Satoru Yokoyama

Training of working memory impacts structural connectivity.

Working memory is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. Individual capacity of working memory is associated with the integrity of white matter in the frontoparietal regions. It is unknown to what extent the integrity of white matter underlying the working memory system is plastic. Using voxel-based analysis (VBA) of fractional anisotropy (FA) measures of fiber tracts, we investigated the effect of working memory training on structural connectivity in an interventional study. The amount of working memory training correlated with increased FA in the white matter regions adjacent to the intraparietal sulcus and the anterior part of the body of the corpus callosum after training. These results showed training-induced plasticity in regions that are thought to be critical in working memory. As changes in myelination lead to FA changes in diffusion tensor imaging, a possible mechanism for the observed FA change is increased myelination after training. Observed structural changes may underlie previously reported improvement of working memory capacity, improvement of other cognitive functions, and altered functional activity following working memory training.

Cortical Mechanisms Involved in the Processing of Verbs: An fMRI Study

In this study, we investigated two aspects of verb processing: first, whether verbs are processed differently from nouns; and second, how verbal morphology is processed. For this purpose, we used functional magnetic resonance imaging to compare three types of lexical processing in Japanese: the processing of nouns, unmarked active verbs, and inflected passive verbs. Twenty-eight healthy subjects were shown a lexical item and asked to judge whether the presented item was a legal word. Although all three conditions activated the bilateral inferior frontal, occipital, the left middle, and inferior temporal cortices, we found differences in the degree of activation for each condition. Verbs elicited greater activation in the left middle temporal gyrus than nouns, and inflected verbs showed greater activation in the left inferior frontal gyrus than unmarked verbs. This study demonstrates that although verbs are basically processed in the same cortical network as nouns, nouns and verbs elicit different degrees of activation due to the cognitive demands involved in lexical semantic processing. Furthermore, this study also shows that the left inferior frontal cortex is related to the processing of verbal inflectional morphology.

Cortical activation in the processing of passive sentences in L1 and L2: An fMRI study

The question of whether the bilingual brain processes a first and second language (L1 and L2, respectively) differently is a central issue in many psycholinguistic and neurolinguistic studies. This study used functional magnetic resonance imaging (fMRI) to investigate whether late bilinguals process structurally complex sentences in L1 and L2 in different cortical networks. For this purpose, we directly compared brain activity during the processing of active and passive sentences in both L1 and L2. We asked 36 healthy subjects to judge whether or not a presented sentence was semantically plausible. Both L1 and L2 activated the left hemispheric language-related regions such as the left inferior frontal, superior/middle temporal, and parietal cortices. However, we found different activation patterns between L1 and L2 in the processing of passive sentences. Passive sentences elicited greater activation than their active counterparts in the left pars triangularis, the premotor area, and the superior parietal lobule in Japanese, but not in English. Furthermore, there was a significant interaction between sentence type (active versus passive) and language (Japanese versus English) in the left pars orbitalis. The results of this study indicate that late bilinguals use similar cortical regions to comprehend both L1 and L2. However, when late bilinguals are presented with structurally complex sentences, the involvement of these regions differs between L1 and L2. These results suggest that, in addition to age of L2 acquisition and L2 proficiency, differences in grammatical construction affect cortical representation during the comprehension of L1 and L2.

OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium

Otx2 is a member of homeodomain-containing transcription factors and is essential for eye morphogenesis in mice. Here we show the expression of OTX2, the human counterpart of Otx2, in cell lines of retinal pigment epithelium (RPE) and in Y79 retinoblastoma cells that exhibit the property of presumptive RPE. These RPE cells express DOPAchrome tautomerase (DCT) that is an enzyme involved in melanin biosynthesis. DCT may contribute to the homeostasis of RPE by detoxifying DOPA-derived metabolites. OTX2 binds to the DCT gene promoter in vivo, as judged by chromatin immunoprecipitation assays. Furthermore, repression of endogenous OTX2 expression in Y79 cells by an anti-sense OTX2 oligonucleotide resulted in the decrease of DCT protein contents. Transient expression assays revealed that OTX2 activated the DCT gene promoter through the OTX-2-binding site in an RPE-specific manner. Therefore, OTX2 may regulate RPE-specific target genes, such as DCT, thereby maintaining the homeostasis of RPE.

