The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain.

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein, and LRRK2 mutants are recognized risk factors for Parkinson's disease (PD). Although the precise mechanisms that control LRRK2 regulation and function are unclear, the importance of the kinase domain is strongly implicated, since 2 of the 5 most common familial LRRK2 mutations (G2019S and I2020T) are localized to the conserved DFGψ motif in the kinase core, and kinase inhibitors are under development. Combining the concept of regulatory (R) and catalytic (C) spines with kinetic and cell-based assays, we discovered a major regulatory mechanism embedded within the kinase domain and show that the DFG motif serves as a conformational switch that drives LRRK2 activation. LRRK2 is quite unusual in that the highly conserved Phe in the DFGψ motif, which is 1 of the 4 R-spine residues, is replaced with tyrosine (DY2018GI). A Y2018F mutation creates a hyperactive phenotype similar to the familial mutation G2019S. The hydroxyl moiety of Y2018 thus serves as a "brake" that stabilizes an inactive conformation; simply removing it destroys a key hydrogen-bonding node. Y2018F, like the pathogenic mutant I2020T, spontaneously forms LRRK2-decorated microtubules in cells, while the wild type and G2019S require kinase inhibitors to form filaments. We also explored 3 different mechanisms that create kinase-dead pseudokinases, including D2017A, which further emphasizes the highly synergistic role of key hydrophobic and hydrophilic/charged residues in the assembly of active LRRK2. We thus hypothesize that LRRK2 harbors a classical protein kinase switch mechanism that drives the dynamic activation of full-length LRRK2

Instanton Contribution to the Proton and Neutron Electric Form Factors

We study the instanton contribution to the proton and neutron electric form factors. Using the single instanton approximation, we perform the calculations in a mixed time-momentum representation in order to obtain the form factors directly in momentum space. We find good agreement with the experimentally measured electric form factor of the proton. For the neutron, our result falls short of the experimental data. We argue that this discrepancy is due to the fact that we neglect the contribution of the sea quarks. We compare to lattice calculations and a relativistic version of the quark-diquark model.Comment: 8 pages, 5 figures, updated references, to appear in Phys. Lett.

Extended Gari-Krumpelmann model fits to nucleon electromagnetic form factors

Nucleon electromagnetic form factor data (including recent data) is fitted with models that respect the confinement and asymptotic freedom properties of QCD. Gari-Krumpelmann (GK) type models, which include the major vector meson pole contributions and at high momentum transfer conform to the predictions of perturbative QCD, are combined with Hohler-Pietarinen (HP) models, which also include the width of the rho meson and the addition of higher mass vector meson exchanges, but do not evolve into the explicit form of PQCD at high momentum transfer. Different parameterizations of the GK model's hadronic form factors, the effect of including the width of the rho meson and the addition of the next (in mass) isospin 1 vector meson are considered. The quality of fit and the consistency of the parameters select three of the combined HP/GK type models. Projections are made to the higher momentum transfers which are relevant to electron-deuteron experiments. The projections vary little for the preferred models, removing much of the ambiguity in electron-nucleus scattering predictions.Comment: 18pp, 7 figures, using RevTeX with BoxedEPS macros; 1 new figure, minor textual changes; email correspondence to [email protected]

Spectral functions of isoscalar scalar and isovector electromagnetic form factors of the nucleon at two-loop order

We calculate the imaginary parts of the isoscalar scalar and isovector electromagnetic form factors of the nucleon up to two-loop order in chiral perturbation theory. Particular attention is paid on the correct behavior of Im $\sigma_N(t)$ and Im $G_{E,M}^V(t)$ at the two-pion threshold $t_0=4 m_\pi^2$ in connection with the non-relativistic 1/M-expansion. We recover the well-known strong enhancement near threshold originating from the nearby anomalous singularity at $t_c = 4m_\pi^2-m_\pi^4/M^2 = 3.98 m_\pi^2$. In the case of the scalar spectral function Im $\sigma_N(t)$ one finds a significant improvement in comparison to the lowest order one-loop result. Higher order $\pi\pi$-rescattering effects are however still necessary to close a remaining 20%-gap to the empirical scalar spectral function. The isovector electric and magnetic spectral functions Im $G_{E,M}^V(t)$ get additionally enhanced near threshold by the two-pion-loop contributions. After supplementing their two-loop results by a phenomenological $\rho$-meson exchange term one can reproduce the empirical isovector electric and magnetic spectral functions fairly well.Comment: 10 pages, 6 figures, submitted to Physical Review

Effect of recent R_p and R_n measurements on extended Gari-Krumpelmann model fits to nucleon electromagnetic form factors

The Gari-Krumpelmann (GK) models of nucleon electromagnetic form factors, in which the rho, omega, and phi vector meson pole contributions evolve at high momentum transfer to conform to the predictions of perturbative QCD (pQCD), was recently extended to include the width of the rho meson by substituting the result of dispersion relations for the pole and the addition of rho' (1450) isovector vector meson pole. This extended model was shown to produce a good overall fit to all the available nucleon electromagnetic form factor (emff) data. Since then new polarization data shows that the electric to magnetic ratios R_p and R_n obtained are not consistent with the older G_{Ep} and G_{En} data in their range of momentum transfer. The model is further extended to include the omega' (1419) isoscalar vector meson pole. It is found that while this GKex cannot simultaneously fit the new R_p and the old G_{En} data, it can fit the new R_p and R_n well simultaneously. An excellent fit to all the remaining data is obtained when the inconsistent G_{Ep} and G_{En} is omitted. The model predictions are shown up to momentum transfer squared, Q^2, of 8 GeV^2/c^2.Comment: 14 pages, 8 figures, using RevTeX4; email correspondence to [email protected] ; minor typos corrected, figures added, conclusions extende

Fissile and Non-Fissile Material Detection using Nuclear Acoustic Resonance Signatures

This report reviews progress made on NA22 project LL251DP to develop a novel technique, Nuclear Acoustic Resonance (NAR), for remote, non-destructive, nonradiation-based detection of materials of interest to Nonproliferation Programs, including {sup 235}U and {sup 239}Pu. We have met all milestones and deliverables for FY05, as shown in Table 1. In short, we have developed a magnetic shield chamber and magnetic field, develop a digital lock-in amplifier computer to integrate both the ultrasound radiation with the detector, developed strain measurements, and begin to perform initial measurements to obtain a NAR signal from aluminum at room temperature and near the earth's magnetic field. The results obtained in FY05 further support the feasibility of successful demonstration of an NAR experiment for remote, non-destructive, non-radiation-based detection of materials of interest to Nonproliferation Programs

Fissile and Non-Fissile Material Detection using Nuclear Acoustic Resonance Signatures: Final Report

This is final report on NA-22 project LL251DP, where the goal was to develop a novel technique, Nuclear Acoustic Resonance (NAR), for remote, non-destructive, nonradiation-based detection of materials of interest to Nonproliferation Programs, including {sup 235}U and {sup 239}Pu. In short, we have developed a magnetic shield chamber and magnetic field, develop a digital lock-in amplifier computer to integrate both the ultrasound radiation with the detector, developed strain measurements, and begun to perform initial measurements to obtain a NAR signal from aluminum at room temperature and near the earth's magnetic field. Since our funding was cut in FY06, I will discuss where this project can go in the future with this technology

Measurement of the Electric Form Factor of the Neutron at Q^2 = 0.3-0.8 (GeV/c)^2

The electric form factor of the neutron, G_En, has been measured at the Mainz Microtron by recoil polarimetry in the quasielastic D(e_pol,e'n_pol)p reaction. Three data points have been extracted at squared four-momentum transfers Q^2 = 0.3, 0.6 and 0.8 (GeV/c)^2. Corrections for nuclear binding effects have been applied.Comment: 9 pages, 7 figures, 2 tables. Accepted for publication in EPJ

"MY PKU": increasing self-management in patients with phenylketonuria. A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism. The inability to convert phenylalanine (Phe) into tyrosine causes Phe to accumulate in the body. Adherence to a protein restricted diet, resulting in reduced Phe levels, is essential to prevent cognitive decline. Frequent evaluation of plasma Phe levels and, if necessary, adjustment of the diet are the mainstay of treatment. We aimed to assess whether increased self-management of PKU patients and/or their parents is feasible and safe, by providing direct online access to blood Phe values without immediate professional guidance.</p> <p>Methods</p> <p>Thirty-eight patients aged ≥ 1 year participated in a 10 month randomized controlled trial. Patients were randomized into a study group (1) or a control group (2). Group 2 continued the usual procedure: a phone call or e-mail by a dietician in case of a deviant Phe value. Group 1 was given a personal "My PKU" web page with a graph of their recent and previous Phe values, online general information about the dietary treatment and the Dutch PKU follow-up guidelines, and a message-box to contact their dietician if necessary. Phe values were provided on "My PKU" without advice. Outcome measures were: differences in mean Phe value, percentage of values above the recommended range and Phe sample frequency, between a 10-month pre-study period and the study period in each group, and between the groups in both periods. Furthermore we assessed satisfaction of patients and/or parents with the 'My PKU' procedure of online availability.</p> <p>Results</p> <p>There were no significant differences in mean Phe value, percentage of values above recommended range or in frequency of blood spot sampling for Phe determination between the pre-study period and the study period in each group, nor between the 2 groups during the periods. All patients and/or parents expressed a high level of satisfaction with the new way of disease management.</p> <p>Conclusions</p> <p>Increased self-management in PKU by providing patients and/or parents their Phe values without advice is feasible and safe and is highly appreciated.</p> <p>Trial registration</p> <p>The trial was registered with The Netherlands National Trial Register (<a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1171">NTR #1171</a>) before recruitment of patients.</p