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The North American-Caribbean genera Pholcophora Banks, 1896 and Tolteca Huber, 2000 are representatives of Ninetinae, a group of small, cryptic, and thus poorly known pholcid spiders. We present the first comprehensive revisions of the two genera, including extensive SEM data and descriptions of seven new species from Mexico (Pholcophora mazatlan Huber sp. nov., P. papanoa Huber sp. nov., P. tehuacan Huber sp. nov., Tolteca huahua Huber sp. nov., T. manzanillo Huber sp. nov., T. oaxaca Huber sp. nov., and T. sinnombre Huber sp. nov.). We add new CO1 sequences of nine species to previously published molecular data and use these for a preliminary analysis of relationships. We recover a North American-Caribbean clade including ‘true’ (mainland) Pholcophora, Tolteca (Mexico), and a Caribbean clade consisting of the genus Papiamenta Huber, 2000 (Curaçao) and Caribbean ‘Pholcophora’. First karyotype data for Tolteca (2n♂ = 13, X1X2Y and 15, X1X2Y, respectively) reveal a strong reduction of the number of chromosome pairs within the North American-Caribbean clade, and considerable karyotype differentiation among congeners. This agrees with considerable CO1 divergence among species of Tolteca but contrasts with very inconspicuous morphological divergence. Environmental niche analyses show that the widespread P. americana Banks, 1896 (western USA, SW Canada) occupies a very different niche than its Mexican congeners and other close relatives. Caribbean taxa also have a low niche overlap with ‘true’ Pholcophora and Tolteca, supporting the idea that Caribbean ‘Pholcophora’ are taxonomically misplaced.
Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
Introduction: The rational development of new therapeutics requires a thorough understanding of how aberrant signalling affects cellular homeostasis and causes human disease. Chemical probes are tool compounds with well-defined mechanism-of-action enabling modulation of, for example, domain-specific protein properties in a temporal manner, thereby complementing other target validation methods such as genetic gain- and loss-of-function approaches.
Areas covered: In this review, the authors summarize recent advances in chemical probe development for emerging target classes such as solute carriers and ubiquitin-related targets and highlight open resources to inform and facilitate chemical probe discovery as well as tool compound selection for target validation and phenotypic screening.
Expert opinion: Chemical probes are powerful tools for drug discovery that have led to fundamental insights into biological processes and have paved the way for the development of first-in-class drugs. Open resources can inform on various aspects of chemical probe development and provide access to data and recommendations on use of chemical probes to catalyse collaborative science and help accelerate drug target identification and validation.