Replication of genomewide association studies on age at menarche in the Korean population

Early menarche is associated with adverse health outcomes, including breast cancer, endometrial cancer, obesity, type 2 diabetes, and cardiovascular disease. Recently, a genomewide association study (GWAS) of age at menarche (AAM) in 104,533 individuals of European ancestry was reported by the ReproGen consortium. They identified 42 loci known and novel loci that were linked to age at menarche. Because age at menarche varies between ethnic groups, we decided to investigate if these results would be replicated in the Korean population. To this end, we examined the association of the SNPs reported in the ReproGen GWAS with AAM in 3,194 individuals from the Korean Genome and Epidemiology Study (KoGES) cohort. Genotype data for total 17 SNPs (6 genotyped SNPs and 11 imputed SNPs) were available for the association analysis using linear regression analysis for age at menarche with controlling current age, waist-to-hip ratio, and body mass index as the covariates. We found replication of the ReproGen study in two SNPs; one SNP (rs466639) in the retinoic acid receptor gamma gene (RXRG), showing a significant association with early menarche (beta = ?0.224 ± 0.065, p value = 5.2 × 10^?4, Bonferroni-corrected p value = 0.009), and the other (rs10899489), in GRB2 (growth factor receptor bound protein 2)-associated binding protein 2 (GAB2), linked to late menarche (beta = 0.140 ± 0.047, p value = 2.8 × 10^?3, Bonferroni-corrected p value = 0.049). This result possibly suggests that genetic factors governing AAM in the Korean population would be distinct from those in the Europeans, implying roles of modulating or interacting factors in determining AAM, including environmental factors such as nutritional status.     

Dynamic Modeling and Experiment of a Fish Robot with a Flexible Tail Fin

This paper presents the dynamic modeling of a flexible tail for a robotic fish. For this purpose firstly, the flexible tail was simplified as a slewing beam actuated by a driving moment. The governing equation of the flexible tail was derived by using the Euler-Bernoulli theory. In this equation, the resistive forces were estimated as a term analogous to viscous damping. Then, the modal analysis method was applied in order to derive an analytical solution of the governing equation, by which the relationship between the driving moment and the lateral movement of the flexible tail was described. Finally, simulations and experiments were carried out and the results were compared to verify the accuracy of the dynamic model. It was proved that the dynamic model of a fish robot with a flexible tail fin well explains the real behavior of robotic fish in underwater environment.     

Testing of divergent patterns of butterfly niche breadth in a peninsula

The butterfly fauna on the Korean peninsula are comprised of both the Palearctic and Oriental species. We hypothesized that the Oriental species (immigrated across the sea) tend to have a wider niche breadth compared with the Palearctic species (immigrated from the continent) since the former migrates long distances across the sea and has to adapt to new environments. We tested this hypothesis using Korean butterfly data on distribution, habitat, food and life history traits. The distribution and ecological traits such as habitat breadth, overwintering stage, and voltinism of the Oriental species were found to be significantly different from the Palearctic species. However, the diet breadth and food plant type were not different. These results partly confirm the peninsula niche breadth hypothesis, which predicted that Oriental species have a broader niche breadth than Palearctic species.     

Overexpression of Arabidopsis ABF3 gene confers enhanced tolerance to drought and heat stress in creeping bentgrass

The Arabidopsis, abscisic acid responsive element-binding factor 3, ABF3 is known to play an important role in stress responses via regulating the expression of stress-responsive genes. In this study, we introduced pCAMBIA3301 vector harboring the ABF3 gene into creeping bentgrass (Agrostis stolonifera) through Agrobacterium-mediated transformation in order to develop a stress-tolerant variety of turfgrass. After transformation, putative transgenic plants were selected using the herbicide resistance assay. Genomic integration of the transgene was confirmed by genomic PCR and Southern blot analysis, and gene expression was validated by northern blot analysis. Under drought-stressed condition, the transgenic plants overexpressing ABF3 displayed significantly enhanced drought tolerance with higher water content and slower water loss rate than the control plants. Furthermore, the stomata of the ABF3 transgenic plants closed more than those of wild-type creeping bentgrass plants, under both non-stressed and ABA treatment conditions. In addition, the transgenic plants showed enhanced tolerance to heat stress. These results suggest that the overexpression of the ABF3 gene in creeping bentgrass might enhance survival in water-limiting and high temperature environments through increased stomatal closure and reduced water losses.     

