Minimal ureagenesis is necessary for survival in the murine model of hyperargininemia treated by AAV-based gene therapy.

Hyperammonemia is less severe in arginase 1 deficiency compared with other urea cycle defects. Affected patients manifest hyperargininemia and infrequent episodes of hyperammonemia. Patients typically suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation, seizures and intellectual disability; death is less common than with other urea cycle disorders. In a mouse model of arginase I deficiency, the onset of symptoms begins with weight loss and gait instability, which progresses toward development of tail tremor with seizure-like activity; death typically occurs at about 2 weeks of life. Adeno-associated viral vector gene replacement strategies result in long-term survival of mice with this disorder. With neonatal administration of vector, the viral copy number in the liver greatly declines with hepatocyte proliferation in the first 5 weeks of life. Although the animals do survive, it is not known from a functional standpoint how well the urea cycle is functioning in the adult animals that receive adeno-associated virus. In these studies, we administered [1-13C] acetate to both littermate controls and adeno-associated virus-treated arginase 1 knockout animals and examined flux through the urea cycle. Circulating ammonia levels were mildly elevated in treated animals. Arginine and glutamine also had perturbations. Assessment 30 min after acetate administration demonstrated that ureagenesis was present in the treated knockout liver at levels as low at 3.3% of control animals. These studies demonstrate that only minimal levels of hepatic arginase activity are necessary for survival and ureagenesis in arginase-deficient mice and that this level of activity results in control of circulating ammonia. These results may have implications for potential therapy in humans with arginase deficiency

Packing While Traveling: Mixed Integer Programming for a Class of Nonlinear Knapsack Problems

Packing and vehicle routing problems play an important role in the area of supply chain management. In this paper, we introduce a non-linear knapsack problem that occurs when packing items along a fixed route and taking into account travel time. We investigate constrained and unconstrained versions of the problem and show that both are NP-hard. In order to solve the problems, we provide a pre-processing scheme as well as exact and approximate mixed integer programming (MIP) solutions. Our experimental results show the effectiveness of the MIP solutions and in particular point out that the approximate MIP approach often leads to near optimal results within far less computation time than the exact approach

Robust Structured Low-Rank Approximation on the Grassmannian

Over the past years Robust PCA has been established as a standard tool for reliable low-rank approximation of matrices in the presence of outliers. Recently, the Robust PCA approach via nuclear norm minimization has been extended to matrices with linear structures which appear in applications such as system identification and data series analysis. At the same time it has been shown how to control the rank of a structured approximation via matrix factorization approaches. The drawbacks of these methods either lie in the lack of robustness against outliers or in their static nature of repeated batch-processing. We present a Robust Structured Low-Rank Approximation method on the Grassmannian that on the one hand allows for fast re-initialization in an online setting due to subspace identification with manifolds, and that is robust against outliers due to a smooth approximation of the $\ell_p$-norm cost function on the other hand. The method is evaluated in online time series forecasting tasks on simulated and real-world data

Duality Invariant M-theory: Gauged supergravities and Scherk-Schwarz reductions

We consider the reduction of the duality invariant approach to M-theory by a U-duality group valued Scherk-Schwarz twist. The result is to produce potentials for gauged supergravities that are normally associated with non-geometric compactifications. The local symmetry reduces to gauge transformations with the gaugings exactly matching those of the embedding tensor approach to gauged supergravity. Importantly, this approach now includes a nontrivial dependence of the fields on the extra coordinates of the extended space.Comment: 22 pages Latex; v2: typos corrected and references adde

Boundary Conditions for Interacting Membranes

We investigate supersymmetric boundary conditions in both the Bagger-Lambert and the ABJM theories of interacting membranes. We find boundary conditions associated to the fivebrane, the ninebrane and the M-theory wave. For the ABJM theory we are able to understand the enhancement of supersymmetry to produce the (4,4) supersymmetry of the self-dual string. We also include supersymmetric boundary conditions on the gauge fields that cancel the classical gauge anomaly of the Chern-Simons terms.Comment: 36 pages, latex, v2 minor typos correcte

The Conformal Anomaly of M5-Branes

We show that the conformal anomaly for N M5-branes grows like $N^3$. The method we employ relates Coulomb branch interactions in six dimensions to interactions in four dimensions using supersymmetry. This leads to a relation between the six-dimensional conformal anomaly and the conformal anomaly of N=4 Yang-Mills. Along the way, we determine the structure of the four derivative interactions for the toroidally compactified (2,0) theory, while encountering interesting novelties in the structure of the six derivative interactions.Comment: 38 pages, LaTeX; references adde

Structural Change in (Economic) Time Series

Methods for detecting structural changes, or change points, in time series data are widely used in many fields of science and engineering. This chapter sketches some basic methods for the analysis of structural changes in time series data. The exposition is confined to retrospective methods for univariate time series. Several recent methods for dating structural changes are compared using a time series of oil prices spanning more than 60 years. The methods broadly agree for the first part of the series up to the mid-1980s, for which changes are associated with major historical events, but provide somewhat different solutions thereafter, reflecting a gradual increase in oil prices that is not well described by a step function. As a further illustration, 1990s data on the volatility of the Hang Seng stock market index are reanalyzed.Comment: 12 pages, 6 figure

Mirror Dark Matter

There appear to be three challenges that any theory of dark matter must face: (i) why is $\Omega_{DM}$ of the same order as $\Omega_{Baryons}$ ? (ii) what are the near solar mass objects ($\sim 0.5 M_{\odot}$) observed by the MACHO microlensing project ? and (iii) understanding the shallow core density profile of the halos of dwarf as well as low surface brightness galaxies. The popular cold dark matter candidates, the SUSY LSP and the axion fail to meet these challenges. We argue that in the mirror model suggested recently to explain the neutrino anomalies, the mirror baryons being 15-20 times heavier than familiar baryons, can play the role of the cold dark matter and provide reasonable explanation of all three above properties without extra assumptions.Comment: Latex, 10 pages; Invited talk presented in PASCOS99 workshop, held in Lake Tahoe, Dec. 1999 and DM2000 workshop held in Los Angeles, February, 200

Evaluating 35 Methods to Generate Structural Connectomes Using Pairwise Classification

There is no consensus on how to construct structural brain networks from diffusion MRI. How variations in pre-processing steps affect network reliability and its ability to distinguish subjects remains opaque. In this work, we address this issue by comparing 35 structural connectome-building pipelines. We vary diffusion reconstruction models, tractography algorithms and parcellations. Next, we classify structural connectome pairs as either belonging to the same individual or not. Connectome weights and eight topological derivative measures form our feature set. For experiments, we use three test-retest datasets from the Consortium for Reliability and Reproducibility (CoRR) comprised of a total of 105 individuals. We also compare pairwise classification results to a commonly used parametric test-retest measure, Intraclass Correlation Coefficient (ICC).Comment: Accepted for MICCAI 2017, 8 pages, 3 figure

Massive Type II in Double Field Theory

We provide an extension of the recently constructed double field theory formulation of the low-energy limits of type II strings, in which the RR fields can depend simultaneously on the 10-dimensional space-time coordinates and linearly on the dual winding coordinates. For the special case that only the RR one-form of type IIA carries such a dependence, we obtain the massive deformation of type IIA supergravity due to Romans. For T-dual configurations we obtain a `massive' but non-covariant formulation of type IIB, in which the 10-dimensional diffeomorphism symmetry is deformed by the mass parameter.Comment: 21 page