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1.  Reciprocal regulation of the Autophosphorylation of Enzyme INtr by Glutamine and α-Ketoglutarate in Escherichia coli 
Molecular microbiology  2013;88(3):473-485.
Summary
In addition to the phosphoenolpyruvate:sugar phosphotransferase system (sugar PTS), most proteobacteria possess a paralogous system (nitrogen phosphotransferase system, PTSNtr). The first proteins in both pathways are enzymes (enzyme Isugar and enzyme INtr) that can be autophosphorylated by phosphoenolpyruvate. The most striking difference between enzyme Isugar and enzyme INtr is the presence of a GAF domain at the N-terminus of enzyme INtr. Since the PTSNtr was identified in 1995, it has been implicated in a variety of cellular processes in many proteobacteria and many of these regulations have been shown to be dependent on the phosphorylation state of PTSNtr components. However, there has been little evidence that any component of this so-called PTSNtr is directly involved in nitrogen metabolism. Moreover, a signal regulating the phosphorylation state of the PTSNtr had not been uncovered. Here, we demonstrate that glutamine and α-ketoglutarate, the canonical signals of nitrogen availability, reciprocally regulate the phosphorylation state of the PTSNtr by direct effects on enzyme INtr autophosphorylation and the GAF signal transduction domain is necessary for the regulation of enzyme INtr activity by the two signal molecules. Taken together, our results suggest that the PTSNtr senses nitrogen availability.
doi:10.1111/mmi.12196
PMCID: PMC3633653  PMID: 23517463
GAF domain; glutamine; α–ketoglutarate; nitrogen PTS; phosphorylation-dependent mobility shift
2.  Cyr61 Expression is associated with prognosis in patients with colorectal cancer 
BMC Cancer  2014;14:164.
Background
Cysteine-rich 61 (Cyr61), a member of the CCN protein family, possesses diverse functionality in cellular processes such as adhesion, migration, proliferation, and survival. Cyr61 can also function as an oncogene or a tumour suppressor, depending on the origin of the cancer. Only a few studies have reported Cyr61 expression in colorectal cancer. In this study, we assessed the Cyr61 expression in 251 colorectal cancers with clinical follow up.
Methods
We examined Cyr61 expression in 6 colorectal cancer cell lines (HT29, Colo205, Lovo, HCT116, SW480, SW620) and 20 sets of paired normal and colorectal cancer tissues by western blot. To validate the association of Cyr61 expression with clinicopathological parameters, we assessed Cyr61 expression using tissue microarray analysis of primary colorectal cancer by immunohistochemical analysis.
Results
We verified that all of the cancer cell lines expressed Cyr61; 2 cell lines (HT29 and Colo205) demonstrated Cyr61 expression to a slight extent, while 4 cell lines (Lovo, HCT116, SW480, SW620) demonstrated greater Cyr61 expression than HT29 and Colo205 cell lines. Among the 20 cases of paired normal and tumour tissues, greater Cyr61 expression was observed in 16 (80%) tumour tissues than in normal tissues. Furthermore, 157 out of 251 cases (62.5%) of colorectal cancer examined in this study displayed strong Cyr61 expression. Cyr61 expression was found to be associated with pN (p = 0.018). Moreover, Cyr61 expression was associated with statistically significant cancer-specific mortality (p = 0.029). The duration of survival was significantly lesser in patients with Cyr61 high expression than in patients with Cyr61 low expression (p = 0.001). These results suggest that Cyr61 expression plays several important roles in carcinogenesis and may also be a good prognostic marker for colorectal cancer.
Conclusions
Our data confirmed that Cyr61 was expressed in colorectal cancers and the expression was correlated with worse prognosis of colorectal cancers.
doi:10.1186/1471-2407-14-164
PMCID: PMC3975645  PMID: 24606730
Colorectal cancer; Cyr61; Immunohistochemistry; Prognosis
3.  Impact of Korean pine nut oil on weight gain and immune responses in high-fat diet-induced obese mice 
Nutrition Research and Practice  2013;7(5):352-358.
Korean pine nut oil (PNO) has been reported to have favorable effects on lipid metabolism and appetite control. We investigated whether PNO consumption could influence weight gain, and whether the PNO-induced effect would result in an improvement of immune function in high-fat diet (HFD)-induced obese mice. C57BL/6 mice were fed control diets with 10% energy fat from either PNO or soybean oil (SBO), or HFDs with 45% energy fat from 10% PNO or SBO and 35% lard, 20% PNO or SBO and 25% lard, or 30% PNO or SBO and 15% lard for 12 weeks. The proliferative responses of splenocytes upon stimulation with concanavalin A (Con A) or lipopolysaccharide (LPS), Con A-stimulated production of interleukin (IL)-2 and interferon (IFN)-γ, and LPS-stimulated production of IL-6, IL-1β, and prostaglandin E2 (PGE2) by splenocytes were determined. Consumption of HFDs containing PNO resulted in significantly less weight gain (17% less, P < 0.001), and lower weight gain was mainly due to less white adipose tissue (18% less, P = 0.001). The reduction in weight gain did not result in the overall enhancement in splenocyte proliferation. Overall, PNO consumption resulted in a higher production of IL-1β (P = 0.04). Replacement of SBO with PNO had no effect on the production of IL-2, IFN-γ, IL-6, or PGE2 in mice fed with either the control diets or HFDs. In conclusion, consumption of PNO reduced weight gain in mice fed with HFD, but this effect did not result in the overall improvement in immune responses.
doi:10.4162/nrp.2013.7.5.352
PMCID: PMC3796659  PMID: 24133613
Pine nut oil; obesity; high-fat diet; immune response; inflammatory cytokine
4.  Effects of Somatic Mutations Are Associated with SNP in the Progression of Individual Acute Myeloid Leukemia Patient: The Two-Hit Theory Explains Inherited Predisposition to Pathogenesis 
Genomics & Informatics  2013;11(1):34-37.
This study evaluated the effects of somatic mutations and single nucleotide polymorphisms (SNPs) on disease progression and tried to verify the two-hit theory in cancer pathogenesis. To address this issue, SNP analysis was performed using the UCSC hg19 program in 10 acute myeloid leukemia patients (samples, G1 to G10), and somatic mutations were identified in the same tumor sample using SomaticSniper and VarScan2. SNPs in KRAS were detected in 4 out of 10 different individuals, and those of DNMT3A were detected in 5 of the same patient cohort. In 2 patients, both KRAS and DNMT3A were detected simultaneously. A somatic mutation in IDH2 was detected in these 2 patients. One of the patients had an additional mutation in FLT3, while the other patient had an NPM1 mutation. The patient with an FLT3 mutation relapsed shortly after attaining remission, while the other patient with the NPM1 mutation did not suffer a relapse. Our results indicate that SNPs with additional somatic mutations affect the prognosis of AML.
doi:10.5808/GI.2013.11.1.34
PMCID: PMC3630383  PMID: 23613680
acute myeloid leukemia; high-throughput nucleotide sequencing; point mutation; single nucleotide polymorphism
5.  A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency 
Background/Aims
Recessive mutations in the LHX3 ho-meodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3.
Methods
Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized.
Results
A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the α-glycoprotein and PRL target genes.
Conclusion
The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene.
doi:10.1159/000335929
PMCID: PMC3355643  PMID: 22286346
Growth; Transcription; LIM; Development; Pediatric patients
6.  Zolpidem Use and Risk of Fracture in Elderly Insomnia Patients 
Objectives
To evaluate the risk of fractures related with zolpidem in elderly insomnia patients.
Methods
Health claims data on the entire South Korean elderly population from January 2005 to June 2006 were extracted from the Health Insurance Review and Assessment Service database. We applied a case-crossover design. Cases were defined as insomnia patients who had a fracture diagnosis. We set the hazard period of 1 day length prior to the fracture date and four control periods of the same length at 5, 10, 15, and 20 weeks prior to the fracture date. Time independent confounding factors such as age, gender, lifestyle, cognitive function level, mobility, socioeconomic status, residential environment, and comorbidity could be controlled using the casecrossover design. Time dependent confounding factors, especially co-medication of patients during the study period, were adjusted by conditional logistic regression analysis. The odds ratios and their 95% confidence intervals (CIs) were estimated for the risk of fracture related to zolpidem.
