ARHGEF7 (BETA-PIX) Acts as Guanine Nucleotide Exchange Factor for Leucine-Rich Repeat Kinase 2

Background: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson’s disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro. Methodology/Principal Findings: Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro and in vivo. GTPase activity of full-length LRRK2 increases in the presence of recombinant ARHGEF7. Interestingly, LRRK2 phosphorylates ARHGEF7 in vitro at previously unknown phosphorylation sites. We provide evidence that ARHGEF7 might act as a guanine nucleotide exchange factor for LRRK2 and that R1441C mutant LRRK2 with reduced GTP hydrolysis activity also shows reduced binding to ARHGEF7. Conclusions/Significance: Downstream effects of phosphorylation of ARHGEF7 through LRRK2 could be (i) a feedback control mechanism for LRRK2 activity as well as (ii) an impact of LRRK2 on actin cytoskeleton regulation. A newly identified familial mutation N1437S, localized within the GTPase domain of LRRK2, further underlines the importance of the GTPas

Signal Transduction Protein Array Analysis Links LRRK2 to Ste20 Kinases and PKC Zeta That Modulate Neuronal Plasticity

substrate phosphorylation..Ste20 kinases and PKC zeta contribute to neuronal Tau phosphorylation, neurite outgrowth and synaptic plasticity under physiological conditions. Our data suggest that these kinases may also be involved in synaptic dysfunction and neurite fragmentation in transgenic mice and in human PD patients carrying toxic gain-of-function LRRK2 mutations

Toward a Consistent Description of the PNC Experiments in A=18-21 Nuclei

The experimental PNC results in $^{18}$F, $^{19}$F, $^{21}$Ne and the current theoretical analysis show a discrepancy . If one interprets the small limit of the experimentally extracted PNC matrix element for $^{21}$Ne as a destructive interference between the isoscalar and the isovector contribution, then it is difficult to understand why the isovector contribution in $^{18}$F is so small while the isoscalar + isovector contribution in $^{19}$F is relatively large. In order to understand the origin of this discrepancy a comparison of the calculated PNC matrix elements was performed. It is shown that the $^{18}$F and $^{21}$Ne matrix elements contain important contributions from 3$\hbar \omega$ and 4$\hbar \omega$ configuration and that the (0+1)$\hbar \omega$ calculations give distorted results.Comment: REVTEX, 16 pages, 1 postscriptum figure uuencoded and appende

Microscopic theories of neutrino-^{12}C reactions

In view of the recent experiments on neutrino oscillations performed by the LSND and KARMEN collaborations as well as of future experiments, we present new theoretical results of the flux averaged $^{12}C(\nu_e,e^-)^{12}N$ and $^{12}C(\nu_{\mu},{\mu}^-)^{12}N$ cross sections. The approaches used are charge-exchange RPA, charge-exchange RPA among quasi-particles (QRPA) and the Shell Model. With a large-scale shell model calculation the exclusive cross sections are in nice agreement with the experimental values for both reactions. The inclusive cross section for $\nu_{\mu}$ coming from the decay-in-flight of $\pi^+$ is $15.2 \times 10^{-40} cm^2$ to be compared to the experimental value of $12.4 \pm 0.3 \pm 1.8 \times 10^{-40} cm^2$, while the one due to $\nu_{e}$ coming from the decay-at-rest of $\mu^+$ is $16.4 \times 10^{-42} cm^2$ which agrees within experimental error bars with the measured values. The shell model prediction for the decay-in-flight neutrino cross section is reduced compared to the RPA one. This is mainly due to the different kind of correlations taken into account in the calculation of the spin modes and partially due to the shell-model configuration basis which is not large enough, as we show using arguments based on sum-rules.Comment: 17 pages, latex, 5 figure

Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease

Loss of intestinal barrier function plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Shedding of intestinal epithelial cells is a potential cause of barrier loss during inflammation. The objectives of the study were (1) to determine whether cell shedding and barrier loss in humans can be detected by confocal endomicroscopy and (2) whether these parameters predict relapse of IBD

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely \u3b23-Cav2.1 at N-terminus part and \u3b2-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause diseas

Gamow-Teller Strength in the Region of 100^{100}Sn

New calculations are presented for Gamow-Teller beta decay of nuclei near $^{100}$Sn. Essentially all of the $^{100}$Sn Gamow-Teller decay strength is predicted to go to a single state at an excitation energy of 1.8 MeV in $^{100}$In. The first calculations are presented for the decays of neighboring odd-even and odd-odd nuclei which show, in contrast to $^{100}$Sn, surprisingly complex and broad Gamow-Teller strength distributions. The results are compared to existing experimental data and the resulting hindrance factors are discussed.Comment: 12 pages (latex) and 2 figures available on reques

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging

Social sciences research in neglected tropical diseases 2: A bibliographic analysis

The official published version of the article can be found at the link below.Background There are strong arguments for social science and interdisciplinary research in the neglected tropical diseases. These diseases represent a rich and dynamic interplay between vector, host, and pathogen which occurs within social, physical and biological contexts. The overwhelming sense, however, is that neglected tropical diseases research is a biomedical endeavour largely excluding the social sciences. The purpose of this review is to provide a baseline for discussing the quantum and nature of the science that is being conducted, and the extent to which the social sciences are a part of that. Methods A bibliographic analysis was conducted of neglected tropical diseases related research papers published over the past 10 years in biomedical and social sciences. The analysis had textual and bibliometric facets, and focussed on chikungunya, dengue, visceral leishmaniasis, and onchocerciasis. Results There is substantial variation in the number of publications associated with each disease. The proportion of the research that is social science based appears remarkably consistent (<4%). A textual analysis, however, reveals a degree of misclassification by the abstracting service where a surprising proportion of the "social sciences" research was pure clinical research. Much of the social sciences research also tends to be "hand maiden" research focused on the implementation of biomedical solutions. Conclusion There is little evidence that scientists pay any attention to the complex social, cultural, biological, and environmental dynamic involved in human pathogenesis. There is little investigator driven social science and a poor presence of interdisciplinary science. The research needs more sophisticated funders and priority setters who are not beguiled by uncritical biomedical promises