Aggregate formation in Cu,Zn superoxide dismutase-related proteins

Aggregation of Cu,Zn superoxide dismutase (SOD1) protein is a pathologic hallmark of familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene, although the structural motifs within mutant SOD1 that are responsible for its aggregation are unknown. Copper chaperone for SOD1 (CCS) and extracellular Cu,Zn superoxide dismutase (SOD3) have some sequence identity with SOD1, particularly in the regions of metal binding, but play no significant role in mutant SOD1-induced disease. We hypothesized that it would be possible to form CCS- or SOD3-positive aggregates by making these molecules resemble mutant SOD1 via the introduction of point mutations in codons homologous to a disease causing G85R SOD1 mutation. Using an in vitro assay system, we found that expression of wild type human CCS or a modified intracellular wild type SOD3 does not result in significant aggregate formation. In contrast, expression of G168R CCS or G146R SOD3 produced aggregates as evidenced by the presence of high molecular weight protein complexes on Western gels or inclusion bodies on immunofluorescence. CCS- and SOD3-positive inclusions appear to be ubiquitinated and localized to aggresomes. These results suggest that proteins sharing structural similarities to mutant SOD1 are also at risk for aggregate formation.     

Enhancement of BACE1 Activity by p25/Cdk5-Mediated Phosphorylation in Alzheimer’s Disease

The activity of beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is elevated during aging and in sporadic Alzheimer’s disease (AD), but the underlying mechanisms of this change are not well understood. p25/Cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathogenesis of several neurodegenerative diseases, including AD. Here, we describe a potential mechanism by which BACE activity is increased in AD brains. First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity. Then, we demonstrate that the level of phospho-BACE1 is increased in the brains of AD patients and in mammalian cells and transgenic mice that overexpress p25. Furthermore, the fraction of p25 prepared from iodixanol gradient centrifugation was unexpectedly protected by protease digestion, suggesting that p25/Cdk5-mediated BACE1 phosphorylation may occur in the lumen. These results reveal a link between p25 and BACE1 in AD brains and suggest that upregulated Cdk5 activation by p25 accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation.     

The Chloroplast Genome of Elaeagnus macrophylla and trnH Duplication Event in Elaeagnaceae

Elaeagnaceae, which harbor nitrogen-fixing actinomycetes, is a plant family of the Rosales and sister to Rhamnaceae, Barbeyaceae and Dirachmaceae. The results of previous molecular studies have not strongly supported the families of Elaeagnaceae, Rhamnaceae, Barbeyaceae and Dirachmaceae. However, chloroplast genome studies provide valuable phylogenetic information; therefore, we determined the chloroplast genome of Elaeaganus macrophylla and compared it to that of Rosales such as IR junction and infA gene. The chloroplast genome of Elaeagnus macrophylla is 152,224 bp in length and the infA gene of E. macrophylla was psuedogenation. Phylogenetic analyses based on 79 genes in 30 species revealed that Elaeagnus was closely related to Morus. Comparison of the IR junction in six other rosids revealed that the trnH gene contained the LSC region, whereas E. macrophylla contained a trnH gene duplication in the IR region. Comparison of the LSC/IRb (J_LB) and the IRa/LSC (J_LA) regions of Elaeagnaceae (Elaeagnus and Shephedia) and Rhamnaceae (Rhamnus) showed that trnH gene duplication only occurred in the Elaeagnaceae. The complete chloroplast genome of Elaeagnus macrophylla provides unique characteristics in rosids. The infA gene has been lost or transferred to the nucleus in rosids, while E. macrophylla lost the infA gene. Evaluation of the chloroplast genome of Elaeagnus revealed trnH gene duplication for the first time in rosids. The availability of Elaeagnus cp genomes provides valuable information describing the relationship of Elaeagnaceae, Barbeyaceae and Dirachmaceae, IR junction that will be valuable to future systematics studies.     

