Miracle-dz/UniFAR-FTUs huggingface dataset:
Resource Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK 1

Mutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson’s disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub-family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser) in response to PINK1 activation. Using phospho-specific antibodies raised against Ser of each of the Rabs, we demonstrate that Rab Ser phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient-derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser. We further show mechanistically that phosphorylation at Ser significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/ 8B/13 at Ser may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPasemediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson’s disease.
Structure-Function Analysis of Mammalian CYP 2 B Enzymes Using 7-Substituted Coumarin Derivatives as Probes : Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism s

Crystal structures of CYP2B35 and CYP2B37 from the desert woodrat were solved in complex with 4-(4-chlorophenyl)imidazole (4-CPI). The closed conformation of CYP2B35 contained two molecules of 4-CPI within the active site, whereas the CYP2B37 structure demonstrated an open conformation with three 4-CPI molecules, one within the active site and the other two in the substrate access channel. To probe structurefunction relationships of CYP2B35, CYP2B37, and the related CYP2B36, we tested the O-dealkylation of three series of related substrates—namely, 7-alkoxycoumarins, 7-alkoxy-4(trifluoromethyl)coumarins, and 7-alkoxy-4-methylcoumarins— with a C1-C7 side chain. CYP2B35 showed the highest catalytic efficiency (kcat/KM) with 7-heptoxycoumarin as a substrate, followed by 7-hexoxycoumarin. In contrast, CYP2B37 showed the highest catalytic efficiency with 7-ethoxy-4-(trifluoromethyl) coumarin (7-EFC), followed by 7-methoxy-4-(trifluoromethyl) coumarin (7-MFC). CYP2B35 had no dealkylation activity with 7-MFC or 7-EFC. Furthermore, the new CYP2B–4-CPI–bound structures were used as templates for docking the 7-substituted coumarin derivatives, which revealed orientations consistent with the functional studies. In addition, the observation of multiple –Cl and –NH-p interactions of 4-CPI with the aromatic side chains in the CYP2B35 and CYP2B37 structures provides insight into the influence of such functional groups on CYP2B ligand binding affinity and specificity. To conclude, structural, computational, and functional analysis revealed striking differences between the active sites of CYP2B35 and CYP2B37 that will aid in the elucidation of new structure-activity relationships.
Measurement of blood volume with a new apparatus.

THE prevailing methods for measuring blood volume have failed to find widespread clinical application. This is because the technics are cumbersome, and because accurate, repeated measurements cannot be made with sufficient frequency to be of value in the management of persisting derangements of blood volume. The need for an accurate, freely repetitive and, if possible, semiautomatic method is obvious. Appraisals of blood volume during major surgical procedures, after extensive burns and during therapy for cardiac decompensation, acute renal failure and other major disorders as a rule are based upon data that at best allow only rough approximations. These are often .
Evaluation of Human Immunodeficiency Virus Biomarkers: Inferences From Interval and Clinical Cohort Studies

Introduction: Among individuals infected with the human immunodeficiency virus (HIV), biomarkers that predict mortality are also used to determine the time when antiretroviral therapy is initiated. No studies have evaluated the impact of the frequency of marker measurements for either their predictive value of mortality or how they may influence inference of the effect of therapy initiation in analyses from observational data. Methods: We identified 244 persons who were contemporaneously enrolled in both the AIDS Link to the IntraVenous Experience (an interval cohort) and the Johns Hopkins HIV Clinical Cohort between 1995 and 2004. Data from each study were used separately in 2 ways. We applied time-dependent proportional hazards models to examine the predictive associations between markers and mortality, and marginal structural models to examine the causal inference of therapy on mortality. Biomarkers were used to derive the inverse probability weights. Results: The timing frequencies of marker measurements in the interval cohort (CD4 interquartile range = 175–194 days) were less heterogeneous than in the clinical cohort (interquartile range = 38–121 days). Despite this, the results were concordant for CD4 (R2 = 0.537 [95% confidence interval = 0.345–0.707] and (R2 = 0.488 [0.297–0.666], respectively). Similar concordance was found for the HIV-1 RNA and hemoglobin analyses. When evaluating the causal effect of highly active antiretroviral therapy (HAART), the relative hazards were 0.34 for the interval cohort study (95% CI = 0.15–0.77) and 0.27 for the clinical cohort study (0.11–0.66). Conclusion: Utilizing a unique co-enrollment of patients in 2 different types of cohort studies, we find empirical evidence that inferences drawn from these different structures are similar.
Bed rest affects ventricular and arterial elastances in monkeys: implications for humans.