Results
One thousand five hundred and eight cases of fracture were detected in insomnia patients during the study period. In our data, the use of zolpidem increased the risk of fracture significantly (adjusted odds ratio [aOR], 1.72; 95% CI, 1.37 to 2.16). However, the association between benzodiazepine hypnotics and the risk of fracture was not statistically significant (aOR, 1.00; 95% CI, 0.83 to 1.21). Likewise, the results were not statistically significant in stratified analysis with each benzodiazepine generic subgroup.
Conclusions
Zolpidem could increase the risk of fracture in elderly insomnia patients. Therefore zolpidem should be prescribed carefully and the elderly should be provided with sufficient patient education.
doi:10.3961/jpmph.2012.45.4.219
PMCID: PMC3412984  PMID: 22880153
Zolpidem; Bone fractures; Case-crossover design; Aged; Hypnotic; Sleep initiation and maintenance disorders
7.  The von Economo neurons in fronto-insular and anterior cingulate cortex 
The von Economo neurons (VENs) are large bipolar neurons located in fronto-insular cortex (FI) and anterior limbic area (LA) in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week post conception, with numbers increasing during the first eight months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of fronto-temporal dementia implies that they are involved in empathy, social awareness, and self-control, consistent with evidence from functional imaging.
doi:10.1111/j.1749-6632.2011.06011.x
PMCID: PMC3140770  PMID: 21534993
fronto-temporal dementia; autism; schizophrenia; empathy; disgust; self-awareness; hemispheric specialization
8.  Detection of BRAFV600E Mutations in Papillary Thyroid Carcinomas by Peptide Nucleic Acid Clamp Real-Time PCR: A Comparison with Direct Sequencing 
Korean Journal of Pathology  2012;46(1):61-67.
Background
Papillary thyroid carcinoma (PTC) of the thyroid is the most common endocrine malignancy. High prevalence of an activating point mutation of BRAF gene, BRAFV600E, has been reported in PTC. We assessed the efficiency of peptide nucleic acid clamp real-time polymerase chain reaction (PNAcqPCR) for the detection of BRAFV600E mutation in PTC in comparison with direct sequencing (DS).
Methods
A total of 265 thyroid lesions including 200 PTCs, 5 follicular carcinomas, 60 benign lesions and 10 normal thyroid tissues were tested for BRAFV600E mutation by PNAcqPCR and DS.
Results
The sensitivity and accuracy of the PNAcqPCR method were both higher than those of DS for the detection of the BRAFV600E mutation. In clinical samples, 89% of PTCs harbored the BRAFV600E mutation, whereas 5 follicular carcinomas, 50 benign lesions and 10 normal thyroid tissues lacked the mutation. The mutation was associated with aggressive clinical behaviors as extrathyroid invasion (p=0.015), lymph node metastasis (p=0.002) and multiple tumor numbers (p=0.016) with statistical significance.
Conclusions
The PNAcqPCR method is efficiently applicable for the detection of the BRAFV600E mutation in PTCs in a clinical setting.
doi:10.4132/KoreanJPathol.2012.46.1.61
PMCID: PMC3479705  PMID: 23109980
Thyroid; Thyroid cancer, papillary; BRAF; Peptide nucleic acids
9.  Indoor Physical Activity Reduces All-Cause and Cardiovascular Disease Mortality Among Elderly Women 
Objectives
The aim of this study was to investigate whether a medium to high degree of total physical activity and indoor physical activity were associated with reduced all-cause and cardiovascular mortality among elderly Korean women.
Methods
A prospective cohort study was done to evaluate the association between physical activity and mortality. The cohort was made up of elderly (≥65 years of age) subjects. Baseline information was collected with a self-administered questionnaire and linked to death certificates retrieved from a database. Cox proportional hazard models were used to estimate the hazard ratios (HRs) with 95% confidence interval (CI) levels.
Results
Women who did not suffer from stroke, cancer, or ischemic heart disease were followed for a median of 8 years (n=5079). A total of 1798 all-cause deaths were recorded, of which 607 (33.8%) were due to cardiovascular disease. The group with the highest level of total physical activity and indoor physical activity was significantly associated to a reduced all-cause mortality (HR, 0.60; 95% CI, 0.51 to 0.71 and HR, 0.58; 95% CI, 0.50 to 0.67, respectively) compared to the group with the lowest level of total physical activity and indoor physical activity. Additionally, the group with the highest level of total physical activity and indoor physical activity was significantly associated to a lower cardiovascular disease mortality (HR, 0.53; 95% CI, 0.40 to 0.71 and HR, 0.51; 95% CI, 0.39 to 0.67, respectively) compared to the group with the lowest level of total physical activity and indoor physical activity.
Conclusions
Our study showed that regular indoor physical activity among elderly Korean women has healthy benefits.
doi:10.3961/jpmph.2012.45.1.21
PMCID: PMC3278601  PMID: 22389755
Cardiovascular diseases; Exercise; Indoor physical activity; Mortality
10.  The Claustrum and Insula in Microcebus murinus: A High Resolution Diffusion Imaging Study 
The claustrum and the insula are closely juxtaposed in the brain of the prosimian primate, the gray mouse lemur (Microcebus murinus). Whether the claustrum has closer affinities with the cortex or the striatum has been debated for many decades. Our observation of histological sections from primate brains and genomic data in the mouse suggest former. Given this, the present study compares the connections of the two structures in Microcebus using high angular resolution diffusion imaging (HARDI, with 72 directions), with a very small voxel size (90 micra), and probabilistic fiber tractography. High angular and spatial resolution diffusion imaging is non-destructive, requires no surgical interventions, and the connection of each and every voxel can be mapped, whereas in conventional tract tracer studies only a few specific injection sites can be assayed. Our data indicate that despite the high genetic and spatial affinities between the two structures, their connectivity patterns are very different. The claustrum connects with many cortical areas and the olfactory bulb; its strongest probabilistic connections are with the entorhinal cortex, suggesting that the claustrum may have a role in spatial memory and navigation. By contrast, the insula connects with many subcortical areas, including the brainstem and thalamic structures involved in taste and visceral feelings. Overall, the connections of the Microcebus claustrum and insula are similar to those of the rodents, cat, macaque, and human, validating our results. The insula in the Microcebus connects with the dorsolateral frontal cortex in contrast to the mouse insula, which has stronger connections with the ventromedial frontal lobe, yet this is consistent with the dorsolateral expansion of the frontal cortex in primates. In addition to revealing the connectivity patterns of the Microcebus brain, our study demonstrates that HARDI, at high resolutions, can be a valuable tool for mapping fiber pathways for multiple sites in fixed brains in rare and difficult-to-obtain species.
doi:10.3389/fnana.2012.00021
PMCID: PMC3374366  PMID: 22707933
Microcebus murinus; gray mouse lemur; claustrum; insula; HARDI; probabilistic fiber tractography
11.  Prefrontal Cortex Fails to Learn from Reward Prediction Errors in Alcohol Dependence 
Patients suffering from addiction persist in consuming substances of abuse, despite negative consequences or absence of positive consequences. One potential explanation is that these patients are impaired at flexibly adapting their behavior to changes in reward contingencies. A key aspect of adaptive decision-making involves updating the value of behavioral options. This is thought to be mediated via a teaching signal expressed as a reward prediction error (PE) in the striatum. However, to exert control over adaptive behavior, value signals need to be broadcast to higher executive regions, such as prefrontal cortex. Here we used functional MRI and a reinforcement learning task to investigate the neural mechanisms underlying maladaptive behavior in human male alcohol-dependent patients. We show that in alcohol-dependent patients the expression of striatal PEs is intact. However, abnormal functional connectivity between striatum and dorsolateral prefrontal cortex (dlPFC) predicted impairments in learning and the magnitude of alcohol craving. These results are in line with reports of dlPFC structural abnormalities in substance dependence and highlight the importance of frontostriatal connectivity in addiction, and its pivotal role in adaptive updating of action values and behavioral regulation. Furthermore, they extend the scope of neurobiological deficits underlying addiction beyond the focus on the striatum.
doi:10.1523/JNEUROSCI.5587-09.2010
PMCID: PMC3047386  PMID: 20519550

Results 1-11 (11)