Cross-linguistic influence on brain activation during second language processing: An fMRI study

The goal of this study was to examine the effect of the linguistic distance between a first language (L1) and a second language (L2) on neural activity during second language relative to first language processing. We compared different L1–L2 pairs in which different linguistic features characterize linguistic distance. Chinese and Korean native speakers were instructed to perform sentence comprehension tasks in two L2s (English and Japanese) and their respective L1s. Activation while understanding English sentences relative to understanding sentences in L1 was greater for the Korean group than the Chinese group in the left inferior frontal gyrus, bilateral posterior superior temporal gyri, and right cerebellum. Activation while understanding Japanese sentences relative to understanding sentences in L1 was greater for the Chinese group than the Korean group in the anterior portion of the left superior temporal gyrus. The results demonstrated that the location of the L2–L1 processing-induced cortical activation varies between different L1–L2 pairs.

siRNA-mediated knockdown against CDCA1 and KNTC2, both frequently overexpressed in colorectal and gastric cancers, suppresses cell proliferation and induces apoptosis

Ndc80 has been shown to play an important role in stable microtubule-kinetochore attachment, chromosome alignment, and spindle checkpoint activation in mitosis. It is composed of two heterodimers, CDCA1-KNTC2 and SPC24-SPC25. Overexpression of CDCA1 and KNTC2 is reported to be associated with poor prognosis in non-small cell lung cancers (NSCLC), and siRNA-mediated knockdown against CDCA1 or KNTC2 has been found to inhibit cell proliferation and induction of apoptosis in NSCLC, ovarian cancer, cervical cancer and glioma. Therefore, CDCA1 and KNTC2 can be considered good candidates for molecular target therapy as well as diagnosis in some cancers. However, the role of the Ndc80 complex in colorectal and gastric cancers (CRC and GC) still remains unclear. In the present study, we used qRT-PCR to evaluate the expression levels of CDCA1, KNTC2, SPC24 and SPC25 in CRC and GC and employed siRNA-mediated knockdown to examine cell proliferation and apoptosis. mRNA overexpression of these four genes was observed in CRCs and GCs when compared with the corresponding normal mucosae. Additionally, the expression levels of tumor/normal ratios of CDCA1, KNTC2, SPC24 and SPC25 correlated with each other in CRCs. MTT assays revealed that cell growths after the siRNA-mediated knockdown of either CDCA1 or KNTC2 were significantly suppressed, and flow cytometry analyses revealed significant increases of the subG1 fractions after knockdown against both genes. Our present results suggest that expressional control of component molecules of Ndc80 can be utilized for molecular target therapy of patients with CRC and GC.

Is Broca's area involved in the processing of passive sentences? An event-related fMRI study.

We used functional magnetic resonance imaging (fMRI) to investigate whether activation in Brocas area is greater during the processing of passive versus active sentences in the brains of healthy subjects. Twenty Japanese native speakers performed a visual sentence comprehension task in which they were asked to read a visually presented sentence and to identify the agent or the patient in the sentence by pressing a button. We found that the processing of passive sentences elicited no greater activation than that of active sentences in Brocas area. However, passive sentences elicited greater activation than active sentences in the left frontal operculum and the inferior parietal lobule. Thus, our neuroimaging results suggest that deficits in the comprehension of passive sentences in Japanese aphasics are induced not by lesions to Brocas area, but to the left frontal operculum and/or the inferior parietal lobule.

