Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism

Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency

Turbo-FLASH based arterial spin labeled perfusion MRI at 7 T.

Motivations of arterial spin labeling (ASL) at ultrahigh magnetic fields include prolonged blood T1 and greater signal-to-noise ratio (SNR). However, increased B0 and B1 inhomogeneities and increased specific absorption ratio (SAR) challenge practical ASL implementations. In this study, Turbo-FLASH (Fast Low Angle Shot) based pulsed and pseudo-continuous ASL sequences were performed at 7T, by taking advantage of the relatively low SAR and short TE of Turbo-FLASH that minimizes susceptibility artifacts. Consistent with theoretical predictions, the experimental data showed that Turbo-FLASH based ASL yielded approximately 4 times SNR gain at 7T compared to 3T. High quality perfusion images were obtained with an in-plane spatial resolution of 0.85×1.7 mm(2). A further functional MRI study of motor cortex activation precisely located the primary motor cortex to the precentral gyrus, with the same high spatial resolution. Finally, functional connectivity between left and right motor cortices as well as supplemental motor area were demonstrated using resting state perfusion images. Turbo-FLASH based ASL is a promising approach for perfusion imaging at 7T, which could provide novel approaches to high spatiotemporal resolution fMRI and to investigate the functional connectivity of brain networks at ultrahigh field

Implementasi Discrete Cosine Transform Pada Field Programmable Gate Array

Pengurangan jumlah perkalian, merupakan suatu cara untuk menghasilkan komputasi cepat Discrete Cosine Transform (DCT). Algoritma 1-D DCT Loeffler merupakan modifikasi dari persamaan 1-D DCT klasik yang mampu meminimumkan penggunaan operasi perkalian dari 64 pengali menjadi 11 pengali. Implementasi DCT ke perangkat keras FPGA Xilinx Spartan 3E dilakukan sebagai upaya efektifitas dan untuk mempercepat proses komputasi. Implementasi dengan FPGA artinya kita merancang sebuah perangkat keras langsung dengan cara mengkonfigurasi unit yang ada di FPGA. Pengkonfigurasian unit yang ada di dalam FPGA dapat dilakukan melalui skematic maupun dengan menggunakan Hardware Description Language (Verilog atau VHDL). Sumber data untuk implementasi DCT menggunakan mikrokontroler dengan operasi interupsi dengan pemicu clock FPGA. Akurasi perhitungan implementasi DCT menunjukkan adanya error yang masih dapat ditoleransi terhadap perhitungan DCT dengan MATLAB. Jumlah slice yang digunakan untuk implementasi unit 2-D DCT pada penelitian ini sebesar 54 % dari total 4656 slices

Intimate partner sexual aggression against Chinese women: a mixed methods study

Abstract Background: Although intimate partner sexual aggression has been shown to be associated with adverse mental health outcomes, there is scant information about sexual aggression in Chinese intimate relationships in general and about its mental health impact in particular. This article aimed to investigate sexual aggression in Chinese intimate relationships, including the use of force or threat of force and non-physical coercive tactics in unwanted sex. Methods: The quantitative and qualitative data used in this paper were drawn from a prospective cohort study conducted in Hong Kong between September 2010 and September 2012. A total of 745 Chinese women aged 18 or older who had been in an intimate relationship in the preceding 12 months were recruited from sites in all districts of Hong Kong. Multiple logistic regression analysis, ordinary linear regression, and t-tests were used in quantitative analysis. Directed content analysis was used to analyze the transcripts of 59 women who revealed experiences of intimate partner sexual aggression in individual in-depth interviews. Results: Of the 745 Chinese women in the study, 348 (46.7%) had experienced intimate partner physical violence in the past year, and 179 (24%) had experienced intimate partner physical violence and sexual aggression in the past year. Intimate partner sexual aggression significantly predicted PTSD and depressive symptoms after controlling for intimate partner physical violence. Among the 179 women reporting intimate partner physical violence and sexual coercion in the past year, 75 indicated that their partners used force or threat of force to make them have sex, and 104 of them reported that they gave in to sex because of non-physical coercive tactics used by their partners. Qualitative data revealed a variety of non-physical coercive tactics with different degrees of subtlety used to coerce women into unwanted sex with their partners. Chinese women experiencing physically forced sex had significantly more depressive symptoms and PTSD symptoms. Conclusions: Our findings indicate that sexual aggression in Chinese intimate relationships has specific mental health consequences over and above those associated with physical violence. Assessment of partner violence in Chinese relationships should include screening for sexual aggression in order to provide appropriate interventions. Trial registration: ClinicalTrials gov NCT01206192 Keywords: Intimate partner, Sexual aggression, Mental health, Women, Chinesepublished_or_final_versio

