Spatio-Temporal Updating in the Left Posterior Parietal Cortex

Adopting an unusual posture can sometimes give rise to paradoxical experiences. For example, the subjective ordering of successive unseen tactile stimuli delivered to the two arms can be affected when people cross them. A growing body of evidence now highlights the role played by the parietal cortex in spatio-temporal information processing when sensory stimuli are delivered to the body or when actions are executed; however, little is known about the neural basis of such paradoxical feelings resulting from such unusual limb positions. Here, we demonstrate increased fMRI activation in the left posterior parietal cortex when human participants adopted a crossed hands posture with their eyes closed. Furthermore, by assessing tactile temporal order judgments (TOJs) in the same individuals, we observed a positive association between activity in this area and the degree of reversal in TOJs resulting from crossing arms. The strongest positive association was observed in the left intraparietal sulcus. This result implies that the left posterior parietal cortex may be critically involved in monitoring limb position and in spatio-temporal binding when serial events are delivered to the limbs

Lactams. VI. Synthesis and Nuclear Magnetic Resonance Study of 1-Aralkyl-3-methyl- and -5-methyl-2(1H)-pyridones

The alkaline ferricyanide oxidation of the quaternary pyridinium salts (Ia-g) furnished pairs of the isomeric 2-pyridones (IIa-g) and 6-pyridones (IIIa-g) in good total yields. In all cases, the oxidation at the 2-position was much favored over that at the 6-position. The effect of the aryl group in the N-aralkyl chain on the orientation of the oxidation seemed to be negligibly small regardless of the number of the methylene groups separating the aryl group from the nitrogen. The extent of the 6-oxidation was slightly increased as the alkyl group at the 3-position was changed from the methyl to the ethyl group. The nuclear magnetic resonance spectra of these pyridones were measured in deuteriochloroform, carbon tetrachloride, and benzene-d_6. On the basis of the results summarized in Tables III-VI, the effects of the aryl group and the number of the methylene groups in the N-substituent on the chemical shifts for the pyridone-ring and neighboring group protons are discussed

Arachidonic Acid Drives Postnatal Neurogenesis and Elicits a Beneficial Effect on Prepulse Inhibition, a Biological Trait of Psychiatric Illnesses

Prepulse inhibition (PPI) is a compelling endophenotype (biological markers) for mental disorders including schizophrenia. In a previous study, we identified Fabp7, a fatty acid binding protein 7 as one of the genes controlling PPI in mice and showed that this gene was associated with schizophrenia. We also demonstrated that disrupting Fabp7 dampened hippocampal neurogenesis. In this study, we examined a link between neurogenesis and PPI using different animal models and exploring the possibility of postnatal manipulation of neurogenesis affecting PPI, since gene-deficient mice show biological disturbances from prenatal stages. In parallel, we tested the potential for dietary polyunsaturated fatty acids (PUFAs), arachidonic acid (ARA) and/or docosahexaenoic acid (DHA), to promote neurogenesis and improve PPI. PUFAs are ligands for Fabp members and are abundantly expressed in neural stem/progenitor cells in the hippocampus. Our results are: (1) an independent model animal, Pax6 (+/−) rats, exhibited PPI deficits along with impaired postnatal neurogenesis; (2) methylazoxymethanol acetate (an anti-proliferative drug) elicited decreased neurogenesis even in postnatal period, and PPI defects in young adult rats (10 weeks) when the drug was given at the juvenile stage (4–5 weeks); (3) administering ARA for 4 weeks after birth promoted neurogenesis in wild type rats; (4) raising Pax6 (+/−) pups on an ARA-containing diet enhanced neurogenesis and partially improved PPI in adult animals. These results suggest the potential benefit of ARA in ameliorating PPI deficits relevant to psychiatric disorders and suggest that the effect may be correlated with augmented postnatal neurogenesis

Quinolizidines. I. : Quaternization of the Quinolizidine System : Effect of β, γ-Unsaturation on Stereoselectivity in Methiodide Formation

Quaternization of benzo [a] quinolizidine (Ib) with methyl iodide gave a 3.6 : 1 mixture of the cis- (IIb : X=I) and the trans-methiodide (IIIb : X=I). The 9,10-dimethoxy derivative (Ia) also gave the corresponding cis- (IIa : X=I) and trans-methiodide (IIIa : X=I) in a ratio of 3.3 to 1. Treatment of enamines Va, b with methyl iodide furnished the N-methylated product (VIa, b) and the C-methylated product (VIIa, b) in a ratio of 1.2 : 1. Catalytic hydrogenation of VIa, b produced a mixture of the cis- (IIa, b) and the trans-methosalt (IIIa, b) in a rough ratio of 2.8 : 1,whereas that of VIIa, b gave the 1-methylated benzo [a] quinolizidine (VIIIa, b). Compound VIIIa was alternatively prepared from piperidone IX by the Bischler-Napieralski cyclization and subsequent hydrogenation. In the case of the simple quinolizidine system with the simplest β, γ-unsaturation (XV), the quaternization with methyl iodide produced the cis- (XVI) and the trans-methiodide (XVII) almost equally. Repetition of the known methiodide formation of XXVI and hydrogenation of enamine methiodide XIX confirmed their reported high stereoselectivity, and factors responsible for the difference in stereoselectivity between these reactions of the β, γ-unsaturated system and the saturated system have been discussed. At 250° the cis-methiodides (IIa, b, XX) isomerized to the corresponding trans-fused salts (IIIa, b, XXI) to some extent and one may roughly compare the susceptibilities of IIa, IIb, and XX, which decrease in that order

Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Funding Information: We thank Dr. David James, Dr. Frederick Lang, Dr. Cameron Brennan, and Dr. Harley Kornblum for GBM-PDX neurospheres. We thank Dr. Karen Arden for continuous support and critical evaluation of the results. We thank Dr. Robert Davis, Dr. German Gomez, Dr. Tiffany Taylor, Dr. Rachel Reed, Dr. Melissa Mcalonis, and Dr. Sora Lee for technical support. In memory of Rosa Lupo. This work was supported by the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F. and P.S.M.), R01-NS080939 (F.B.F.), the James S. McDonnell Foundation (F.B.F.), the National Cancer Institute (2T32CA009523-29A1) (A.H.T), and 1RO1NS097649-01 (C.C.C.). C.Z. was partially supported by an American-Italian Cancer Foundation post-doctoral research fellowship. F.L. received a Gao Feng Gao Yuan Scholarship Award. T.C.G., A.K.S., P.S.M., W.K.C., and F.B.F. receive salary and additional support from the Ludwig Institute for Cancer Research. Publisher Copyright: © 2017 Zanca et al.In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.publishersversionPeer reviewe

A Single Amino Acid Mutation in SNAP-25 Induces Anxiety-Related Behavior in Mouse

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic protein essential for neurotransmitter release. Previously, we demonstrate that protein kinase C (PKC) phosphorylates Ser187 of SNAP-25, and enhances neurotransmitter release by recruiting secretory vesicles near to the plasma membrane. As PKC is abundant in the brain and SNAP-25 is essential for synaptic transmission, SNAP-25 phosphorylation is likely to play a crucial role in the central nervous system. We therefore generated a mutant mouse, substituting Ser187 of SNAP-25 with Ala using “knock-in” technology. The most striking effect of the mutation was observed in their behavior. The homozygous mutant mice froze readily in response to environmental change, and showed strong anxiety-related behavior in general activity and light and dark preference tests. In addition, the mutant mice sometimes exhibited spontaneously occurring convulsive seizures. Microdialysis measurements revealed that serotonin and dopamine release were markedly reduced in amygdala. These results clearly indicate that PKC-dependent SNAP-25 phosphorylation plays a critical role in the regulation of emotional behavior as well as the suppression of epileptic seizures, and the lack of enhancement of monoamine release is one of the possible mechanisms underlying these defects

Evaluation of Pax6 Mutant Rat as a Model for Autism

Autism is a highly variable brain developmental disorder and has a strong genetic basis. Pax6 is a pivotal player in brain development and maintenance. It is expressed in embryonic and adult neural stem cells, in astrocytes in the entire central nervous system, and in neurons in the olfactory bulb, amygdala, thalamus, and cerebellum, functioning in highly context-dependent manners. We have recently reported that Pax6 heterozygous mutant (rSey2/+) rats with a spontaneous mutation in the Pax6 gene, show impaired prepulse inhibition (PPI). In the present study, we further examined behaviors of rSey2/+ rats and revealed that they exhibited abnormality in social interaction (more aggression and withdrawal) in addition to impairment in rearing activity and in fear-conditioned memory. Ultrasonic vocalization (USV) in rSey2+ rat pups was normal in male but abnormal in female. Moreover, treatment with clozapine successfully recovered the defects in sensorimotor gating function, but not in fear-conditioned memory. Taken together with our prior human genetic data and results in other literatures, rSey2/+ rats likely have some phenotypic components of autism

Sound to Language: Different Cortical Processing for First and Second Languages in Elementary School Children as Revealed by a Large-Scale Study Using fNIRS

A large-scale study of 484 elementary school children (6–10 years) performing word repetition tasks in their native language (L1-Japanese) and a second language (L2-English) was conducted using functional near-infrared spectroscopy. Three factors presumably associated with cortical activation, language (L1/L2), word frequency (high/low), and hemisphere (left/right), were investigated. L1 words elicited significantly greater brain activation than L2 words, regardless of semantic knowledge, particularly in the superior/middle temporal and inferior parietal regions (angular/supramarginal gyri). The greater L1-elicited activation in these regions suggests that they are phonological loci, reflecting processes tuned to the phonology of the native language, while phonologically unfamiliar L2 words were processed like nonword auditory stimuli. The activation was bilateral in the auditory and superior/middle temporal regions. Hemispheric asymmetry was observed in the inferior frontal region (right dominant), and in the inferior parietal region with interactions: low-frequency words elicited more right-hemispheric activation (particularly in the supramarginal gyrus), while high-frequency words elicited more left-hemispheric activation (particularly in the angular gyrus). The present results reveal the strong involvement of a bilateral language network in children’s brains depending more on right-hemispheric processing while acquiring unfamiliar/low-frequency words. A right-to-left shift in laterality should occur in the inferior parietal region, as lexical knowledge increases irrespective of language