Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.

Real-time functional magnetic resonance imaging (rtfMRI) is a novel technique that has allowed subjects to achieve self-regulation of circumscribed brain regions. Despite its anticipated therapeutic benefits, there is no report on successful application of this technique in psychiatric populations. The objectives of the present study were to train schizophrenia patients to achieve volitional control of bilateral anterior insula cortex on multiple days, and to explore the effect of learned self-regulation on face emotion recognition (an extensively studied deficit in schizophrenia) and on brain network connectivity. Nine patients with schizophrenia were trained to regulate the hemodynamic response in bilateral anterior insula with contingent rtfMRI neurofeedback, through a 2-weeks training. At the end of the training stage, patients performed a face emotion recognition task to explore behavioral effects of learned self-regulation. A learning effect in self-regulation was found for bilateral anterior insula, which persisted through the training. Following successful self-regulation, patients recognized disgust faces more accurately and happy faces less accurately. Improvements in disgust recognition were correlated with levels of self-activation of right insula. RtfMRI training led to an increase in the number of the incoming and outgoing effective connections of the anterior insula. This study shows for the first time that patients with schizophrenia can learn volitional brain regulation by rtfMRI feedback training leading to changes in the perception of emotions and modulations of the brain network connectivity. These findings open the door for further studies of rtfMRI in severely ill psychiatric populations, and possible therapeutic applications.

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Acute toxicities of 34 naturally occurring monoterpenoids were evaluated against 3 important arthropod pest species; the larva of the western corn rootworm, Diabrotica virgifera virgifera LeConte; the adult of the twospotted spider mite. Tetranychus urticae Koch; and the adult house fly. Musca domestica L. Potential larvicidal or acaricidal activities of each monoterpenoid were determined by topical application, leaf-dip method, soil bioassay, and greenhouse pot tests. Phytotoxicity was also tested on a corn plant. Citronellic acid and thymol were the most topically toxic against the house fly, and citronellol and thujone were the most effective on the western corn rootworm. Most of the monoterpenoids were lethal to the twospotted spider mite at high concentrations; carvomenthenol and terpinen-4-ol were especially effective. A wide range of monoterpenoids showed some larvicidal activity against the western corn rootworm in the soil bioassay. Perillaldehyde, the most toxic (LC50 = 3 micrograms/g) in soil, was only 1/3 as toxic as carbofuran, a commercial soil insecticide (LC50 = 1 microgram/g). Selected monoterpenoids also effectively protected corn roots from attack by the western corn rootworm larvae under greenhouse conditions. alpha-Terpineol was the best monoterpenoid in the greenhouse pot test. The acute toxicity of monoterpenoids was low relative to conventional insecticides. Some monoterpenoids were phytotoxic to corn roots and leaves. l-Carvone was the most phytotoxic, whereas pulegone was the safest. The results with thymyl ethyl ether, one of the synthetic derivatives of thymol, showed a potential of derivatization to reduce monoterpenoid phytotoxicity.

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