Quantification of Plasma and Urine Thymidine and 2'-Deoxyuridine by LC-MS/MS for the Pharmacodynamic Evaluation of Erythrocyte Encapsulated Thymidine Phosphorylase in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disorder caused by mutations in TYMP, leading to a deficiency in thymidine phosphorylase and a subsequent systemic accumulation of thymidine and 2'-deoxyuridine. Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is under clinical development as an enzyme replacement therapy for MNGIE. Bioanalytical methods were developed according to regulatory guidelines for the quantification of thymidine and 2'-deoxyuridine in plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for supporting the pharmacodynamic evaluation of EE-TP. Samples were deproteinized with 5% perchloric acid (v/v) and the supernatants analyzed using a Hypercarb column (30 × 2.1 mm, 3 µm), with mobile phases of 0.1% formic acid in methanol and 0.1% formic acid in deionized water. Detection was conducted using an ion-spray interface running in positive mode. Isotopically labelled thymidine and 2'-deoxyuridine were used as internal standards. Calibration curves for both metabolites showed linearity (r > 0.99) in the concentration ranges of 10-10,000 ng/mL for plasma, and 1-50 µg/mL for urine, with method analytical performances within the acceptable criteria for quality control samples. The plasma method was successfully applied to the diagnosis of two patients with MNGIE and the quantification of plasma metabolites in three patients treated with EE-TP

Implications of Minimal Length Scale on the Statistical Mechanics of Ideal Gas

Several alternative approaches to quantum gravity problem suggest the modification of the {\it fundamental volume $\omega_{0}$} of the accessible phase space for representative points. This modified fundamental volume has a novel momentum dependence. In this paper, we study the effects of this modification on the thermodynamics of an ideal gas within the microcanonical ensemble and using the generalized uncertainty principle(GUP). Although the induced modifications are important only in quantum gravity era, possible experimental manifestation of these effects may provides strong support for underlying quantum gravity proposal.Comment: 14 Pages, No Figures, Title Changed, Revised Versio

Size and charge effects on the deposition of Na on Ar

We discuss the dynamical deposition of the Na atom, the Na$^+$ in and the Na$_6$ cluster on finite Ar clusters mocking up an infinite Ar surface. We analyze this scenario as a function of projectile initial kinetic energy and of the size the target cluster.Comment: 14 pages, 6 figures, Proceedings of the XIth European Workshop on Quantum Systems in Chemistry and Physics (QSCP-XI), Aug. 20-25 2006, St-Petersburg, Russia, submitted to Intern. J. Quant. Che

Possible Disintegrating Short-Period Super-Mercury Orbiting KIC 12557548

We report here on the discovery of stellar occultations, observed with Kepler, that recur periodically at 15.685 hour intervals, but which vary in depth from a maximum of 1.3% to a minimum that can be less than 0.2%. The star that is apparently being occulted is KIC 12557548, a K dwarf with T_eff = 4400 K and V = 16. Because the eclipse depths are highly variable, they cannot be due solely to transits of a single planet with a fixed size. We discuss but dismiss a scenario involving a binary giant planet whose mutual orbit plane precesses, bringing one of the planets into and out of a grazing transit. We also briefly consider an eclipsing binary, that either orbits KIC 12557548 in a hierarchical triple configuration or is nearby on the sky, but we find such a scenario inadequate to reproduce the observations. We come down in favor of an explanation that involves macroscopic particles escaping the atmosphere of a slowly disintegrating planet not much larger than Mercury. The particles could take the form of micron-sized pyroxene or aluminum oxide dust grains. The planetary surface is hot enough to sublimate and create a high-Z atmosphere; this atmosphere may be loaded with dust via cloud condensation or explosive volcanism. Atmospheric gas escapes the planet via a Parker-type thermal wind, dragging dust grains with it. We infer a mass loss rate from the observations of order 1 M_E/Gyr, with a dust-to-gas ratio possibly of order unity. For our fiducial 0.1 M_E planet, the evaporation timescale may be ~0.2 Gyr. Smaller mass planets are disfavored because they evaporate still more quickly, as are larger mass planets because they have surface gravities too strong to sustain outflows with the requisite mass-loss rates. The occultation profile evinces an ingress-egress asymmetry that could reflect a comet-like dust tail trailing the planet; we present simulations of such a tail.Comment: 14 pages, 7 figures; submitted to ApJ, January 10, 2012; accepted March 21, 201

