A-term has a safe completion at any type and that it is unique modulo a suitable congruence relation. Furthermore, we present a rewriting system for generating minimal completions. Assuming strong normalization of this rewriting system we show that every U-term has a minimal completion at any type, which is furthermore unique modulo equality in the dynamically typed A-calculus.