LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: Impairment of the kinase activity by Parkinson’s disease-associated mutations

AbstractLRRK2 is the causal molecule for autosomal-dominant familial Parkinson’s disease, although its true function, including its physiological substrates, remains unknown. Here, using in vitro kinase assay with recombinant proteins, we demonstrated for the first time that LRRK2 directly phosphorylates Akt1, a central molecule involved in signal transduction for cell survival and prevention of apoptosis. Ser473, one of two amino acids essential for Akt1 activation, was the target site for LRRK2. A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. The disease-associated mutations, R1441C, G2019S, and I2020T, exhibited reduced interaction with, and phosphorylation of, Akt1, suggesting one possible mechanism for the neurodegeneration caused by LRRK2 mutations.Structured summary of protein interactionsLRRK2phosphorylates Akt1 by protein kinase assay (View Interaction 1, 2, 3).LRRK2 phosphorylates MBP by protein kinase assay (View Interaction 1, 2).LRRK2 binds to Akt1 by pull down (View Interaction 1, 2, 3)

Emergence of physiological rhythmicity in term and preterm neonates in a neonatal intensive care unit

BACKGROUND: Biological rhythmicity, particularly circadian rhythmicity, is considered to be a key mechanism in the maintenance of physiological function. Very little is known, however, about biological rhythmicity pattern in preterm and term neonates in neonatal intensive care units (NICU). In this study, we investigated whether term and preterm neonates admitted to NICU exhibit biological rhythmicity during the neonatal period. METHODS: Twenty-four-hour continuous recording of four physiological variables (heart rate: HR recorded by electrocardiogram; pulse rate: PR recorded by pulse oxymetry; respiratory rate: RR; and oxygen saturation of pulse oxymetry: SpO(2)) was conducted on 187 neonates in NICU during 0–21 days of postnatal age (PNA). Rhythmicity was analyzed by spectral analysis (SPSS procedure Spectra). The Fisher test was performed to test the statistical significance of the cycles. The cycle with the largest peak of the periodogram intensities was determined as dominant cycle and confirmed by Fourier analysis. The amplitudes and amplitude indexes for each dominant cycle were calculated. RESULTS: Circadian cycles were observed among 23.8% neonates in HR, 20% in PR, 27.8% in RR and 16% in SpO(2 )in 0–3 days of PNA. Percentages of circadian cycles were the highest (40%) at <28 wks of gestational age (GA), decreasing with GA, and the lowest (14.3%) at >= 37 wks GA within 3 days of PNA in PR and were decreased in the later PNA. An increase of the amplitude with GA was observed in PR, and significant group differences were present in all periods. Amplitudes and amplitude indexes were positively correlated with postconceptional age (PCA) in PR (p < 0.001). Among clinical parameters, oxygen administration showed significant association (p < 0.05) with circadian rhythms of PR in the first 3 days of life. CONCLUSION: Whereas circadian rhythmicity in neonates may result from maternal influence, the increase of amplitude indexes in PR with PCA may be related to physiological maturity. Further studies are needed to elucidate the effect of oxygenation on physiological rhythmicity in neonates

Tight-Binding Molecular Dynamics with Fermi Operator Expansion:Application to Vacancy Defects in Silicon

By using tight-binding molecular dynamics with Fermi operator expansion, we study vacancy defects in Silicon. The code has been developed for checking silicon crystal, point defect formation energies, etc. The crystal configuration for checking varies among the systems of 64, 216, 512, and 1000 atoms. We have also checked the expansion condition of Fermi operator; the smearing width (∆ε), the maximum order of expansion polynomials. The testing shows the good results, compared with the ab initio results. The dynamical behaviors of defects both in the liquid state and the non-self-diffusion state, are still being investigated. In order to support the data analysis, a visualization of multi-vacancy is also constructed

Implementation of Parallel Matrix Diagonalization for Ab-Initio Molecular Dynamics Program using ScaLAPACK

A matrix diagonalization is one of the most time-consuming parts of the ab-initio molecular dynamics programs. The bigger system to be simulated, the bigger matrix needs to be diagonalized to obtain the eigenvalues and eigenvectors. To raise this matter, we have applied ma-trix diagonalization provided by Scalable Linear Algebra PACKage (ScaLAPACK) to the ab-initio molecular dynamics program. We analyzed the efficiency of RS routine provided by EISPACK and PDSYEVX and PZHEEVX by ScaLAPACK

Magnetic, structural, and electronic properties of Co doped Fe/MgO interface: Density functional approach

We performed ab-initio electronic structure calculation in Co doped Fe/MgO interface on the basis of density functional theory. Two different slab models are considered, depending on the place of Co atom; at the interface and in the Fe layer. With using atomic forces, we obtained the optimized structure at the interface and discussed the layer distance of interface and the local structure around Co. Spin magnetic moments on Fe and Co atoms are also discussed. In the band dispersion at the Fermi level, distribution of the angular orbital component shows the possibility of perpendicular magnetic anisotropy

Wigner formula of rotation matrices and quantum walks

Quantization of a random-walk model is performed by giving a qudit (a multi-component wave function) to a walker at site and by introducing a quantum coin, which is a matrix representation of a unitary transformation. In quantum walks, the qudit of walker is mixed according to the quantum coin at each time step, when the walker hops to other sites. As special cases of the quantum walks driven by high-dimensional quantum coins generally studied by Brun, Carteret, and Ambainis, we study the models obtained by choosing rotation as the unitary transformation, whose matrix representations determine quantum coins. We show that Wigner's $(2j+1)$-dimensional unitary representations of rotations with half-integers $j$'s are useful to analyze the probability laws of quantum walks. For any value of half-integer $j$, convergence of all moments of walker's pseudovelocity in the long-time limit is proved. It is generally shown for the present models that, if $(2j+1)$ is even, the probability measure of limit distribution is given by a superposition of $(2j+1)/2$ terms of scaled Konno's density functions, and if $(2j+1)$ is odd, it is a superposition of $j$ terms of scaled Konno's density functions and a Dirac's delta function at the origin. For the two-, three-, and four-component models, the probability densities of limit distributions are explicitly calculated and their dependence on the parameters of quantum coins and on the initial qudit of walker is completely determined. Comparison with computer simulation results is also shown.Comment: v2: REVTeX4, 15 pages, 4 figure

Isolated gestational proteinuria preceding the diagnosis of preeclampsia : an observational study

Introduction. Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases. Material and methods. This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously. Results. IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2-18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031]. Conclusions. IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE