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

Imaging high-dimensional spatial entanglement with a camera

The light produced by parametric down-conversion shows strong spatial entanglement that leads to violations of EPR criteria for separability. Historically, such studies have been performed by scanning a single-element, single-photon detector across a detection plane. Here we show that modern electron-multiplying charge-coupled device cameras can measure correlations in both position and momentum across a multi-pixel field of view. This capability allows us to observe entanglement of around 2,500 spatial states and demonstrate Einstein-Podolsky-Rosen type correlations by more than two orders of magnitude. More generally, our work shows that cameras can lead to important new capabilities in quantum optics and quantum information science.Comment: 5 pages, 4 figure

Insight into Protein Conformation and Subcharging by DMSO from Native Ion Mobility Mass Spectrometry

Electrospray ionization-mass spectrometry (ESI-MS) interfaced with ion-mobility (IM) spectrometry has enabled the study of protein structure and interactions under native-like conditions. In biological assays, dimethyl sulfoxide (DMSO) is often included as a co-solvent to dissolve organic molecules. While low levels of DMSO are known to reduce the charge of protein ions generated by ESI, the exact mechanism by which this occurs has been debated. In this study, we describe the first application of IM–MS to study the effect of DMSO subcharging on native protein conformation. We find that at low concentrations, DMSO induces modest (1-2 %), but repeatable, reductions in protein collision-cross sections (CCSs) of four different protein complexes, avidin, concanavalin A, alcohol dehydrogenase, and pyruvate kinase, as measured by traveling-wave (TW) IM–MS. Individual protein charge states also experienced compaction in size, suggesting that this effect could not be attributed to the shift of charge state distribution by DMSO alone.D.S.-H. Chan acknowledges the support of the Croucher Foundation and the Cambridge Commonwealth, European and International Trust for receipt of a Croucher Cambridge International Scholarship

Online unit clustering in higher dimensions

We revisit the online Unit Clustering and Unit Covering problems in higher dimensions: Given a set of $n$ points in a metric space, that arrive one by one, Unit Clustering asks to partition the points into the minimum number of clusters (subsets) of diameter at most one; while Unit Covering asks to cover all points by the minimum number of balls of unit radius. In this paper, we work in $\mathbb{R}^d$ using the $L_\infty$ norm. We show that the competitive ratio of any online algorithm (deterministic or randomized) for Unit Clustering must depend on the dimension $d$. We also give a randomized online algorithm with competitive ratio $O(d^2)$ for Unit Clustering}of integer points (i.e., points in $\mathbb{Z}^d$, $d\in \mathbb{N}$, under $L_{\infty}$ norm). We show that the competitive ratio of any deterministic online algorithm for Unit Covering is at least $2^d$. This ratio is the best possible, as it can be attained by a simple deterministic algorithm that assigns points to a predefined set of unit cubes. We complement these results with some additional lower bounds for related problems in higher dimensions.Comment: 15 pages, 4 figures. A preliminary version appeared in the Proceedings of the 15th Workshop on Approximation and Online Algorithms (WAOA 2017

Dark Matter, Muon g-2 and Other SUSY Constraints

Recent developments constraining the SUSY parameter space are reviewed within the framework of SUGRA GUT models. The WMAP data is seen to reduce the error in the density of cold dark matter by about a factor of four, implying that the lightest stau is only 5 -10 GeV heavier than the lightest neutralino when m_0, m_{1/2} < 1 TeV. The CMD-2 re-analysis of their data has reduced the disagreement between the Standard Model prediction and the Brookhaven measurement of the muon magnetic moment to 1.9 sigma, while using the tau decay data plus CVC, the disagreement is 0.7 sigma. (However, the two sets of data remain inconsistent at the 2.9 sigma level.) The recent Belle and BABAR measurements of the B -> phi K CP violating parameters and branching ratios are discussed. They are analyzed theoretically within the BBNS improved factorization method. The CP parameters are in disagreement with the Standard Model at the 2.7 sigma level, and the branching ratios are low by a factor of two or more over most of the parameter space. It is shown that both anomalies can naturally be accounted for by adding a non-universal cubic soft breaking term at M_G mixing the second and third generations.Comment: 16 pages, 7 figures, plenary talk at Beyond The Desert '03, Castle Ringberg, Germany, June 9, 2003. Typos correcte

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD

Pityriasis rubra pilaris presenting with an abnormal autoimmune profile: two case reports

<p>Abstract</p> <p>Introduction</p> <p>Pityriasis rubra pilaris is an uncommon inflammatory and hyperproliferative dermatosis of juvenile or adult onset. The etiology of the disease is still unknown.</p> <p>Case presentation</p> <p>We present the cases of two Caucasian men aged 53 and 48 who presented with pityriasis rubra pillaris type 1; both patients also exhibited an abnormal immunological profile.</p> <p>Conclusion</p> <p>Pityriasis rubra pillaris is currently classified as a keratinization disorder. The abnormal immunological profile reported in our patients along with the comorbidity of pityriasis rubra pilaris with autoimmune disorders reported in the literature poses the question of a possible pathogenetic role for the immune response in this disorder.</p

A Randomized Double-Blind Crossover Study of Phase-Shift Sound Therapy for Tinnitus

Objective. The purpose of this study was to compare the efficacy of the treatment of tinnitus with a phase-shifting pure tone to that of the same tone treatment without phase shifting. Study Design. A double-blind crossover randomized controlled trial. Setting. This study was conducted at the University Medical Center Groningen. Subjects and Methods. Twenty-two patients with predominantly tonal tinnitus underwent both intervention and control treatments. Each treatment consisted of three 30-minute sessions in 1 week. The control treatment was identical to the intervention treatment, except that the stimulus was a pure tone without phase shifting. Questionnaires, tinnitus loudness match, and annoyance and loudness ratings were used to measure treatment effects. Results. Pure-tone treatment and phase-shift treatment had no significant effect on tinnitus according to questionnaires (Tinnitus Handicap Index, Tinnitus Reaction Questionnaire, Hospital Anxiety and Depression Scale, and Maastricht Questionnaire), audiological matching procedures, and loudness and annoyance ratings of tinnitus. Furthermore, phase-shift treatment showed no additional significant improvement in comparison with pure-tone treatment. Changes in questionnaire scores due to pure-tone and the phase-shift treatment were correlated. Conclusion. On average across the group, both treatments failed to demonstrate a significant effect. Both treatments were beneficial for some patients. However, a positive effect was not demonstrated that could be attributed to the periodic shifting of the phase of the stimulus tone

Soil methane sink capacity response to a long-term wildfire chronosequence in Northern Sweden

Boreal forests occupy nearly one fifth of the terrestrial land surface and are recognised as globally important regulators of carbon (C) cycling and greenhouse gas emissions. Carbon sequestration processes in these forests include assimilation of CO2 into biomass and subsequently into soil organic matter, and soil microbial oxidation of methane (CH4). In this study we explored how ecosystem retrogression, which drives vegetation change, regulates the important process of soil CH4 oxidation in boreal forests. We measured soil CH4 oxidation processes on a group of 30 forested islands in northern Sweden differing greatly in fire history, and collectively representing a retrogressive chronosequence, spanning 5000 years. Across these islands the build-up of soil organic matter was observed to increase with time since fire disturbance, with a significant correlation between greater humus depth and increased net soil CH4 oxidation rates. We suggest that this increase in net CH4 oxidation rates, in the absence of disturbance, results as deeper humus stores accumulate and provide niches for methanotrophs to thrive. By using this gradient we have discovered important regulatory controls on the stability of soil CH4 oxidation processes that could not have not been explored through shorter-term experiments. Our findings indicate that in the absence of human interventions such as fire suppression, and with increased wildfire frequency, the globally important boreal CH4 sink could be diminished

Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups