EDA-BASED ESTIMATION OF VISUAL ATTENTION BY OBSERVATION OF EYE BLINK FREQUENCY

This paper describes the relationship between visual attention and eye blink frequency. In an experiment, we prompted the activation of a subject's visual attention and examined the influence of visual attention (as measured using electrodermal activity (EDA), which is meaningfully correlated with visual attention) on the subject's eye blink frequency. Experimental results show that engagement of visual attention decreased eye blink frequency and that when visual attention was not activated, eye blink frequency increased. Knowledge of this relationship provides a technique using EDA to objectively determining a subject's visual attention status

Severity and Progression Rate of Cerebellar Ataxia in 16q-linked Autosomal Dominant Cerebellar Ataxia (16q-ADCA) in the Endemic Nagano Area of Japan

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5' untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 +/- 9.8 years, n = 66) than in SCA6 patients (41.1 +/- 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant.ArticleCEREBELLUM. 8(1):46-51 (2009)journal articl

Exome Sequencing Reveals a Homozygous SYT14 Mutation in Adult-Onset, Autosomal-Recessive Spinocerebellar Ataxia with Psychomotor Retardation

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a TaqMan assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders

Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan

Spinocerebellar ataxia type 31 (SCA31) is a recently defined subtype of autosomal dominant cerebellar ataxia (ADCA) characterized by adult-onset, pure cerebellar ataxia. The C/T substitution in the 5′-untranslated region of the puratrophin-1 gene (PLEKHG4) or a disease-specific haplotype within the 900-kb SCA31 critical region just upstream of PLEKHG4 has been used for the diagnosis of SCA31. Very recently, a disease-specific insertion containing penta-nucleotide (TGGAA)n repeats has been found in this critical region in SCA31 patients. SCA31 was highly prevalent in Nagano, Japan, where SCA31 accounts for approximately 42% of ADCA families. We screened the insertion in 94 SCA31 patients from 71 families in Nagano. All patients had a 2.6- to 3.7-kb insertion. The size of the insertion was inversely correlated with the age at onset but not associated with the progression rate after onset. (TAGAA)n repeats at the 5′-end of the insertion were variable in number, ranging from 0 (without TAGAA sequence) to 4. The number of (TAGAA)n repeats was inversely correlated to the total size of the insertion. The number of (TAGAA)n repeats was comparatively uniform within patients from the three endemic foci in Nagano. Only one patient, heterozygous for the C/T substitution in PLEKHG4, had the insertions in both alleles; they were approximately 3.0 and 4.3 kb in size. Sequencing and Southern hybridization using biotin-labeled (TGGAA)5 probe strongly indicated that the 3.0-kb insertion, but not the 4.3-kb insertion, contained (TGGAA)n stretch. We also found that 3 of 405 control individuals (0.7%) had the insertions from 1.0 to 3.5 kb in length. They were negative for the C/T substitution in PLEKHG4, and neither of the insertions contained (TGGAA)n stretch at their 5′-end by sequencing. The insertions in normal controls were clearly detected by Southern hybridization using (TAAAA)5 probe, while they were not labeled with (TGGAA)5 or (TAGAA)5 probe. These data indicate that control alleles very rarely have a nonpathogenic large insertion in the SCA31 critical region and that not only the presence of the insertion but also its size is not sufficient evidence for a disease-causing allele. We approve of the view that (TGGAA)n repeats in the insertion are indeed related to the pathogenesis of SCA31, but it remains undetermined whether a large insertion lacking (TGGAA)n is nonpathogenic

New host records of three Kudoa spp. (K-yasunagai, K-thalassomi, and K-igami) with notable variation in the number of shell valves and polar capsules in spores