Strategies to rescue the consequences of inducible arginase-1 deficiency in mice

Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken beta-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies

The differential effects of intimate terrorism and situational couple violence on mental health outcomes among abused Chinese women: a mixed-method study

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Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1

TopBP1 is a scaffold protein that coordinates activation of the DNA-damage-checkpoint response by coupling binding of the 9-1-1 checkpoint clamp at sites of ssDNA, to activation of the ATR-ATRIP checkpoint kinase complex. We have now determined the crystal structure of the N-terminal region of human TopBP1, revealing an unexpected triple-BRCT domain structure. The arrangement of the BRCT domains differs significantly from previously described tandem BRCT domain structures, and presents two distinct sites for binding phosphopeptides in the second and third BRCT domains. We show that the site in the second but not third BRCT domain in the N-terminus of TopBP1, provides specific interaction with a phosphorylated motif at pSer387 in Rad9, which can be generated by CK2

The nature of iron-oxygen vacancy defect centers in PbTiO3

The iron(III) center in ferroelectric PbTiO3 together with an oxygen vacancy forms a charged defect associate, oriented along the crystallographic c-axis. Its microscopic structure has been analyzed in detail comparing results from a semi-empirical Newman superposition model analysis based on finestructure data and from calculations using density functional theory. Both methods give evidence for a substitution of Fe3+ for Ti4+ as an acceptor center. The position of the iron ion in the ferroelectric phase is found to be similar to the B-site in the paraelectric phase. Partial charge compensation is locally provided by a directly coordinated oxygen vacancy. Using high-resolution synchrotron powder diffraction, it was verified that lead titanate remains tetragonal down to 12 K, exhibiting a c/a-ratio of 1.0721.Comment: 11 pages, 5 figures, accepted in Phys. Rev.

Potential impacts on ecosystem services of land use transitions to second-generation bioenergy crops in GB

We present the first assessment of the impact of land use change (LUC) to second-generation (2G) bioenergy crops on ecosystem services (ES) resolved spatially for Great Britain (GB). A systematic approach was used to assess available evidence on the impacts of LUC from arable, semi-improved grassland or woodland/forest, to 2G bioenergy crops, for which a quantitative ‘threat matrix’ was developed. The threat matrix was used to estimate potential impacts of transitions to either Miscanthus, short-rotation coppice (SRC, willow and poplar) or short-rotation forestry (SRF). The ES effects were found to be largely dependent on previous land uses rather than the choice of 2G crop when assessing the technical potential of available biomass with a transition from arable crops resulting in the most positive effect on ES. Combining these data with constraint masks and available land for SRC and Miscanthus (SRF omitted from this stage due to lack of data), south-west and north-west England were identified as areas where Miscanthus and SRC could be grown, respectively, with favourable combinations of economic viability, carbon sequestration, high yield and positive ES benefits. This study also suggests that not all prospective planting of Miscanthus and SRC can be allocated to agricultural land class (ALC) ALC 3 and ALC 4 and suitable areas of ALC 5 are only minimally available. Beneficial impacts were found on 146 583 and 71 890 ha when planting Miscanthus or SRC, respectively, under baseline planting conditions rising to 293 247 and 91 318 ha, respectively, under 2020 planting scenarios. The results provide an insight into the interplay between land availability, original land uses, bioenergy crop type and yield in determining overall positive or negative impacts of bioenergy cropping on ecosystems services and go some way towards developing a framework for quantifying wider ES impacts of this important LUC