d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia

The N-methyl-D-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by D-amino acid oxidase. Both D-serine and its metabolizing enzymes are implicated in N-methyl-D-aspartate receptor hypofunction thought to occur in schizophrenia. We studied D-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. D-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, D-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or D-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and D-amino acid oxidase are expressed in human brain and provide some support for aberrant D-serine metabolism in schizophrenia. However, they raise further questions as to the roles of D-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain.     

Interrelationships Between Human Classical Differential Electrodermal Conditioning, Orienting Reaction, Responsivity, and Awareness of Stimulus Contingencies

The main purpose of studying the interrelationships listed in the title was to examine the orienting-reaction (OR) and cognitive (awareness) interpretations of differential electrodermal conditioning (DEC). The method was to perform correlational analyses on the data obtained from three DEC experiments (N = 32, 40, and 32, respectively) which together provided variations in such factors as the CS-US interval, and the sensitivity of the awareness measure of subjective contingency (SC). Following Zeiner and Schell (1971), the OR and responsivity measures were obtained, respectively, from preliminary CS+ trials (tone and light) to-be-paired with the US and from US (shock) trials. The results clearly disconfirmed the cognitive interpretation, since SC was not correlated either with DEC or with OR in any of the experiments. The OR interpretation received some support, but could handle the following aspects of the results only with difficulty: (a) some significant correlations of responsivity with DEC; (b) the fact that the apparently large OR-DEC correlations were reduced when statistical control (through partial correlations) was imposed for the influence of consistent individual differences in responding to the CS+ and CS- stimuli before any conditioning had taken place; (c) the fact that when these individual differences were not significantly present (in Exp. III), the OR-DEC correlation was also not significant. It was noted that the first aspect supported an S-R, contiguity-reinforcement account of DEC, an account which differs from the cognitive and OR interpretations inasmuch as it does not attempt to reduce DEC to some other process.     

Significance of NMDA receptor-related glutamatergic amino acid levels in peripheral blood of patients with schizophrenia

Hypo-function of N-methyl d-aspartate (NMDA) receptors is strongly involved in the brain pathophysiology of schizophrenia. Several excitatory amino acids, such as endogenous glutamate, glycine, serine and alanine, which are involved in glutamate neurotransmission via NMDA receptors, were studied to further understand the pathophysiology of schizophrenia and to find a biological marker for this disease, particularly in peripheral blood. In this literature review, we connect several earlier clinical studies and several studies of excitatory amino acid levels in peripheral blood in a historical context. Finally, we join these results and our previous studies, the Juntendo University Schizophrenia Projects (JUSP), which investigated plasma glutamatergic amino acid levels in detail, and considered whether these amino acid levels may be diagnostic, therapeutic, or symptomatic biological markers. This review concludes that peripheral blood levels of endogenous glycine and alanine could be a symptomatic marker in schizophrenia, while peripheral blood levels of exogenous glycine and alanine in augmentation therapies could be therapeutic markers. Noteworthy peripheral blood levels of endogenous d-serine could reflect its brain levels, and may prove to be a useful diagnostic and therapeutic marker in schizophrenia. In addition, measurements of new endogenous molecules, such as glutathione, are promising. Finally, for future therapies with glutamatergic agents still being examined in animal studies, the results of these biological marker studies may lay the foundation for the development of next-generation antipsychotics.     

Physiological and Subjective Reactions to Being Touched

The physiological and subjective effects of being touched on the wrist by another person were investigated in 20 normal adults at rest and during immersion of the hand in ice water. Touching reliably reduced heart rate compared to an immediately preceding baseline and compared to an alpha biofeedback condition. Heart rate during painful ice water stimulation was also lower when the subject was touched as compared to when he/she practiced alpha biofeedback, but this effect was not mediated by a reduction in the perceived painfulness of the ice water. Instead, touching and pain had independent, additive effects on heart rate. Touching did not produce generalized reductions in respiratory rate, SRR frequency, or frontalis EMG activity, although subjects did rate being touched as more pleasant and more relaxing than practicing alpha.     