Tree distribution pattern and fate of juveniles in a lowland tropical rain forest – implications for regeneration and maintenance of species diversity

Three analyses of species diversity in a lowland dipterocarp forest were conducted to examine whether the nature of forest community dynamics are determined by density-dependent recruitment and mortality of saplings with a data set obtained in a 50 ha plot in Pasoh Forest Reserve. The first analysis examined whether sapling density varied as a function of distance from the nearest conspecific adult. The second analysis assessed the relationship between the spatial distribution patterns of saplings and adult trees. A third analysis examined sapling recruitment and mortality based on data from 2 censuses, taken in 1985 and 1990. Four hundred forty-four species (each with more than 100 individuals) out of the total of 814 species recorded in the plot, were chosen for the analyses. Of these selected species, 56 species showed significant reduction in sapling densities close to the conspecific adults. Within this group, 11 species were in the emergent layer (29.0% of the total species in this layer), 17 were in the canopy layer (10.5%), 18 were in the understory layer (11.3%), and 10 were in treelet and shrub layer (11.8%). In contrast, the sapling densities of 53 species decreased with increasing distance from conspecific adults; 2 of these species were in the emergent layer (5.2% of the total species in this layer), 14 were in the canopy layer (8.6%), 21 were in the understory layer (13.2%), and 16 were in the treelet and shrub layer (18.8%). The saplings of 35 of the 444 total selected species were clumped, while adults were regularly or randomly distributed. Of the remaining species, in 183 species (41.2%), the distributions of both adults and saplings were clumped. Thus, these 2 analyses do not support the prediction that most of the species of lowland tropical forests fail to produce new adults in their vicinity and as a result of this, adult trees are more regularly distributed than their conspecific juveniles (Janzen 1970). In the third analysis, the recruitment of saplings of species in the emergent and canopy layers increased significantly and in proportion with mortality, suggesting that the dominant species suffer higher mortality than do less common species. This trend is not so apparent in the understory, and the treelet and shrub layers. The results imply that a dynamic equilibrium process, which prevents competitive exclusion and maintains space for minor species, may be active among the species in the upper layers (particularly the emergent layer); however, such a dynamic equilibrium condition is not due exclusively to the reduced recruitment of saplings near conspecific adults, and the dynamic equilibrium condition is not prevalent among the lower story species.     

Androgens and eye movements in women and men during a test of mental rotation ability

Eye movements were monitored in 16 women and 20 men during completion of a standard diagram-based test of mental rotation ability to provide measures of cognitive function not requiring conscious, decisional processes. Overall, women and men allocated visual attention during task performance in very similar, systematic ways. However, consistent with previous suggestions that sex differences in attentional processes during completion of the mental rotation task may exist, eye movements in men compared to women indicated greater discrimination and longer processing of correct alternatives during task performance. Other findings suggested that androgens may enhance cognitive processes that are recruited differentially by women and men as a function of the task. Specifically, smaller (i.e., more masculine) digit ratios were associated with men's shorter fixations on distracters, suggesting that perinatal androgen action may influence brain systems that facilitate the identification of relevant task stimuli. In women, higher circulating testosterone levels appeared to contribute to more general processes engaged during task performance, for example higher levels of visual persistence. It is possible that variability in the relative contribution of such hormone sensitive cognitive processes to accuracy scores as a function of different sample characteristics or assessment methods may partially account for the inconsistent findings of previous research on hormonal factors in mental rotation ability.     

Gender Differences in the Association of Smoking and Drinking with the Development of Cognitive Impairment

Modifiable lifestyle-related factors such as smoking and alcohol drinking are associated with cognitive impairment in the elderly population but the relationships have shown various results. To evaluate the relationship of alcohol drinking and smoking in the early 60 s with the risk of developing incident cognitive impairment. In 1999, we evaluated cognitive function, smoking, and drinking status in 3,174 inhabitants aged 60–64 years in a rural area of Korea, with a follow-up assessment of cognitive function 7 years later. A total of 1,810 individuals who did not show cognitive impairment at baseline were included. A stratified analysis was applied to evaluate how smoking and alcohol drinking affected the risk of developing cognitive impairment based on gender. Current smokers showed a higher risk for developing cognitive impairment than did never smokers (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.09–2.15). The OR for female current smokers compared with never smokers was 1.62 (95% CI, 1.05–2.52), and smokers with higher pack-years were more likely to develop cognitive impairment than never smokers, showing a dose–response relationship (P for trend = 0.004). Frequent alcohol consumption increased the risk of developing cognitive impairment (OR, 1.68; 95% CI, 1.01–2.78), and a dose–response relationship was observed among male subjects (P for trend = 0.044). Infrequent drinking in females decreased the odds of developing cognitive impairment (OR, 0.67; 95% CI, 0.42–1.00), whereas frequent drinking tended to increase the odds, although this trend was not significant, suggesting a U-shaped relationship. Although the sample was small for some analyses, especially in female, our data suggest that smoking and drinking in the early 60 s are associated with a risk of developing cognitive impairment, and this relationship is characterized by gender differences.     

ERK-mediated production of neurotrophic factors by astrocytes promotes neuronal stem cell differentiation by erythropoietin

Erythropoietin (EPO), a hematopoietic factor, is also required for normal brain development, and its receptor is localized in brain. Our previous study showed that EPO promotes differentiation of neuronal stem cells into astrocytes. Since astrocytes have influence on the neuronal function, we investigated whether EPO-activated astrocytes could stimulate differentiation of neuronal stem cells into neurons. EPO did not promote neuronal differentiation of neuronal stem cells isolated from 17 day embryos, however, neuronal differentiation was promoted when the neuronal stem cells were co-cultured with astrocyte isolated from post neonatal (Day 1) rat brain. Moreover, neuronal differentiation was further promoted when the neuronal stem cells were cultured with astrocyte culture medium treated by EPO (10U/ml) showing increase of morphological differentiation, and expression of neuronal differentiation marker proteins, neurofilament, and tyrosine hydroxylase. The promoting effect of EPO-treated astrocyte medium was also found in the differentiation of PC12 cells. EPO-promoted morphological differentiation of neuronal stem cells as well as astrocytes was dose dependently reduced by treatment with anti-EPO receptor antibodies in culture with astrocyte culture medium. To clarify whether EPO itself or via production of well-known neurotropic factor could promote neuronal cell differentiation, we determined the level of neurotropic factors in the EPO-treated astrocytes. Compared to untreated astrocytes, EPO-treated astrocytes increased about 2-fold in beta-NGF and 3-4-fold in BMP2, but did not increase BNDF and NT-3 levels. Since the previous study showed that extracellular signal-regulated kinase (ERK) is involved in activation of astrocytes by EPO, we determined whether generation of neurotrophic factor may also be involved with the ERK pathway. In the presence of ERK inhibitor, PD98059, the generation of beta-NGF was diminished in a dose dependent manner consistent with the inhibiting effect on neuronal differentiation. These data demonstrate that EPO promotes neuronal cell differentiation through increased release of beta-NGF and BMP2 from astrocytes, and this effect may be associated with ERK pathway signals.     

The impact of heat,cold, and heat waves on hospital admissions in eight cities in Korea

Although the impact of temperature on mortality is well documented, relatively fewer studies have evaluated the associations of temperature with morbidity outcomes such as hospital admissions, and most studies were conducted in North America or Europe. We evaluated weather and hospital admissions including specific causes (allergic disease, asthma, selected respiratory disease, and cardiovascular disease) in eight major cities in Korea from 2003 to 2008. We also explored potential effect modification by individual characteristics such as sex and age. We used hierarchical modeling to first estimate city-specific associations between heat, cold, or heat waves and hospitalizations, and then estimated overall effects. Stratified analyses were performed by cause of hospitalization, sex, and age (0–14, 15–64, 65–74, and ≥75 years). Cardiovascular hospitalizations were significantly associated with high temperature, whereas hospitalizations for allergic disease, asthma, and selected respiratory disease were significantly associated with low temperature. The overall heat effect for cardiovascular hospitalization was a 4.5 % (95 % confidence interval 0.7, 8.5 %) increase in risk comparing hospitalizations at 25 to 15 °C. For cold effect, the overall increase in risk of hospitalizations comparing 2 with 15 °C was 50.5 (13.7, 99.2 %), 43.6 (8.9, 89.5 %), and 53.6 % (9.8, 114.9 %) for allergic disease, asthma, and selected respiratory disease, respectively. We did not find statistically significant effects of heat waves compared with nonheat wave days. Our results suggest susceptible populations such as women and younger persons. Our findings provide suggestive evidence that both high and low ambient temperatures are associated with the risk of hospital admissions, particularly in women or younger person, in Korea.