Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins

Amyloid deposits are primarily composed of the amyloid-beta protein, although other proteins (and metal ions) also have been colocalized to these lesions. The pattern of oxidative modifications in amyloid plaques is very different to that associated with neurofibrillary tangles and neuronal cell bodies, likely reflecting the different composition of these structures, accessibility of oxidants, the generation of oxidants in and around these structures and the intrinsic antioxidant defense systems to protect these structures. Future studies directed at understanding Abeta interactions with other amyloid components, the role of oxidative modifications in stabilizing amyloid deposits and the determination of protease cleavage sites on Abeta may provide mechanistic insights regarding both amyloid formation and removal.     

Naturopathy: a critical appraisal

"Naturopathic medicine" is a recent manifestation of the field of naturopathy, a 19th-century health movement espousing "the healing power of nature." "Naturopathic physicians" now claim to be primary care physicians proficient in the practice of both "conventional" and "natural" medicine. Their training, however, amounts to a small fraction of that of medical doctors who practice primary care. An examination of their literature, moreover, reveals that it is replete with pseudoscientific, ineffective, unethical, and potentially dangerous practices. Despite this, naturopaths have achieved legal and political recognition, including licensure in 13 states and appointments to the US Medicare Coverage Advisory Committee. This dichotomy can be explained in part by erroneous representations of naturopathy offered by academic medical centers and popular medical Web sites.     

The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic

Worldwide, millions of people are exposed to arsenic in drinking water that exceeds the World Health Organization standard of 10 microg/liter by as much as 50-300-fold, yet little is known about the molecular basis for arsenic excretion. Here we show that transport of arsenic into bile depends on the MRP2/cMOAT transporter and that glutathione is obligatory for such transport. Using reversed phase liquid chromatography/mass spectrometry, we demonstrate that two arsenic-glutathione complexes not previously identified in vivo, arsenic triglutathione and methylarsenic diglutathione, account for most of the arsenic in the bile. The structure of the compounds was also confirmed by nuclear magnetic resonance spectroscopy. Our findings may help explain the increased susceptibility of malnourished human populations to arsenic.     

JC virus enters human glial cells by clathrin-dependent receptor-mediated endocytosis

The human polyomavirus JC virus (JCV) is the etiologic agent of a fatal central nervous system (CNS) demyelinating disease known as progressive multifocal leukoencephalopathy (PML). PML occurs predominantly in immunosuppressed patients and has increased dramatically as a result of the AIDS pandemic. The major target cell of JCV infection and lytic replication in the CNS is the oligodendrocyte. The mechanisms by which JCV initiates and establishes infection of these glial cells are not understood. The initial interaction between JCV and glial cells involves virus binding to N-linked glycoproteins containing terminal alpha(2-6)-linked sialic acids. The subsequent steps of entry and targeting of the viral genome to the nucleus have not been described. In this report, we compare the kinetics and mechanisms of infectious entry of JCV into human glial cells with that of the related polyomavirus, simian virus 40 (SV40). We demonstrate that JCV, unlike SV40, enters glial cells by receptor-mediated clathrin-dependent endocytosis.     

Multiple Roles for Frequenin/NCS-1 in Synaptic Function and Development

The calcium-binding protein frequenin (Frq), discovered in the fruit fly Drosophila, and its mammalian homologue neuronal calcium sensor 1 (NCS-1) have been reported to affect several aspects of synaptic transmission, including basal levels of neurotransmission and short- and long-term synaptic plasticities. However, discrepant reports leave doubts about the functional roles of these conserved proteins. In this review, we attempt to resolve some of these seemingly contradictory reports. We discuss how stimulation protocols, sources of calcium (voltage-gated channels versus internal stores), and expression patterns (presynaptic versus postsynaptic) of Frq may result in the activation of various protein targets, leading to different synaptic effects. In addition, the potential interactions of Frq's C-terminal and N-terminal domains with other proteins are discussed. Frq also has a role in regulating neurite outgrowth, axonal regeneration, and synaptic development. We examine whether the effects of Frq on neurotransmitter release and neurite outgrowth are distinct or interrelated through homeostatic mechanisms. Learning and memory are affected by manipulations of Frq probably through changes in synaptic transmission and neurite outgrowth, raising the possibility that Frq may be implicated in human pathological conditions, including schizophrenia, bipolar disorder, and X-linked mental retardation.     

