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

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

Low-temperature switching fatigue behavior of ferroelectric SrBi₂Ta₂O[sub 9] thin films

Author name used in this publication: Z. G. LiuAuthor name used in this publication: H. L. W. ChanAuthor name used in this publication: C. L. Choy2003-2004 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Prognostic factors in severe exacerbation of chronic hepatitis B

Forty-seven patients with severe hepatitis B exacerbation were compared with patients who had mild exacerbation (n = 96) or no exacerbation (n = 96). Seventeen patients (36.2%) died or underwent liver transplantation. Preexisting cirrhosis and a prothrombin time (PT) of >30 s were associated with adverse outcome in 60.9% and 87.5% of patients, respectively. The rate of adverse outcome increased to 92.3% when albumin levels of ≤35 g/L and bilirubin levels of >200 μM were present. Other factors associated with adverse outcomes included peak bilirubin level, peak PT, time to reach peak PT, and the presence of encephalopathy and/or ascites. There was no difference in the frequency of precore mutations in patients with severe or mild exacerbation or without exacerbation. A significantly lower prevalence of core promoter mutants was found in patients with severe exacerbation (50%), compared with those who had mild exacerbation (81.3%; P = .004). Patients with severe exacerbation of hepatitis B with poor prognostic factors should be considered for early liver transplantation.published_or_final_versio

What WorX: Measuring the impact of faith-based service and social justice programs on Catholic youth

The Center for FaithJustice (CFJ) offers innovative programs that engage youth in faith, service, and social justice. With the Indiana University Lilly Family School of Philanthropy at IUPUI, they developed a survey to evaluate their programs and measure their longitudinal impact on alumni in those three focus areas. This report will offer related insights on youth engagement and suggest how CFJ’s programs relate to larger trends of youth disaffiliation within the Catholic Church. This study examines survey results from alumni and parents of alumni of CFJ’s youth programs, which are collectively called the “WorX” programs. These include curricula for middle school students (ServiceworX), high school students (JusticeworX, New Jersey Service Project/NJSP, MercyworX, and CommunityworX), young adults (LeaderworX), and adults (FaithJustice Fellows and adult volunteers). The results of this study focused on CFJ’s three core areas of interest: faith, service, and social justice

Age and anatomy of the Gongga Shan batholith, eastern Tibetan Plateau, and its relationship to the active Xianshui-he fault

The Gongga Shan batholith of eastern Tibet, previously documented as a ca. 32–12.8 Ma granite pluton, shows some of the youngest U-Pb granite crystallization ages recorded from the Tibetan Plateau, with major implications for the tectonothermal history of the region. Field observations indicate that the batholith is composite; some localities show at least seven crosscutting phases of granitoids that range in composition from diorite to leucocratic monzogranite. In this study we present U-Pb ages of zircon and allanite dated by laser ablation–inductively coupled plasma–mass spectrometry on seven samples, to further investigate the chronology of the batholith. The age data constrain two striking tectonic-plutonic events: a complex Triassic–Jurassic (ca. 215–159 Ma) record of biotite-hornblende granodiorite, K-feldspar megacrystic granite and leucogranitic plutonism, and a Miocene (ca. 14–5 Ma) record of monzonite-leucogranite emplacement. The former age range is attributed to widespread Indosinian tectonism, related to Paleo-Tethyan subduction zone magmatism along the western Yangtze block of south China. The younger component may be related to localized partial melting (muscovite dehydration) of thickened Triassic flysch-type sediments in the Songpan-Ganze terrane, and are among the youngest crustal melt granites exposed on the Tibetan Plateau. Zircon and allanite ages reflect multiple crustal remelting events; the youngest, ca. 5 Ma, resulted in dissolution and crystallization of zircons and growth and/or resetting of allanites. The young garnet, muscovite, and biotite leucogranites occur mainly in the central part of the batholith and adjacent to the eastern margin of the batholith at Kangding, where they are cut by the left-lateral Xianshui-he fault. The Xianshui-he fault is the most seismically active strike-slip fault in Tibet and is thought to record the eastward extrusion of the central part of the Tibetan Plateau. The fault obliquely cuts all granites of the Gongga Shan massif and has a major transpressional component in the Kangding-Moxi region. The course of the Xianshui Jiang river is offset by ∼62 km along the Xianshui-he fault and in the Kangding area granites as young as ca. 5 Ma are cut by the fault. Our new geochronological data show that only a part of the Gongga Shan granite batholith is composed of young (Miocene) melt, and we surmise that as most of eastern Tibet is composed of Precambrian–Triassic Indosinian rocks, there is no geological evidence to support regional Cenozoic internal thickening or metamorphism and no evidence for eastward-directed lower crustal flow away from Tibet. We suggest that underthrusting of Indian lower crust north as far as the Xianshui-he fault resulted in Cenozoic uplift of the eastern plateau

Precambrian Plate Tectonics in Northern Hudson Bay: Evidence From P and S Wave Seismic Tomography and Analysis of Source Side Effects in Relative Arrival-Time Data Sets

The geology of northern Hudson Bay, Canada, documents more than 2 billion years of history including the assembly of Precambrian and Archean terranes during several Paleoproterozoic orogenies, culminating in the Trans‐Hudson Orogen (THO) ∼1.8 Ga. The THO has been hypothesized to be similar in scale and nature to the ongoing Himalaya‐Karakoram‐Tibetan orogen, but the nature of lithospheric terrane boundaries, including potential plate‐scale underthrusting, is poorly understood. To address this problem, we present new P and S wave tomographic models of the mantle seismic structure using data from recent seismograph networks stretching from northern Ontario to Nunavut (60–100∘W and 50–80∘N). The large size of our network requires careful mitigation of the influence of source side structure that contaminates our relative arrival time residuals. Our tomographic models reveal a complicated internal structure in the Archean Churchill plate. However, no seismic wave speed distinction is observed across the Snowbird Tectonic Zone, which bisects the Churchill. The mantle lithosphere in the central region of Hudson Bay is distinct from the THO, indicating potential boundaries of microcontinents and lithospheric blocks between the principal colliders. Slow wave speeds underlie southern Baffin Island, the leading edge of the generally high wave speed Churchill plate. This is interpreted to be Paleoproterozoic material underthrust beneath Baffin Island in a modern‐style subduction zone setting

MLPerf Inference Benchmark

Machine-learning (ML) hardware and software system demand is burgeoning. Driven by ML applications, the number of different ML inference systems has exploded. Over 100 organizations are building ML inference chips, and the systems that incorporate existing models span at least three orders of magnitude in power consumption and five orders of magnitude in performance; they range from embedded devices to data-center solutions. Fueling the hardware are a dozen or more software frameworks and libraries. The myriad combinations of ML hardware and ML software make assessing ML-system performance in an architecture-neutral, representative, and reproducible manner challenging. There is a clear need for industry-wide standard ML benchmarking and evaluation criteria. MLPerf Inference answers that call. In this paper, we present our benchmarking method for evaluating ML inference systems. Driven by more than 30 organizations as well as more than 200 ML engineers and practitioners, MLPerf prescribes a set of rules and best practices to ensure comparability across systems with wildly differing architectures. The first call for submissions garnered more than 600 reproducible inference-performance measurements from 14 organizations, representing over 30 systems that showcase a wide range of capabilities. The submissions attest to the benchmark's flexibility and adaptability.Comment: ISCA 202

Discovery of high-amplitude X-ray variability in the Seyfert-LINER transition galaxy NGC7589

We present the first result of a programme to search for large flux variations in the X-ray sources of the XMM Serendipitous Survey compared to previous ROSAT observations. An increase in X-ray flux by a factor >10 was discovered from the nucleus of the galaxy NGC7589 on a timescale of less than 5 years. The 0.4-10keV XMM spectrum can be approximated by a power-law with photon index of 1.7-1.8, though it seems to flatten above 5keV, suggesting a possible complex model, such as partial covering or disc reflection. A classification based on an analysis of its optical spectrum places NGC7589 in the Seyfert region, but close to the Seyfert-LINER border-line on the AGN diagnostic diagrams. We classify NGC7589 as either Seyfert1.9 or LINERI, in the light of the detection of a broad H_alpha line, which makes NGC7589 an AGN in the low-luminosity regime. We interpret the observed variability in terms of either changes in covering factor of absorbing gas in the AGN, or variability in the intrinsic X-ray luminosity. Should the latter be the case, the inferred Eddington accretion rate increased from the radiatively inefficient accretion dominated regime to a value close to the putative critical value, at which a transition of the accretion mode is supposed to take place. This possibility presents a new prospect of studying accretion physics in the central black holes of external galaxies by direct observing changes of `spectral state', as is common in stellar black hole binary systems.Comment: 6 pages, 4 figures, accepted for publication in MNRAS Lette