PKCδ as a Regulator for TGFβ1-Induced α-SMA Production in a Murine Nonalcoholic Steatohepatitis Model

The precise mechanism of TGFβ1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCδ affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCδ in TGFβ1 mediated α-SMA expression was investigated using NASH model mice. In preparation of the NASH model, male C57BL6/J mice were fed a methionine-choline-deficient (MCD) diet for 3 weeks, after which time they were intraperitoneally injected with lipopolysaccharide (LPS). In addition, Tlr4^Lps-d (CH3/HeJ) mice were used to demonstrate the TGFβ1 signaling’s dependency on TLR4 induction. Liver histology and hepatic hepatitis markers were investigated, and hepatic gene expression levels were determined by real-time PCR. Acute liver injury by LPS injection specifically elevated not only α-SMA expression but also phospho-PKCδ in this model. In contrast, Tlr4^Lps-d (CH3/HeJ) and blockade of TGFβ1 receptor by SB431542 resulted in a significant reduction of PKCδ activation and α-SMA expression. Moreover, the TGFβ1-induced α-SMA production was significantly reduced by a specific PKCδ inhibitor. These findings suggested that PKCδ plays a critical role in TGFβ1-induced α-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCδ in the regulation of α-SMA expression in NASH liver tissues, and the impaired induction of PKCδ phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCδ inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCδ represents a promising target for treating NASH.     

Whole-brain Functional Networks in Cognitively Normal,Mild Cognitive Impairment,and Alzheimer’s Disease

The conceptual significance of understanding functional brain alterations and cognitive deficits associated with Alzheimer’s disease (AD) process has been widely established. However, the whole-brain functional networks of AD and its prodromal stage, mild cognitive impairment (MCI), are not well clarified yet. In this study, we compared the characteristics of the whole-brain functional networks among cognitively normal (CN), MCI, and AD individuals by applying graph theoretical analyses to [¹⁸F] fluorodeoxyglucose positron emission tomography (FDG-PET) data. Ninety-four CN elderly, 183 with MCI, and 216 with AD underwent clinical evaluation and FDG-PET scan. The overall small-world property as seen in the CN whole-brain network was preserved in MCI and AD. In contrast, individual parameters of the network were altered with the following patterns of changes: local clustering of networks was lower in both MCI and AD compared to CN, while path length was not different among the three groups. Then, MCI had a lower level of local clustering than AD. Subgroup analyses for AD also revealed that very mild AD had lower local clustering and shorter path length compared to mild AD. Regarding the local properties of the whole-brain networks, MCI and AD had significantly decreased normalized betweenness centrality in several hubs regionally associated with the default mode network compared to CN. Our results suggest that the functional integration in whole-brain network progressively declines due to the AD process. On the other hand, functional relatedness between neighboring brain regions may not gradually decrease, but be the most severely altered in MCI stage and gradually re-increase in clinical AD stages.     

Evaluation of Animal Genetic and Physiological Factors That Affect the Prevalence of Escherichia coli O157 in Cattle

Controlling the prevalence of Escherichia coli O157 in cattle at the pre-harvest level is critical to reduce outbreaks of this pathogen in humans. Multilayers of factors including the environmental and bacterial factors modulate the colonization and persistence of E. coli O157 in cattle that serve as a reservoir of this pathogen. Here, we report animal factors contributing to the prevalence of E. coli O157 in cattle. We observe the lowest number of E. coli O157 in Brahman breed when compared with other crosses in an Angus-Brahman multibreed herd, and bulls excrete more E. coli O157 than steers in the pens where cattle were housed together. The presence of super-shedders, cattle excreting >10⁵ CFU/rectal anal swab, increases the concentration of E. coli O157 in the pens; thereby super-shedders enhance transmission of this pathogen among cattle. Molecular subtyping analysis reveal only one subtype of E. coli O157 in the multibreed herd, indicating the variance in the levels of E. coli O157 in cattle is influenced by animal factors. Furthermore, strain tracking after relocation of the cattle to a commercial feedlot reveals farm-to-farm transmission of E. coli O157, likely via super-shedders. Our results reveal high risk factors in the prevalence of E. coli O157 in cattle whereby animal genetic and physiological factors influence whether this pathogen can persist in cattle at high concentration, providing insights to intervene this pathogen at the pre-harvest level.     

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces “mitochondrial priming” by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.