Amyloid-beta precursor protein expression and modulation in human embryonic stem cells: a novel role for human chorionic gonadotropin

The amyloid-β precursor protein (AβPP) is a ubiquitously expressed adhesion and neuritogenic protein whose processing has previously been shown to be regulated by reproductive hormones including the gonadotropin luteinizing hormone (LH) in human neuroblastoma cells. We report for the first time the expression of AβPP in human embryonic stem (hES) cells at the mRNA and protein levels. Using N- and C-terminal antibodies against AβPP, we detected both the mature and immature forms of AβPP as well as truncated variants (∼53 kDa, 47 kDa, and 29 kDa) by immunoblot analyses. Expression of AβPP is regulated by both the stemness of the cells and pregnancy-associated hormones. Addition of human chorionic gonadotropin, the fetal equivalent of LH that is dramatically elevated during pregnancy, markedly increased the expression of all AβPP forms. These results indicate a critical molecular signaling link between the hormonal environment of pregnancy and the expression of AβPP in hES cells that is suggestive of an important function for this protein during early human embryogenesis prior to the formation of neural precursor cells.     

Competitive displacement alters top-down effects on carbon dioxide concentrations in a freshwater ecosystem

Climate change and invasive species have the potential to alter species diversity, creating novel species interactions. Interspecific competition and facilitation between predators may either enhance or dampen trophic cascades, ultimately influencing total predator effects on communities and biogeochemical cycling of ecosystems. However, previous studies have only investigated the effects of a single predator species on CO₂ flux of aquatic ecosystems. In this study, we measured and compared the individual and joint effects of predatory damselfly larvae and diving beetles on total prey biomass, leaf litter processing, and dissolved CO₂ concentrations of experimental bromeliad ecosystems. Damselfly larvae created strong trophic cascades that reduced CO₂ concentrations by ~46 % relative to no-predator treatments. Conversely, the effects of diving beetles on prey biomass, leaf litter processing, and dissolved CO₂ were not statistically different to no-predator treatments. Relative to multiplicative null models, the presence of damselfly larvae and diving beetles together resulted in antagonistic relations that eliminated trophic cascades and top-down influences on CO₂ concentrations. Furthermore, we showed that the antagonistic interactions between predators occurred due to a tactile response that culminated in competitive displacement of damselfly larvae. Our results demonstrate that predator identity and predator–predator interactions can influence CO₂ concentrations of an aquatic ecosystem. We suggest that predator effects on CO₂ fluxes may depend on the particular predator species removed or added to the ecosystem and their interactions with other predators.     

Proteomic analysis of the Trypanosoma cruzi ribosomal proteins

Trypanosoma cruzi is a parasite responsible for Chagas disease. The identification of new targets for chemotherapy is a major challenge for the control of this disease. Several lines of evidences suggest that the translational system in trypanosomatids show important differences compared to other eukaryotes. However, there little is known information about this. We have performed a detailed data mining search for ribosomal protein genes in T. cruzi genome data base combined with mass spectrometry analysis of purified T. cruzi ribosomes. Our results show that T. cruzi ribosomal proteins have ∼50% sequence identity to yeast ones. Nevertheless, some parasite proteins are longer due to the presence of several N- or C-terminal extensions, which are exclusive of trypanosomatids. In particular, L19 and S21 show C-terminal extensions of 168 and 164 amino acids, respectively. In addition, we detected two 60S subunit proteins that had not been previously detected in the T. cruzi total proteome; namely, L22 and L42.     

A 3 kDa peptide is involved in the chemoattraction in vitro of the male Schistosoma mansoni to the female

In vitro experiments on adult Schistosoma mansoni worms have shown the existence of mutual attraction between males and females mediated by factor(s) released by both sexes. Males were attracted to female-released factor(s), which was found in <30 kDa fractions. A combination of bioassays, size fractionations, chromatographic and chemical and enzymatic treatments were used to identify female-released factor(s) that attracted males. Boiling reduced the attraction of males towards female incubate. Male-attractant factor(s) was not in the female vomitus, and TLC showed the absence of lipids and carbohydrates in the female incubate. Male-attractant factor(s) was found to be sensitive to proteases and to be hydrophilic in nature. Using RP-HPLC, a 3260 Da peptide released by S. mansoni adult females that plays a role in attracting the males was identified, purified and partially characterized. A partial amino acid sequence of that peptide was obtained using MALDI peptide-MS and MALDI-TOF/TOF.