To date, 26 Kudoa spp. (Myxozoa: Myxosporea: Multivalvulida) have been recorded in edible marine fishes in Japan. In the future, it is likely that even more marine fish multivalvulid myxosporeans will be characterized morphologically and genetically, which will aid the precise understanding of their biodiversity and biology. We examined 60 individuals of six fish species collected from the Philippine Sea off Kochi or from the border between the Philippine Sea and East China Sea around Miyako Island, Okinawa, i.e., the southern part of Japan. Newly collected parasite species included Kudoa yasunagai from the brain of Japanese meagre (Argyrosomus japonicus) and Japanese parrotfish (Calotomus japonicus), Kudoa miyakoensis n. sp. and Kudoa thalassomi from the brain and trunk muscle, respectively, of bluespine unicornfish (Naso unicornis), and Kudoa igami from the trunk muscle of Carolines parrotfish (Calotomus carolinus), African coris (Coris gaimard), and Pastel ringwrasse (Hologymnosus doliatus). With the exception of Japanese parrotfish for K. yasunagai, all these fish are new host records for each kudoid species. Notable variation in the number of shell valves (SV) and polar capsules (PC) was observed for all four kudoid species. In particular, spores with seven or eight SV/PC were prominent in K. igami isolates, despite the original Japanese parrotfish-derived description characterizing it as having spores with six, or less commonly five, SV/PC. However, molecular genetic characterization based on the ribosomal RNA gene (rDNA) and mitochondrial DNA (cytochrome c oxidase subunit 1 and ribosomal RNA small and large subunits) found no significant differences in the nucleotide sequences of isolates with different phenotypical features as far as examined in the present study. A newly erected species, K. miyakoensis n. sp., was determined to be phylogenetically closest to brain-parasitizing species, such as K. chaetodoni, K. lemniscati, and K. yasunagai based on rDNA nucleotide sequences, but differed from them morphologically.</p

Integration of bioassay and non-target metabolite analysis of tomato reveals that β-carotene and lycopene activate the adiponectin signaling pathway, including AMPK phosphorylation.

Adiponectin, an adipokine, regulates glucose metabolism and insulin sensitivity through the adiponectin receptor (AdipoR). In this study, we searched for metabolites that activate the adiponectin signaling pathway from tomato (Solanum lycopersicu). Metabolites of mature tomato were separated into 55 fractions by liquid chromatography, and then each fraction was examined using the phosphorylation assay of AMP-protein kinase (AMPK) in C2C12 myotubes and in AdipoR-knockdown cells by small interfering RNA (siRNA). Several fractions showed AMPK phosphorylation in C2C12 myotubes and siRNA-mediated abrogation of the effect. Non-targeted metabolite analysis revealed the presence of 721 diverse metabolites in tomato. By integrating the activity of fractions on AMPK phosphorylation and the 721 metabolites based on their retention times of liquid chromatography, we performed a comprehensive screen for metabolites that possess adiponectin-like activity. As the screening suggested that the active fractions contained four carotenoids, we further analyzed β-carotene and lycopene, the major carotenoids of food. They induced AMPK phosphorylation via the AdipoR, Ca2+/calmodulin-dependent protein kinase kinase and Ca2+ influx, in addition to activating glucose uptake via AdipoR in C2C12 myotubes. All these events were characteristic adiponectin actions. These results indicated that the food-derived carotenoids, β-carotene and lycopene, activate the adiponectin signaling pathway, including AMPK phosphorylation

The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

Multiple myeloma (MM) is characterized by remarkable cytogenetic/molecular heterogeneity among patients and intraclonal diversity even in a single patient. We previously demonstrated that PDPK1, the master kinase of series of AGC kinases, is universally active in MM, and plays pivotal roles in cell proliferation and cell survival of myeloma cells regardless of the profiles of cytogenetic and genetic abnormalities. This study investigated the therapeutic efficacy and mechanism of action of dual blockade of two major PDPK1 substrates, RSK2 and AKT, in MM. The combinatory treatment of BI-D1870, an inhibitor for N-terminal kinase domain (NTKD) of RSK2, and ipatasertib, an inhibitor for AKT, showed the additive to synergistic anti-tumor effect on human MM-derived cell lines (HMCLs) with active RSK2-NTKD and AKT, by enhancing apoptotic induction with BIM and BID activation. Moreover, the dual blockade of RSK2 and AKT exerted robust molecular effects on critical gene sets associated with myeloma pathophysiologies, such as those with MYC, mTOR, STK33, ribosomal biogenesis, or cell-extrinsic stimuli of soluble factors, in HMCLs. These results provide the biological and molecular rationales for the dual-targeting strategy for RSK2 and AKT, which may overcome the therapeutic difficulty due to cytogenetic/molecular heterogeneity in MM

LC-MS analysis data of Hexane III—HPLC fraction.

<p>LC-MS analysis data of Hexane III—HPLC fraction.</p