Small molecule activators of the Trk receptors for neuroprotection

The neurotophin signaling network is critical to the development and survival of many neuronal populations. Especially sensitive to imbalances in the neurotrophin system, cholinergic neurons in the basal forebrain are progressively lost in Alzheimer's disease. Therapeutic use of neurotrophins to prevent this loss is hampered, however, by a number of pharmacological challenges. These include a lack of transport across the blood-brain barrier, rapid degradation in the circulation, and difficulty in production. In this review we discuss the evidence supporting the neurotrophin system's role in preventing neurodegeneration and survey some of the pharmacological strategies being pursued to develop effective therapeutics targeting neurotrophin function

Role of the Cellular Prion Protein in Oligodendrocyte Precursor Cell Proliferation and Differentiation in the Developing and Adult Mouse CNS

There are numerous studies describing the signaling mechanisms that mediate oligodendrocyte precursor cell (OPC) proliferation and differentiation, although the contribution of the cellular prion protein (PrPc) to this process remains unclear. PrPc is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein involved in diverse cellular processes during the development and maturation of the mammalian central nervous system (CNS). Here we describe how PrPc influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrPc proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyte lineage markers. In addition, numerous NG2-positive cells were observed in cortical regions of adult PrPc knockout mice, although no significant changes in myelination can be seen, probably due to the death of surplus cells

Activity variations attending tungsten skarn formation, Pine Creek, California

An integrated geochemical analysis of the well-exposed Pine Creek, California tungsten skarn deposit has been undertaken to evaluate changes in chemical gradients across various lithologies. Thermodynamic calculations using available experimental and thermodynamic data allow limits to be assigned to the activities of important chemical components in the metasomatic environment. Quantifiable changes in “non-volatile” component activites (CaO, MgO, Al 2 O 3 , Fe 2 O 3 , WO 3 ) and in fugacities (O 2 , F 2 ) have been traced across the system. The activities of Al 2 O 3 , Fe 2 O 3 and WO 3 generally increase from the marble (<10 2 , <10 −6 , <10 −5 respectively), through the outer skarn zone and into the massive garnet skarn (10 −1.7±0.3 , 10 −3.4±0.4 , 10 −4.8±0.1 ) While CaO and MgO activities decrease for the same traverse from 10 −5 and 10 −2.1±1 respectively, to <10 −5.7 and <10 −3 . Calculated oxygen fugacities are 10 −23.5+1.0 at T =800 K (527° C), about one log unit below QFM, and more reducing than that required by Mt-Py-Po. The high variance of the garnet-pyroxene-quartz assemblages adds sufficient uncertainty to the calculated activities for individual specimens that only the large-scale trends survive the small-scale scatter. None of the chemical variables emerge as major independent or controlling factors for the mineralogy or phase compositions. Changes in the activity of one component may be offset by compensatory changes in another resulting in an environment that, while different from Pine Creek, could still host scheelite mineralization. Mass balance calculations indicate that the exposed endoskarn cannot have supplied the necessary chemical components to convert the country rock to skarn.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47341/1/410_2004_Article_BF00381557.pd

Plio-Pleistocene phylogeography of the Southeast Asian Blue Panchax killifish, Aplocheilus panchax

The complex climatic and geological history of Southeast Asia has shaped this region’s high biodiversity. In particular, sea level fluctuations associated with repeated glacial cycles during the Pleistocene both facilitated, and limited, connectivity between populations. In this study, we used data from two mitochondrial and three anonymous nuclear markers to determine whether a fresh/brackish water killifish, Aplocheilus panchax, Hamilton, 1822, could be used to further understand how climatic oscillations and associated sea level fluctuations have shaped the distribution of biota within this region, and whether such patterns show evidence of isolation within palaeodrainage basins. Our analyses revealed three major mitochondrial clades within A. panchax. The basal divergence of A. panchax mitochondrial lineages was approximately 3.5 Ma, whilst the subsequent divergence timings of these clades occurred early Pleistocene (~2.6 Ma), proceeding through the Pleistocene. Continuous phylogeographic analysis showed a clear west-east dispersal followed by rapid radiation across Southeast Asia. Individuals from Krabi, just north of the Isthmus of Kra, were more closely related to the Indian lineages, providing further evidence for a freshwater faunal disjunction at the Isthmus of Kra biogeographic barrier. Our results suggest that Sulawesi, across the Wallace Line, was colonised relatively recently (~30 ka). Nuclear DNA is less geographically structured, although Mantel tests indicated that nuclear genetic distances were correlated with geographic proximity. Overall, these results imply that recent gene flow, as opposed to historical isolation, has been the key factor determining patterns of nuclear genetic variation in A. panchax, however, some evidence of historical isolation is retained within the mitochondrial genome. Our study further validates the existence of a major biogeographic boundary at the Kra Isthmus, and also demonstrates the use of widely distributed fresh/brackishwater species in phylogeographic studies, and their ability to disperse across major marine barriers in relatively recent time periods

Loss of plant biodiversity eliminates stimulatory effect of elevated CO2 on earthworm activity in grasslands

Earthworms are among the world's most important ecosystem engineers because of their effects on soil fertility and plant productivity. Their dependence on plants for carbon, however, means that any changes in plant community structure or function caused by rising atmospheric CO2 or loss of plant species diversity could affect earthworm activity, which may feed back on plant communities. Production of surface casts measured during three consecutive years in field experimental plots (n = 24, 1.2 m(2)) planted with local calcareous grassland species that varied in plant species richness (diversity levels: high, 31 species; medium, 12; low, 5) and were exposed to ambient (356 μl CO2 l(-1)) or elevated (600 μl CO2 l(-1)) CO2 was only consistently stimulated in high diversity plots exposed to elevated CO2 (+120 %, 31 spp: 603 ± 52 under ambient CO2 vs. 1,325 ± 204 g cast dwt. m(-2) year(-1) under elevated CO2 in 1996; +77 %, 940 ± 44 vs. 1,663 ± 204 g cast dwt. m(-2) year(-1) in 1998). Reductions in plant diversity had little effect on cast production in ecosystems maintained at ambient CO2, but the stimulatory effect of elevated CO2 on cast production disappeared when plant species diversity was decreased to 12 and 5 species. High diversity plots were also the only communities that included plant species that an earlier field study showed to be among the most responsive to elevated CO2 and to be most preferred by earthworms to deposit casts near. Further, the +87 % CO2-induced increase in cast production measured over the 3 years corresponded to a parallel increase in cumulative total nitrogen of 5.7 g N m(-2) and would help explain the large stimulation of aboveground plant biomass production observed in high-diversity communities under elevated CO2. The results of this study demonstrate how the loss of plant species from communities can alter responses of major soil heterotrophs and consequently ecosystem biogeochemistry