Loss of the mitochondrial kinase PINK1 does not alter platelet function

Abstract PTEN-induced putative kinase (PINK) 1 is regarded as a master regulator of cellular mitophagy such that loss of function mutations contribute to early onset Parkinson’s disease, through aberrant mitochondrial control and function. Mitochondrial function is key to platelet procoagulant activity, controlling the haemostatic response to vessel injury, but can also predispose blood vessels to thrombotic complications. Here, we sought to determine the role of PINK1 in platelet mitochondrial health and function using PINK1 knockout (KO) mice. The data largely show an absence of such a role. Haematological analysis of blood counts from KO mice was comparable to wild type. Quantification of mitochondrial mass by citrate synthase activity assay or expression of mitochondrial markers were comparable, suggesting normal mitophagy in KO platelets. Analysis of mitochondrial permeability transition pore opening, changes in mitochondrial membrane potential and calcium signalling to platelet activation were unaffected by loss of PINK1, whereas subtle enhancements of activation-induced reactive oxygen species were detected. Platelet aggregation, integrin activation, α- and dense granule secretion and phosphatidylserine exposure were unaltered in KO platelets while mouse tail bleeding responses were similar to wild type. Together these results demonstrate that PINK1 does not regulate basal platelet mitophagy and is dispensable for platelet function

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β-Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/− ) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb−/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/− ) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non-neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo

Applications of patching to quadratic forms and central simple algebras

This paper provides applications of patching to quadratic forms and central simple algebras over function fields of curves over henselian valued fields. In particular, we use a patching approach to reprove and generalize a recent result of Parimala and Suresh on the u-invariant of p-adic function fields, for p odd. The strategy relies on a local-global principle for homogeneous spaces for rational algebraic groups, combined with local computations.Comment: 48 pages; connectivity now required in the definition of rational group; beginning of Section 4 reorganized; other minor change

Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia

Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia

Association between placentome size, measured using transrectal ultrasonography, and gestational age in cattle

AIM: The aim of this study was to estimate whether fetal age could be accurately estimated using placentome size. METHODS: Fifty-eight cows with confirmed conception dates in two herds were used for the study. The length of the long axis and cross-sectional area of placentomes close to the cervix were measured once every 10 days between approximately 60-130 days of gestation and once every 15 days between 130-160 days of gestation. Four to six placentomes were measured using transrectal ultrasonography in each uterine horn. A linear mixed model was used to establish the factors that were significantly associated with log mean placentome length and to create an equation to predict gestational age from mean placentome length. Limits of agreement analysis was then used to evaluate whether the predictions were sufficiently accurate for mean placentome length to be used, in practice, as a method of determining gestational age. RESULTS: Only age of gestation (

Influences of Myogenin genotypes on birth weight, growth rate, carcass weight, backfat thickness, and lean weight of pigs

Lean weight is related to muscle fiber number. Muscle fiber formation (myogenesis) occurs only during embryonic development when it is under the control of the MyoD gene family consisting of myogenin, MyoD1, myf-5, and myf-6. Myogenin has a central position within the MyoD gene family because myogenin expression abrogates myoblast proliferation potential and regulates the differentiation of single nucleated myoblasts into multinucleated myofibers. Thus, myogenin genotype could be related to variation in the number of muscle fibers formed, leading to variation in muscle mass and, thus, lean weight. A polymorphism at the porcine myogenin locus was associated with birth weight, growth rate, lean weight at 200 d, and backfat thickness. Yorkshire pigs from two commercial lines were genotyped, and crosses between heterozygous pigs and heterozygous and homozygous pigs were made. Resulting litters were genotyped, and phenotypic data were collected. Significant differences were found between the two homozygous myogenin genotypes for birth weight, growth rate, and lean weight, but not for backfat thickness. Variation at the myogenin locus explained 4% of the total phenotypic variation in birth weight, growth rate, and carcass weight, and 5.8% of the total variation in lean weight. We conclude that myogenin genotype influences porcine growth rate and muscle mass