METHODS Experimental data were obtained from five chronically instrumented rhesus monkeys exposed to 96 h of 10 degrees head-down bed rest (HDBR) and another 96 h of 80 degrees upright control separated by 9 d of ambulatory recovery in a counter-balanced, crossover experiment design to test the hypotheses that: 1) headward and footward fluid shifts would increase systemic arterial (Eart) and left ventricular end-systolic (Ees) elastances; and 2) changes in Eart and Ees would be related in magnitude and direction. Ees and Eart were calculated from measurements taken during five observation periods for initial 2-h and 4-d exposures to HDBR that produced headward volume shifts, and acute exposure to graded levels of lower body negative pressure (LBNP) designed to produce orthostatic volume shifts. RESULTS There was no effect of HDBR on Ees and Eart for any observation period (initial 2-h, 4-d, or LBNP). Eart increased in a similar pattern during the 4-d exposure to both control and HDBR. Ees increased with increasing LBNP levels for both control and HDBR while Eart remained unchanged. CONCLUSION Our data are consistent with the notion that elevated Eart may represent an adaptation to physical inactivity that is associated with cardiovascular deconditioning.
Thrombin‐induced CCN2 expression in human lung fibroblasts requires the c‐Src/JAK2/STAT3 pathway

Thrombin is a multifunctional serine protease and an important fibrotic mediator that induces CCN2 expression. We previously showed that thrombin induces CCN2 expression via an ASK1‐dependent JNK/AP‐1 pathway in human lung fibroblasts. In this study, we further investigated the roles of c‐Src, JAK2, and STAT3 in thrombin‐induced CCN2 expression. Thrombin‐induced CCN2 expression and CCN2‐Luc activity were attenuated by a JAK inhibitor (AG490) and JAK2DN, STAT3DN, and the STAT decoy ODN. Moreover, transfection of cells with a CCN2‐mtSTAT‐Luc construct inhibited thrombin‐induced CCN2‐Luc activity. Treatment of cells with thrombin caused JAK2 phosphorylation at Tyr1007/1008 and STAT3 phosphorylation at Tyr705 in time‐dependent manners. Thrombin‐induced STAT3 phosphorylation was inhibited by AG490 and JAK2DN. Thrombin‐induced STAT3 binding to the CCN2 promoter was analyzed by a DNA‐binding affinity pull‐down assay. In addition, thrombin‐induced CCN2 expression and CCN2‐Luc activity were inhibited by c‐SrcDN and PP2 (an Src inhibitor). Transfection of cells with c‐SrcDN also inhibited thrombin‐induced JAK2 and STAT3 phosphorylation. Taken together, these results indicate that thrombin might activate c‐Src to induce JAK2 activation, which in turn, causes STAT3 activation, and finally induces CCN2 expression in human lung fibroblasts.
Recursive updating the eigenvalue decomposition of a covariance matrix

The author addresses the problem of computing the eigensystem of the modified Hermitian matrix, given the prior knowledge of the eigensystem of the original Hermitian matrix. Specifically, an additive rank-k modification corresponding to adding and deleting blocks of data to and from the covariance matrix is considered. An efficient and parallel algorithm which makes use of a generalized spectrum-slicing theorem is derived for computing the eigenvalues. The eigenvector can be computed explicitly in terms of the solution of a much-reduced (k*k) homogeneous Hermitian system. The overall computational complexity is shown to be improved by an order of magnitude from O(N/sup 3/) to O(N/sup 2/k), where N*N is the size of the covariance matrix. It is pointed out that these ideas can be applied to adaptive signal processing applications, such as eigen-based techniques for frequency or angle-of-arrival estimation and tracking. Specifically, adaptive versions of the principal eigenvector method and the total least squares method are derived. >
The Binding of UvrAB Proteins to Bubble and Loop Regions in Duplex DNA*

Based on the binding of the UvrAB complex to a promoter region in transcription open complexes (Ahn, B., and Grossman, L. (1996) J. Biol. Chem. 271, 21453-21461) and the requirement of a single-stranded region for UvrAB helicase activity, we examined the binding of UvrAB proteins to synthetic bubble or loop regions in duplex DNA and the role of these regions in translocation of the UvrAB complex as well as incision of DNA damage. We found that the UvrAB complex was able to bind to bubble and loop regions with an affinity similar to that for damaged DNA in the absence of RNAP. The preferential recognition and incision of damaged sites by the UvrAB complex was observed downstream of the bubble or loop region in the strand complementary to the strand along which the UvrAB complex translocates. These results imply that the bubble region generated in duplex DNA by RNAP serves as a preferred entry site for the translocation of the UvrAB complex, and that preferential binding and unidirectional translocation of the UvrAB complex predetermine where incision is to occur.
Highly Oxidized Peroxisomes Are Selectively Degraded via Autophagy in Arabidopsis[C][W]

Peroxisomes are organelles that generate reactive oxygen species such as hydrogen peroxide. This study shows that peroxisomes damaged by hydrogen peroxide are degraded via autophagy, suggesting that autophagy plays an important role in quality control of peroxisomes. The positioning of peroxisomes in a cell is a regulated process that is closely associated with their functions. Using this feature of the peroxisomal positioning as a criterion, we identified three Arabidopsis thaliana mutants (peroxisome unusual positioning1 [peup1], peup2, and peup4) that contain aggregated peroxisomes. We found that the PEUP1, PEUP2, and PEUP4 were identical to Autophagy-related2 (ATG2), ATG18a, and ATG7, respectively, which are involved in the autophagic system. The number of peroxisomes was increased and the peroxisomal proteins were highly accumulated in the peup1 mutant, suggesting that peroxisome degradation by autophagy (pexophagy) is deficient in the peup1 mutant. These aggregated peroxisomes contained high levels of inactive catalase and were more oxidative than those of the wild type, indicating that peroxisome aggregates comprise damaged peroxisomes. In addition, peroxisome aggregation was induced in wild-type plants by exogenous application of hydrogen peroxide. The cat2 mutant also contained peroxisome aggregates. These findings demonstrate that hydrogen peroxide as a result of catalase inactivation is the inducer of peroxisome aggregation. Furthermore, an autophagosome marker, ATG8, frequently colocalized with peroxisome aggregates, indicating that peroxisomes damaged by hydrogen peroxide are selectively degraded by autophagy in the wild type. Our data provide evidence that autophagy is crucial for quality control mechanisms for peroxisomes in Arabidopsis.
A Single-Phase Four-Switch Rectifier With Significantly Reduced Capacitance

A single-phase four-switch rectifier with considerably reduced capacitance is investigated in this paper. The rectifier consists of one conventional rectification leg and one neutral leg linked with two capacitors that split the dc bus. The ripple energy in the rectifier is diverted into the lower split capacitor so that the voltage across the upper split capacitor, designed to be the dc output voltage, has very small ripples. The voltage across the lower capacitor is designed to have large ripples on purpose so that the total capacitance needed is significantly reduced and highly reliable film capacitors, instead of electrolytic capacitors, can be used. At the same time, the rectification leg is controlled independently from the neutral leg to regulate the input current to achieve unity power factor and also to maintain the dc-bus voltage. Experimental results are presented to validate the performance of the proposed strategy.
Design of a data-oriented cascade control system

In process industries, PID control has been applied to controlled objects such as chemical plants. A cascade control system is applied in order to improve control performance by using several feedback loops. However, it is complicated to design a cascade control system because this control system includes plural controllers. In this paper, a design scheme of data-oriented cascade control system without system identification is proposed. According to the proposed scheme, PID gains included in plural controllers can be determined by using only closed-loop data. The effectiveness of the proposed scheme is verified by using a simulation example and an experiment of the water level control system.
Universal intervention as a protective shield against exposure to substance use: long-term outcomes and public health significance.

OBJECTIVES We examined universal preventive intervention effects on adolescents' exposure to opportunities for substance use and on illicit substance use in the long term. METHODS Public schools (N = 22) were randomly assigned to the Iowa Strengthening Families Program (ISFP) or a control condition. We used odds ratio (OR) calculations and structural modeling to test the effects of the ISFP in the 6th grade on exposure to substance use across adolescence, as well as on 12th-grade illicit substance use occurring via reductions in exposure. RESULTS The ISFP was associated with reduced exposure to illicit substance use (1.25 < or = OR < or = 2.37) that was, in turn, associated with reduced 12th-grade substance use (2.87 < or = OR < or = 6.35). The ISFP also reduced the rate of increase in exposure across adolescence (B = -0.37; P < .001), which was associated with the likelihood of 12th-grade illicit substance use (B = 0.30; P = .021), with a significant indirect effect (B = -0.11; P = .048). CONCLUSIONS The ISFP in the 6th grade reduced substance use through a "protective shield" of reduced exposure. The relative reduction rate was 49%, which suggests that universal prevention shields can contribute to significant reductions in illicit substance use among adolescents.
Weighted roundoff noise and pole sensitivity minimization subject to l2-scaling constraints for 2-D separable-denominator digital filters

The problem of minimizing roundoff noise and pole sensitivity simultaneously subject to l2-norm scaling constraints of dynamic range for 2-D digital filters with separable denominator is investigated. A novel measure for the evaluation of roundoff noise and pole sensitivity is introduced and then an effective method for minimizing the measure is explored by converting the constrained optimization problem into an unconstrained optimization problem and by employing an efficient quasi-Newton method. A numerical example is included to illustrate the effectiveness of the present method.
Modelling aspects of cancer dynamics: a review

Cancer is a complex disease in which a variety of factors interact over a wide range of spatial and temporal scales with huge datasets relating to the different scales available. However, these data do not always reveal the mechanisms underpinning the observed phenomena. In this paper, we explain why mathematics is a powerful tool for interpreting such data by presenting case studies that illustrate the types of insight that realistic theoretical models of solid tumour growth may yield. These range from discriminating between competing hypotheses for the formation of collagenous capsules associated with benign tumours to predicting the most likely stimulus for protease production in early breast cancer. We will also illustrate the benefits that may result when experimentalists and theoreticians collaborate by considering a novel anti-cancer therapy.
B2B e-marketplace adoption in China: From the perspective of innovation diffusion theory and network externalities

Based on innovation diffusion theory and network externalities, this paper explores the key factors affecting B2B e-marketplace adoption in China. First, we classify adoption process into two stages: pre-adoption stage and post-adoption stage. Then, based on relative theory, 4 factors are identified and 8 hypotheses are formulated, which are tested by the data collected from 379 Chinese enterprises. The result indicates that relative advantage and network externality have positive influence on adoption decision in both pre-adoption stage and post-adoption stage, complexity does not show influence on adoption decision in both two stages. However, although Compatibility has significant effect on decision in post-adoption stage, it does not show significant influence in pre-adoption stage.
Intrinsic regulations in neural fate commitment

Neural fate commitment is an early embryonic event that a group of cells in ectoderm, which do not ingress through primitive streak, acquire a neural fate but not epidermal or mesodermal lineages. Several extracellular signaling pathways initiated by the secreted proteins bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), wingless/int class proteins (WNTs) and Nodal play essential roles in the specification of the neural plate. Accumulating evidence from the studies on mouse and pluripotent embryonic stem cells reveals that except for the extracellular signals, the intracellular molecules, including both transcriptional and epigenetic factors, participate in the modulation of neural fate commitment as well. In the review, we mainly focus on recent findings that the initiation of the nervous system is elaborately regulated by the intrinsic programs, which are mediated by transcriptional factors such as Sox2, Zfp521, Sip1 and Pou3f1, as well as epigenetic modifications, including histone methylation/demethylation, histone acetylation/deacetylation, and DNA methylation/demethylation. The discovery of the intrinsic regulatory machineries provides better understanding of the mechanisms by which the neural fate commitment is ensured by the cooperation between extracellular factors and intracellular molecules.
EFFECTS OF EXOGENOUS NITRIC OXIDE ON GERMINATION AND CARBOHYDRATES MOBILIZATION IN ALFALFA SEEDLINGS UNDER CADMIUM STRESS

Alfalfa is widely used as cattle food and as ornamental plant, it is also known to be a bio-accumulator and extremely resistant to heavy metal stress; however there has been a little information about the physiological and biochemical aspects involved in its germination once submitted to Cadmium stress. The aim of this study was to investigate the methods of improving stress resistance and ability of alfalfa seedlings germinated under Cadmium (Cd) stress by applying exogenous Sodium Nitroprusside (SNP) as Nitric oxide donor. Physiological indexes of alfalfa seeds treated by SNP under Cd stress like germination percentage, germination index, shoot length and root length were measured. Mobilization of carbohydrate reserves have been assessed through quantification of soluble proteins, soluble starch, as well as activity of α and β-amylases. Germination parameters of alfalfa seeds treated under 30μmol Cd stress underwent a drastic inhibition. After treatment with different concentrations of SNP every germination indexes were all increased and the seeds that were treated with Cd+200μmol SNP had the most significantly increase (p≤0.05) in every germination parameter as well as carbohydrate mobilization. SNP 200μmol/L could significantly alleviate damages to seeds and seedlings of alfalfa under Cd 30μmol/L stress and promote Cd-resistance of seeds and seedlings during germination.
Nubytics: Scalable cloud services for data analysis and prediction

The analysis of very large data sources requires scalable systems to reduce execution time and make the Big Data paradigm viable. Cloud infrastructures can be effectively used as scalable computing and storage platforms for implementing high-performance data analysis services. Nubytics is a Software-as-a-Service (SaaS) system that exploits Cloud facilities to provide efficient services for analyzing large datasets. The system allows users to import their data to the Cloud, extract knowledge models using high performance data mining services, and exploit the inferred knowledge to predict new data and behaviours. In particular, Nubytics provides data classification and regression services that can be used in a variety of scientific and business applications. Scalability is ensured by a parallel computing approach that fully exploits the resources available on a Cloud. The paper describes the main services provided by Nubytics and presents an experimental performance analysis to show its scalability.