The Expression of S100A4 in Human Pancreatic Cancer Is Associated With Invasion

Objectives Pancreatic cancer is one of the most lethal malignancies; its poor prognosis is strongly associated with invasion and metastasis. Expression of S100A4 has been reported to correlate with poor prognosis in various cancers. We have investigated the role of S100A4 in pancreatic cancer tumorigenesis and its clinicopathologic significance. Methods Protein expression of S100A4 was examined by Western blot in pancreatic cancer cell lines and a human pancreatic ductal epithelium cell line, HPDE-6. Then the expressions of S100A4, TP53, and CD133 were examined immunohistochemically in resected specimens from 83 patients with pancreatic cancer to clarify their clinicopathologic significance. Survival analyses were performed using the Kaplan-Meier method and the Mantel-Cox method. Results Forty-eight (58%) of 83 patients with pancreatic cancer positively expressed S100A4, and 50 (60%) and 29 (36%) patients positively expressed TP53 and CD133, respectively. S100A4 expression was significantly correlated with perineural invasion (P = 0.029) and invasion pattern (P = 0.001). Neither TP53 nor CD133 expression showed significant correlations with any other parameters. Conclusions Our present results suggest that S100A4 plays an important role in the invasiveness, particularly with perineural invasion and invasion pattern, of pancreatic cancer. Development of new strategies targeting S100A4 or its downstream effectors is warranted.

A Prolyl-hydroxylase Inhibitor, Ethyl-3,4-dihydroxybenzoate, Induces Haem Oxygenase-1 Expression in Human Cells Through a Mechanism Independent of Hypoxia-inducible Factor-1α

Hypoxia-inducible factor (HIF)-1 is important for cellular homeostasis under hypoxia. Expression of haem oxygenase-1 (HO-1), an essential enzyme in haem catabolism, varies under hypoxia, depending on cell types. Here, we studied the role of HIF-1alpha, a component of HIF-1, in the regulation of HO-1 expression using three human cell lines: HeLa cervical cancer, and ARPE-19 and D407 retinal pigment epithelial cells. Under hypoxia (1% O(2)), the expression of HO-1 mRNA was decreased in HeLa cells, increased in D407 cells, and unchanged in ARPE-19 cells, while HIF-1alpha protein was accumulated in these cell lines. Thus, HIF-1alpha is unlikely to function as a key regulator for HO-1 expression under hypoxia. We then used ethyl-3,4-dihydroxybenzoate (EDHB), an inhibitor of prolyl hydroxylases, to accumulate HIF-1alpha protein under normoxia. Treatment with EDHB (250-500 microM) increased HIF-1alpha protein levels in HeLa and D407 cells, but not in ARPE-19 cells, whereas EDHB at lower concentrations (50-100 microM) consistently induced HO-1 mRNA expression (about 20-fold) in these three cell lines. Moreover, EDHB increased the HO-1 gene promoter activity via the enhancer that lacks a HIF-1-binding site. In conclusion, the signals evoked by hypoxia and after EDHB treatment differentially regulate HO-1 mRNA expression through HIF-1alpha-independent mechanisms.

Induction of lipocalin-type prostaglandin D synthase in mouse heart under hypoxemia

Hypoxemia is a common manifestation of various disorders and generates pressure overload to the heart. Here we analyzed the expression of lipocalin-type prostaglandin D synthase (L-PGDS) in the heart of C57BL/6 mice kept under normobaric hypoxia (10% O2) that generates hemodynamic stress. Northern and Western blot analyses revealed that the expression levels of L-PGDS mRNA and protein were significantly increased (> twofold) after 14 days of hypoxia, compared to the mice kept under normoxia. Immunohistochemical analysis indicated that L-PGDS was increased in the myocardium of auricles and ventricles and the pulmonary venous myocardium at 28 days of hypoxia. Moreover, using C57BL/6 mice lacking heme oxygenase-2 (HO-2(-/-)), a model of chronic hypoxemia, we showed that the expression level of L-PGDS protein was twofold higher in the heart than that of wild-type mouse. L-PGDS expression is induced in the myocardium under hypoxemia, which may reflect the adaptation to the hemodynamic stress.