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

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

State-of-the-Art Management of Patients Suffering from Chronic Lymphocytic Leukemia

The management of chronic lymphocytic leukemia (CLL) has evolved dramatically in the last decade. For the first time, clinical intervention has been shown to alter the natural history of the disease. Considerable efforts are focussing on better patient selection and response prediction, and it is expected that the publication of the first 200 CLL genomes will spark new insights into risk stratification of CLL patients. Besides, many new agents are being evaluated on their own and in combination therapy in early and late Phase clinical studies. Here, we provide a general clinical introduction into CLL including diagnosis and prognostic markers followed by a summary of the current state-of-the-art treatment. We point to areas of continued clinical research in particular for patients with co-morbidities and highlight the challenges in managing refractory disease

Changes of energy fluxes in marine animal forests of the anthropocene: Factors shaping the future seascape

Climate change is already transforming the seascapes of our oceans by changing the energy availability and the metabolic rates of the organisms. Among the ecosystem-engineering species that structure the seascape, marine animal forests (MAFs) are the most widespread. These habitats, mainly composed of suspension feeding organisms, provide structural complexity to the sea floor, analogous to terrestrial forests. Because primary and secondary productivity is responding to different impacts, in particular to the rapid ongoing environmental changes driven by climate change, this paper presents some directions about what could happen to different MAFs depending on these fast changes. Climate change could modify the resistance or resilience of MAFs, potentially making them more sensitive to impacts from anthropic activities (i.e. fisheries and coastal management), and vice versa, direct impacts may amplify climate change constraints in MAFs. Such changes will have knock-on effects on the energy budgets of active and passive suspension feeding organisms, as well as on their phenology, larval nutritional condition, and population viability. How the future seascape will be shaped by the new energy fluxes is a crucial question that has to be urgently addressed to mitigate and adapt to the diverse impacts on natural systems

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

The Impact of |Delta I|=5/2 Transitions in K-> pi pi Decays

We consider the impact of isospin violation on the analysis of K-> pi pi decays. We scrutinize, in particular, the phenomenological role played by the additional weak amplitude, of |Delta I|=5/2 in character, incurred by the presence of isospin violation. We show that Watson's theorem is appropriate in O(m_d-m_u), so that the inferred pi-pi phase shift at sqrt{s}=m_K determines the strong phase difference between the I=0 and I=2 amplitudes in K-> pi pi decay. We find the magnitude of the |Delta I|=5/2 amplitude thus implied by the empirical branching ratios to be larger than expected from estimates of isospin-violating strong and electromagnetic effects. We effect a new determination of the octet and 27-plet coupling constants with strong-interaction isospin violation and with electromagnetic effects, as computed by Cirigliano, Donoghue, and Golowich, and find that we are unable to resolve the difficulty. Exploring the role of |Delta I|=5/2 transitions in the CP-violating observable epsilon'/epsilon, we determine that the presence of a |Delta I|=5/2 amplitude impacts the empirical determination of omega, the ratio of the real parts of the |Delta I|=3/2 to |Delta I|=1/2 amplitudes, and that it generates a decrease in the estimation of epsilon'/epsilon.Comment: 29 pages, 1 ps fig, refs. added, to appear in Phys. Rev.

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