Triple negative breast cancers comprise a highly tumorigenic cell subpopulation detectable by its high responsiveness to a Sox2 regulatory region 2 (SRR2) reporter

We have recently described a novel phenotypic dichotomy within estrogen receptor-positive breast cancer cells; the cell subset responsive to a Sox2 regulatory region (SRR2) reporter (RR cells) are significantly more tumorigenic than the reporter unresponsive (RU) cells. Here, we report that a similar phenomenon also exists in triple negative breast cancer (TNBC), with RR cells more tumorigenic than RU cells. First, examination of all 3 TNBC cell lines stably infected with the SRR2 reporter revealed the presence of a cell subset exhibiting reporter activity. Second, RU and RR cells purified by flow cytometry showed that RR cells expressed higher levels of CD44, generated more spheres in a limiting dilution mammosphere formation assay, and formed larger and more complex structures in Matrigel. Third, within the CD44^High/CD24⁻ tumor-initiating cell population derived from MDA-MB-231, RR cells were significantly more tumorigenic than RU cells in an in vivo SCID/Beige xenograft mouse model. Examination of 4 TNBC tumors from patients also revealed the presence of a RR cell subset, ranging from 1.1-3.8%. To conclude, we described a novel phenotypic heterogeneity within TNBC, and the SRR2 reporter responsiveness is a useful marker for identifying a highly tumorigenic cell subset within the CD44^High/CD24⁻tumor-initiating cell population.     

鞍钢炼焦工人的癌症流行病学研究

本文对三十年代开始生产的鞍钢焦化厂,进行了癌症回顾性队列研究。队列由4,197名男职工组成,以1971年-1981年的11年为观察期。在11年期间积累了42,995人年。与初轧厂比较,焦炉作业工人的肺癌SRR为6.21(P<0.01),其它工作区的肺癌无明显超出量。     

The evolutionary conserved <Emphasis Type="Italic">BER1</Emphasis> gene is involved in microtubule stability in yeast

In yeast, microtubules are dynamic filaments necessary for spindle and nucleus positioning, as well as for proper chromosome segregation. We identify a function for the yeast gene BER1 (Benomyl REsistant 1) in microtubule stability. BER1 belongs to an evolutionary conserved gene family whose founding member Sensitivity to Red light Reduced is involved in red-light perception and circadian rhythms in Arabidopsis. Here, we present data showing that the ber1Δ mutant is affected in microtubule stability, particularly in presence of microtubule-depolymerising drugs. The pattern of synthetic lethal interactions obtained with the ber1Δ mutant suggests that Ber1 may function in N-terminal protein acetylation. Our work thus suggests that microtubule stability might be regulated through this post-translational modification on yet-to-be determined proteins. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

碳素厂沥青作业工人癌症死亡十五年(1971-1985)回顾调查

对吉林碳素厂1990名从事沥青作业人员中恶性肿瘤死亡情况及该厂1590名不接触沥青工人死亡情况进行调查。沥青组发现肺癌死亡12例,对照组死亡5例,标化率比率(SRR)1.94。沥青组肺癌死亡与当地不接触沥青工厂比较,SRR为2.18。与当地居民比较肺癌标化死亡比(SMR)为2.70。认为使用沥青工种存在着肺癌死亡率增高趋势.     

Response Relationships in SRR Conditioning

Relationships among orienting responses (ORs), anticipatory responses (ARs), and both unconditioned responses. (UCRs) and the UCR-latency responses which occur on acquisition test trials were examined in an 8 sec CS/UCS skin resistance response (SRR) conditioning schedule, Response characteristics were scored objectively by means of a Linc-8 program based on the rate of change of amplitude, and included response frequency, amplitude, onset and peak latencies. Substantial interaction were observed between AR and UCR characteristics, Negative correlations were obtained between AR and UCR occurrences on reinforced trials, shown to be associated with a long peak latency of the AR. AR/UCR amplitude relationships were also negative, indicating that high amplitude ARs lend to occur with low amplitude UCRs. Results on reinforced trials, however, showed a positive relationship between AR/UCR-latency frequency.     

Requirement of NMDA receptor reactivation for consolidation and storage of nondeclarative taste memory revealed by inducible NR1 knockout

We employed an inducible, reversible and region-specific gene knockout technique to investigate the requirements for cortical NMDA receptors (NMDAR) during the various stages (acquisition, consolidation and storage, and retrieval) of nondeclarative, hippocampal-independent memory in mice using a conditioned taste aversion memory paradigm. Here we show that temporary knockout of the cortical NMDAR during either the learning or postlearning consolidation stage, but not during the retrieval stage, causes severe performance deficits in the 1-month taste memory retention tests. More importantly, we found that the consolidation and storage of the long-term nondeclarative taste memories requires cortical NMDAR reactivation. Thus, the dynamic engagement of the NMDAR during the postlearning stage leads us to postulate that NMDAR reactivation-mediated synaptic re-entry reinforcement is crucial for overcoming the destabilizing effects intrinsic to synaptic protein turnover and for achieving consolidation and storage of nondeclarative memories in the brain.