A compact proton synchrotron with combined-function lattice dedicated for cancer therapy

A compact proton synchrotron with combined function lattice has been designed as a dedicated machine for cancer therapy because of its merits of easy operation and low construction cost. The lattice has a six-fold symmetry and its radius of curvature and circumference are 1.9 m and 23.9 m, respectively. For the purpose of establishing a good reference design, we have constructed a model magnet based on the three-dimensional magnetic field calculation. A magnetic field measurement has been performed with use of a three-dimensional Hall- probe. In the present paper, the results of these developments is presented together with the outline of the reference design. (3 refs)

Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism.

Background: Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that d-aspartate and d-serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out. Methods: Through HPLC and qPCR analyses we investigated d-aspartate and d-serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2-/-, Shank3-/-, and 16p11.2+/- mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations. Results: Biochemical and gene expression mapping in Cntnap2-/-, Shank3-/-, and 16p11.2+/- failed to find gross cerebral and serum alterations in d-aspartate and d-serine metabolism. Conversely, we found a striking and stereoselective increased d-aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of d-aspartate oxidase, encoding the enzyme responsible for d-aspartate catabolism. Conclusions: Our results demonstrated the presence of disrupted d-aspartate metabolism in a widely used animal model of idiopathic ASD. General significance: Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders

Prenatal expression of d-aspartate oxidase causes early cerebral d-aspartate depletion and influences brain morphology and cognitive functions at adulthood

The free d-amino acid, d-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its intracellular occurrence, d-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and mGlu5 receptors. These findings suggest that d-aspartate is a candidate signaling molecule involved in neural development, influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in which the enzyme regulating d-aspartate catabolism, d-aspartate oxidase (DDO), is expressed starting from the zygotic stage, to enable the removal of d-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of cerebral d-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of d-aspartate content, Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early d-aspartate depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time a biological significance of precocious d-aspartate in regulating mouse brain formation and function at adulthood

Cerebrospinal fluid and serum D-serine concentrations are unaltered across the whole clinical spectrum of Alzheimer's disease

The diagnosis of Alzheimer's disease (AD) relies on the presence of amyloidosis and tauopathy, as reflected in cerebrospinal fluid (CSF), independently from the clinical stage. Recently, CSF D-serine has been proposed as a possible new AD biomarker, reflecting dysfunctional activation of neuronal glutamatergic N-methyl-D-aspartate receptor (NMDAR). In this study, we measured blood serum and CSF concentration of two NMDAR modulators, such as D-serine and D-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum. In addition, we also analyzed D-serine levels in a cohort of post-mortem AD and control cortex samples. We reported unaltered serum and CSF concentrations of D-serine and D-aspartate in AD patients both during the AD progression and compared to non-demented controls. Accordingly, no correlation was detected between serum or CSF D-serine content and mini-mental state examination or Clinical Dementia Rating. Similarly, cortical D-serine levels were also unaltered in post-mortem samples of AD patients. Overall, our results failed to confirm previous findings indicating the CSF D-serine as a novel biomarker for AD

Prenatal expression of d‑aspartate oxidase causes early cerebral d‑aspartate depletion and influences brain morphology and cognitive functions at adulthood

The free d-amino acid, d-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its intracellular occurrence, d-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and mGlu5 receptors. These findings suggest that d-aspartate is a candidate signaling molecule involved in neural development, influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in which the enzyme regulating d-aspartate catabolism, d-aspartate oxidase (DDO), is expressed starting from the zygotic stage, to enable the removal of d-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of cerebral d-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of d-aspartate content, Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early d-aspartate depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time a biological significance of precocious d-aspartate in regulating mouse brain formation and function at adulthood