Bounded and unitary elements in pro-C^*-algebras

A pro-C^*-algebra is a (projective) limit of C^*-algebras in the category of topological *-algebras. From the perspective of non-commutative geometry, pro-C^*-algebras can be seen as non-commutative k-spaces. An element of a pro-C^*-algebra is bounded if there is a uniform bound for the norm of its images under any continuous *-homomorphism into a C^*-algebra. The *-subalgebra consisting of the bounded elements turns out to be a C^*-algebra. In this paper, we investigate pro-C^*-algebras from a categorical point of view. We study the functor (-)_b that assigns to a pro-C^*-algebra the C^*-algebra of its bounded elements, which is the dual of the Stone-\v{C}ech-compactification. We show that (-)_b is a coreflector, and it preserves exact sequences. A generalization of the Gelfand-duality for commutative unital pro-C^*-algebras is also presented.Comment: v2 (accepted

A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: The role of muscle biopsy in diagnosis and defining pathogenicity

Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic challenge and with genomic testing still necessitating a muscle biopsy in many cases. Here we describe an adult patient who presented with progressive ataxia, neuropathy and exercise intolerance in whom the application of numerous Mendelian gene panels had failed to make a genetic diagnosis. Muscle biopsy revealed characteristic mitochondrial pathology (cytochrome c oxidase deficient, ragged-red fibers) prompting a thorough investigation of the mitochondrial genome. Two heteroplasmic MT-CO2 gene variants (NC_012920.1: m.7887G>A and m.8250G>A) were identified, necessitating single fiber segregation and familial studies – including the biopsy of the patient's clinically-unaffected mother - to demonstrate pathogenicity of the novel m.7887G>A p.(Gly101Asp) variant and establishing this as the cause of the mitochondrial biochemical defects and clinical presentation. In the era of high throughput whole exome and genome sequencing, muscle biopsy remains a key investigation in the diagnosis of patients with non-syndromic presentations of adult-onset mitochondrial disease and fully defining the pathogenicity of novel mtDNA variants

A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A>G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxi

Correction to: Spontaneous discontinuation of distressing auditory verbal hallucinations in a school-based sample of adolescents:A longitudinal study

In the Original Publication Table 2 was incorrectly published. The correct table is given below

Spontaneous discontinuation of distressing auditory verbal hallucinations in a school-based sample of adolescents:a longitudinal study

Auditory verbal hallucinations (AVH) can be transiently present in both clinical and healthy adolescent populations. It is not yet fully understood why AVH discontinue in some adolescents and persist in others. The aim of this explorative study is to investigate predictors of spontaneous discontinuation of distressing AVH in a school-based sample of adolescents. 1841 adolescents (mean age 12.4 years, 58% female) completed self-report questionnaires at baseline. The current study included 123 adolescents (7%; 63% female) who reported at least mild distressing AVH at baseline and completed follow-up measurements. LASSO analyses were used to uncover predictors of spontaneous discontinuation of distressing AVH. During follow-up, 43 adolescents (35%) reported having experienced distressing AVH during the last 12 months, while 80 adolescents did not. Spontaneous discontinuation of distressing AVH was predicted by never having used cannabis, parents not being divorced in the past year, never having been scared by seeing a deceased body, less prosocial behaviour, school grade repetition, having the feeling that others have it in for you, having anxiety when meeting new people, having lived through events exactly as if they happened before and having the feeling as if parts of the body have changed. No associations between spontaneous discontinuation of distressing AVH and age or ethnicity were found. Distressing AVH in non-clinical adolescents are mostly transient. Discontinuation was predicted up to a certain extent. However, several predictors were difficult to interpret and do not provide leads for preventive measures, except for discouraging cannabis use.</p

Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. While dominantly-inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remain challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G > C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G > C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the nineteenth (19th) locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes