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1.  Association between cardiorespiratory fitness and the prevalence of metabolic syndrome among Korean adults: a cross sectional study 
BMC Public Health  2014;14:481.
The purpose of the current study was to investigate the association between cardiorespiratory fitness (CRF), measured by a simple step test, and the prevalence of metabolic syndrome among Korean adults, in a cross sectional design.
A total of 1,007 Korean adults (488 men and 519 women) who underwent routine health checkups were recruited. CRF was measured by Tecumseh step test. The National Cholesterol Education Program’s Adult Treatment Panel III guideline was used to determine the prevalence of metabolic syndrome. A logistic regression was performed to reveal possible associations.
The results of the study showed that a lower level of CRF was significantly associated with a higher prevalence of metabolic syndrome in men, but not in women. On the other hand, higher BMI was associated with a higher prevalence of metabolic syndrome in both men and women. However, BMI was not associated with fasting glucose nor hemoglobinA1c in men. When the combined impact of BMI and CRF on the prevalence of metabolic syndrome was analyzed, a significantly increased prevalence of metabolic syndrome was found in both men (odds ratio [OR]: 18.8, 95% Confidence Interval [CI]: 5.0 - 70.5) and women (OR: 8.1, 95% CI: 2.8 - 23.9) who had high BMI and low cardiorespiratory fitness. On the other hand, the prevalence of metabolic syndrome was only increased 7.9 times (95% CI: 2.0 - 31.2) in men and 5.4 times (95% CI: 1.9 - 15.9) in women who had high level of CRF and high BMI.
In conclusion, the current study demonstrated the low CRF and obesity was a predictor for metabolic syndrome in Korean adults.
PMCID: PMC4066707  PMID: 24886636
Cardiorespiratory fitness; Simple step test; Obesity; Metabolic syndrome; Korean adults
2.  Naringenin stimulates cholecystokinin secretion in STC-1 cells 
Nutrition Research and Practice  2014;8(2):146-150.
Cholecystokinin (CCK), a hormone or neuropeptide, is secreted in response to intraluminal nutrients by enteroendocrine I-cells of the intestine and has important physiological actions related to appetite regulation and satiety. The stimulation on CCK secretion from the intestine is of potential relevance for body weight management. Naringenin (4',5,7-trihydroxyflavanone) and its glycoside naringin (naringenin 7-rhamnoglucoside) have been reported to have many biological functions. In the current study, we investigated the question of whether naringenin and naringin could stimulate CCK secretion and then examined the mechanisms involved in CCK release.
STC-1 cells were used as a model of enteroendocrine cells. CCK release and changes in intracellular Ca2+ ([Ca2+]i) were measured after incubation of cells with naringenin and naringin for 1 h.
Naringenin caused significant (P < 0.05) stimulation of CCK secretion, but naringin did not. In addition, regarding the secretory mechanisms, naringenin-induced CCK secretion involved increases in [Ca2+]i, influx of extracellular Ca2+, at least in part, and activation of TRP channels, including TRPA1.
Findings of this study suggest that naringenin could have a role in appetite regulation and satiety.
PMCID: PMC3988502  PMID: 24741397
Naringenin; cholecystokinin; TRPA1; enteroendocrine cells; appetite
3.  Use of online clinical videos for clinical skills training for medical students: benefits and challenges 
BMC Medical Education  2014;14:56.
Multimedia learning has been shown effective in clinical skills training. Yet, use of technology presents both opportunities and challenges to learners. The present study investigated student use and perceptions of online clinical videos for learning clinical skills and in preparing for OSCE (Objective Structured Clinical Examination). This study aims to inform us how to make more effective us of these resources.
A mixed-methods study was conducted for this study. A 30-items questionnaire was administered to investigate student use and perceptions of OSCE videos. Year 3 and 4 students from 34 Korean medical schools who had access to OSCE videos participated in the online survey. Additionally, a semi-structured interview of a group of Year 3 medical students was conducted for an in-depth understanding of student experience with OSCE videos.
411 students from 31 medical schools returned the questionnaires; a majority of them found OSCE videos effective for their learning of clinical skills and in preparing for OSCE. The number of OSCE videos that the students viewed was moderately associated with their self-efficacy and preparedness for OSCE (p < 0.05). One-thirds of those surveyed accessed the video clips using mobile devices; they agreed more with the statement that it was convenient to access the video clips than their peers who accessed the videos using computers (p < 0.05). Still, students reported lack of integration into the curriculum and lack of interaction as barriers to more effective use of OSCE videos.
The present study confirms the overall positive impact of OSCE videos on student learning of clinical skills. Having faculty integrate these learning resources into their teaching, integrating interactive tools into this e-learning environment to foster interactions, and using mobile devices for convenient access are recommended to help students make more effective use of these resources.
PMCID: PMC3994418  PMID: 24650290
4.  BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK 
Autophagy  2013;9(3):345-360.
BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) is an atypical BH3-only protein that is induced by hypoxia-inducible factor 1 (HIF1) under hypoxia. BNIP3 is primarily regulated at the transcriptional level. However, little is known about the underlying mechanism of BNIP3 degradation. In this study, we found that BNIP3 was downregulated when hypoxia was accompanied by amino acid starvation. The BNIP3 downregulation did not occur at the transcription level and was independent of HIF1A. BNIP3 was primarily degraded by the proteasome, but BNIP3 was subjected to both proteasomal and autophagic degradation in response to starvation. The autophagic degradation of BNIP3 was dependent on ATG7 and MAP1LC3. We determined that autophagic degradation of BNIP3 was specifically regulated by ULK1 via the MTOR-AMPK pathway. Moreover, we confirmed that BNIP3 could play a protective role in tumor cells under hypoxia, and the treatment with Torin1, an MTOR inhibitor, decreased the BNIP3 level and enhanced the death of hypoxic tumor cells.
PMCID: PMC3590255  PMID: 23291726
hypoxia; autophagy; BNIP3; MTOR; AMPK; BECN1; ULK1; Torin1
5.  Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington's Disease 
Experimental Neurobiology  2014;23(1):36-44.
Huntington's disease (HD) is a late-onset and progressive neurodegenerative disorder that is caused by aggregation of mutant huntingtin protein which contains expanded-polyglutamine. The molecular chaperones modulate the aggregation in early stage and known for the most potent protector of neurodegeneration in animal models of HD. Over the past decades, a number of studies have demonstrated molecular chaperones alleviate the pathogenic symptoms by polyQ-mediated toxicity. Moreover, chaperone-inducible drugs and anti-aggregation drugs have beneficial effects on symptoms of disease. Here, we focus on the function of molecular chaperone in animal models of HD, and review the recent therapeutic approaches to modulate expression and turn-over of molecular chaperone and to develop anti-aggregation drugs.
PMCID: PMC3984955  PMID: 24737938
protein aggregation; Molecular chaperone; Huntington; anti-aggregation drug
6.  AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation 
Nucleic Acids Research  2014;42(6):3590-3606.
In the present study, we investigated the 3′ untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3′UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3′UTR is widely known to function as a cis-acting element of mRNA degradation. The 3′UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3′UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3′UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3′UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3′UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3′UTR facilitates interaction with the 5′ end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA.
PMCID: PMC3973335  PMID: 24423872
7.  Clinical Experiences of Incidental Prostate Cancer after Transurethral Resection of Prostate (TURP) According to Initial Treatment: A Study of a Korean High Volume Center 
Yonsei Medical Journal  2013;55(1):78-83.
These are the clinical experiences of Korean incidental prostate cancer patients detected by transurethral resection of the prostate according to initial treatment: active surveillance (AS), radical prostatectomy (RP) and hormone therapy (HT).
Materials and Methods
We retrospectively reviewed the records of 156 incidental prostate cancer patients between 2001 and 2012. The clinicopathologic outcomes were reviewed and follow-up results were obtained.
Among 156 patients, 97 (62.2%) had T1a and 59 (37.8%) had T1b. Forty-six (29.5%) received AS, 67 (42.9%) underwent RP, 34 (21.8%) received HT, 4 (2.6%) received radiotherapy, and 5 (3.2%) chose watchful waiting. Of 46 patients on AS, prostate-specific antigen (PSA) progression occurred in 12 (26.1%) patients. Among them, 3 patients refused treatment despite PSA progression. Five patients, who underwent RP as an intervention, all had organ-confined Gleason score ≤6 disease. In 67 patients who underwent RP, 50 (74.6%) patients had insignificant prostate cancer and 8 (11.9%) patients showed unfavorable features. During follow-up, biochemical recurrence occurred in 2 patients. Among 34 patients who received HT, 3 (8.8%) patients had PSA progression. Among 156 patients, 6 patients died due to other causes during follow-up. There were no patients who died due to prostate cancer.
The clinical outcomes of incidental prostate cancer were satisfactory regardless of the initial treatment. However, according to recent researches and guidelines, immediate definite therapy should be avoided without a careful assessment. We also believe that improved clinical staging is needed for these patients.
PMCID: PMC3874906  PMID: 24339290
Incidental prostate cancer; radical prostatectomy; active surveillance
8.  MicroRNA-185 oscillation controls circadian amplitude of mouse Cryptochrome 1 via translational regulation 
Molecular Biology of the Cell  2013;24(14):2248-2255.
The role of the 3′-untranslated region of the mouse Cryptochrome 1 (mCry1) gene is studied at the posttranscriptional level. The results suggest that miR-185 plays a role in the fine-tuned regulation of mCRY1 protein expression by controlling the rhythmicity of mCry1 mRNA translation.
Mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Investigation of the regulation of clock gene expression has mainly focused on transcriptional and posttranslational modifications, and little is known about the posttranscriptional regulation of these genes. In the present study, we investigate the role of microRNAs (miRNAs) in the posttranscriptional regulation of the 3′-untranslated region (UTR) of the mouse Cryptochrome 1 (mCry1) gene. Knockdown of Drosha, Dicer, or Argonaute2 increased mCry1-3′UTR reporter activity. The presence of the miRNA recognition element of mCry1 that is important for miR-185 binding decreased mCRY1 protein, but not mRNA, level. Cytoplasmic miR-185 levels were nearly antiphase to mCRY1 protein levels. Furthermore, miR-185 knockdown elevated the amplitude of mCRY1 protein oscillation. Our results suggest that miR-185 plays a role in the fine-tuned regulation of mCRY1 protein expression by controlling the rhythmicity of mCry1 mRNA translation.
PMCID: PMC3708730  PMID: 23699394
9.  Delayed Surgery for Parathyroid Adenoma Misdiagnosed as a Thyroid Nodule and Treated with Radiofrequency Ablation 
Endocrinology and Metabolism  2013;28(3):231-235.
Primary hyperparathyroidism occurs as a result of isolated parathyroid adenoma in 80% to 85% of all cases. A 99mtechnetium (99mTc) sestamibi scan or neck ultrasonography is used to localize the neoplasm prior to surgical intervention. A 53-year-old female was referred for the exclusion of metabolic bone disease. She presented with low back pain that had persisted for the past 6 months and elevated serum alkaline phosphatase (1,253 IU/L). Four years previously, she had been diagnosed at a local hospital with a 2.3-cm thyroid nodule, which was determined to be pathologically benign. Radiofrequency ablation was performed at the same hospital because the nodule was still growing during the follow-up period 2 years before the visit to our hospital, and the procedure was unsuccessful in reducing the size of the nodule. The results of the laboratory tests in our hospital were as follows: serum calcium, 14.6 mg/dL; phosphorus, 3.5 mg/dL; and intact parathyroid hormone (iPTH), 1,911 pg/mL. Neck ultrasonography and 99mTc sestamibi scan detected a 5-cm parathyroid neoplasm in the left lower lobe of the patient's thyroid; left parathyroidectomy was performed. This case indicated that thyroid ultrasonographers and pathologists need to be experienced enough to differentiate a parathyroid neoplasm from a thyroid nodule; 99mTc sestamibi scan, serum calcium, and iPTH levels can help to establish the diagnosis of parathyroid neoplasm.
PMCID: PMC3811690  PMID: 24396684
Parathyroid neoplasms; Thyroid nodule; Thyroid ultrasonography
10.  The Korean Mistletoe (Viscum album coloratum) Extract Has an Antiobesity Effect and Protects against Hepatic Steatosis in Mice with High-Fat Diet-Induced Obesity 
This study investigates the inhibitory effects of Korean mistletoe extract (KME) on adipogenic factors in 3T3-L1 cells and obesity and nonalcoholic fatty liver disease (NAFLD) in mice fed a high-fat diet. Male C57Bl/6 mice fed a high-fat diet were treated with KME (3 g/kg/day) for 15 weeks for the antiobesity and NAFLD experiments. Body weight and daily food intake were measured regularly during the experimental period. The epididymal pad was measured and liver histology was observed. The effects of KME on thermogenesis and endurance capacity were measured. The effects of KME on adipogenic factors were examined in 3T3-L1 cells. Body and epididymal fat pad weights were reduced in KME-treated mice, and histological examination showed an amelioration of fatty liver in KME-treated mice, without an effect on food consumption. KME potently induces mitochondrial activity by activating thermogenesis and improving endurance capacity. KME also inhibited adipogenic factors in vitro. These results demonstrate the inhibitory effects of KME on obesity and NAFLD in mice fed a high-fat diet. The effects appear to be mediated through an enhanced mitochondrial activity. Therefore, KME may be an effective therapeutic candidate for treating obesity and fatty liver caused by a high-fat diet.
PMCID: PMC3725881  PMID: 23935653
11.  What is different about medical students interested in non-clinical careers? 
BMC Medical Education  2013;13:81.
The proportion of medical school graduates who pursue careers other than full-time clinical practice has increased in some countries as the physician’s role has evolved and diversified with the changing landscape of clinical practice and the advancement of biomedicine. Still, past studies of medical students’ career choices have focused on clinical specialties and little is known about their choice of non-clinical careers. The present study examined backgrounds, motivation and perceptions of medical students who intended non-clinical careers.
A questionnaire was administered to students at six Korean medical schools distributed across all provinces in the nation. The questionnaire comprised 40 items on respondents’ backgrounds, their motivation for and interest in the study of medicine, their perceptions of medical professions, and their career intentions. Data was analyzed using various descriptive and inferential statistics.
In total, 1,388 students returned the questionnaire (60% response rate), 12.3% of whom intended non-clinical careers (i.e., basic sciences, non-clinical medical fields, and non-medical fields). Those who planned non-clinical careers were comparable with their peers in their motivation for studying medicine and in their views of medical professions, but they were less interested in the study of medicine (P < 0.01). The two groups also differed significantly on their perceptions of what was uninteresting about the study of medicine (P < 0.01). The two groups were comparable in gender and entry-level ratios but their distributions across ages and years of study differed significantly (P < 0.01). A majority of respondents agreed with the statements that “it is necessary for medical school graduates to pursue non-clinical careers” and that “medical schools need to offer programs that provide information on such careers.” Still, our finding indicates that medical school curricula do not address such needs sufficiently.
Our study found some differences in backgrounds and perceptions of the study of medicine in medical students interested in non-clinical careers from their peers. Future studies are suggested to enhance our understanding of medical students” choice of non-clinical careers.
PMCID: PMC3679731  PMID: 23731551
12.  Mitogen-activated protein kinase phosphatase 2 regulates histone H3 phosphorylation via interaction with vaccinia-related kinase 1 
Molecular Biology of the Cell  2013;24(3):373-384.
Vaccinia-related kinase 1 (VRK1) is a histone kinase that phosphorylates histone H3 at Thr-3 and Ser-10. This study shows that mitogen-activated protein kinase phosphatase 2 regulates this phosphorylation negatively via interaction with VRK1, regardless of VRK1’s phosphatase activity.
Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate MAP kinase signaling. However, MKP2 functions are still largely unknown. In this study, we showed that MKP2 could regulate histone H3 phosphorylation under oxidative stress conditions. We found that MKP2 inhibited histone H3 phosphorylation by suppressing vaccinia-related kinase 1 (VRK1) activity. Moreover, this regulation was dependent on the selective interaction with VRK1, regardless of its phosphatase activity. The interaction between MKP2 and VRK1 mainly occurred in the chromatin, where histones are abundant. We also observed that the protein level of MKP2 and its interaction with histone H3 increased from G1 to M phase during the cell cycle, which is similar to the VRK1 profile. Furthermore, MKP2 specifically regulated the VRK1-mediated histone H3 phosphorylation at M phase. Taken together, these data suggest a novel function of MKP2 as a negative regulator of VRK1-mediated histone H3 phosphorylation.
PMCID: PMC3564537  PMID: 23223570
13.  Disruption of Sorting Nexin 5 Causes Respiratory Failure Associated with Undifferentiated Alveolar Epithelial Type I Cells in Mice 
PLoS ONE  2013;8(3):e58511.
Sorting nexin 5 (Snx5) has been posited to regulate the degradation of epidermal growth factor receptor and the retrograde trafficking of cation-independent mannose 6-phosphate receptor/insulin-like growth factor II receptor. Snx5 has also been suggested to interact with Mind bomb-1, an E3 ubiquitin ligase that regulates the activation of Notch signaling. However, the in vivo functions of Snx5 are largely unknown. Here, we report that disruption of the Snx5 gene in mice (Snx5-/- mice) resulted in partial perinatal lethality; 40% of Snx5-/- mice died shortly after birth due to cyanosis, reduced air space in the lungs, and respiratory failure. Histological analysis revealed that Snx5-/- mice exhibited thickened alveolar walls associated with undifferentiated alveolar epithelial type I cells. In contrast, alveolar epithelial type II cells were intact, exhibiting normal surfactant synthesis and secretion. Although the expression levels of surfactant proteins and saturated phosphatidylcholine in the lungs of Snx5-/- mice were comparable to those of Snx5+/+ mice, the expression levels of T1α, Aqp5, and Rage, markers for distal alveolar epithelial type I cells, were significantly decreased in Snx5-/- mice. These results demonstrate that Snx5 is necessary for the differentiation of alveolar epithelial type I cells, which may underlie the adaptation to air breathing at birth.
PMCID: PMC3602295  PMID: 23526992
14.  Improvement of Glycemic Control after Re-Emphasis of Lifestyle Modification in Type 2 Diabetic Patients Reluctant to Additional Medication 
Yonsei Medical Journal  2013;54(2):345-351.
The aim of this study is to observe glycemic changes after emphasizing the importance of lifestyle modification in patients with mild or moderately uncontrolled type 2 diabetes.
Materials and Methods
We examined 51 type 2 diabetic patients with 7.0-9.0% hemoglobin A1c (HbA1c) who preferred to change their lifestyle rather than followed the recommendation of medication change. At the enrollment, the study subjects completed questionnaires about diet and exercise. After 3 months, HbA1c levels were determined and questionnaires on the change of lifestyle were accomplished. We divided the study subjects into 3 groups: improved (more than 0.3% decrease of HbA1c), aggravated (more than 0.3% increase of HbA1c) and not changed (-0.3%
Among the total 51 subjects, 18 patients (35.3%) showed the decreased levels of HbA1c after 3 months with mean change of -0.74±0.27%, and HbA1c values of 11 patients (21.5%) were less than 7%. In addition, the HbA1c level was significantly reduced in patients who reportedly followed the lifestyle modification such as diet and exercise for 3 months, compared with the one obtained from patients who refused this lifestyle change (p=0.002).
In this study, 35.3% of the patients with mild or moderately uncontrolled type 2 diabetes showed the significant improvement of HbA1c levels after 3 months by simply regulating their daily diet and exercise without change of medication. This suggests that the lifestyle modification is significantly associated with the improvement of glucose control.
PMCID: PMC3575963  PMID: 23364966
Diabetes mellitus; glycemic control; lifestyle; modification
Biomolecules & Therapeutics  2013;21(2):121-125.
Hesperetin (3',5,7-trihydroxy 4'-methoxyflavanone) and its glycoside hesperidin (hesperetin 7-rhamnoglucoside) in oranges have been reported to possess pharmacological effects related to anti-obesity. However, hesperetin and hesperidin have not been studied on suppressive effects on appetite. This study examined that hesperetin and hesperidin can stimulate the release of cholecystokinin (CCK), one of appetite-regulating hormones, from the enteroendocrine STC-1 cells, and then examined the mechanisms involved in the CCK release. Hesperetin significantly and dose-dependently stimulated CCK secretion with an EC50 of 0.050 mM and increased the intracellular Ca2+ concentrations ([Ca2+]i) compared to the untreated control. The stimulatory effect by hesperetin was mediated via the entry of extracellular Ca2+ and the activation of TRP channels including TRPA1. These results suggest that hesperetin can be a candidate biomolecule for the suppression of appetite and eventually for the therapeutics of obesity.
PMCID: PMC3762311  PMID: 24009869
Hesperetin; Cholecystokinin; Intracellular Ca2+; TRP ankyrin 1; Enteroendocrine cells
PLoS ONE  2013;8(1):e53577.
Mitochondria are key organelles dedicated to energy production. Crif1, which interacts with the large subunit of the mitochondrial ribosome, is indispensable for the mitochondrial translation and membrane insertion of respiratory subunits. To explore the physiological function of Crif1 in the heart, Crif1f/f mice were crossed with Myh6-cre/Esr1 transgenic mice, which harbor cardiomyocyte-specific Cre activity in a tamoxifen-dependent manner. The tamoxifen injections were given at six weeks postnatal, and the mutant mice survived only five months due to hypertrophic heart failure. In the mutant cardiac muscles, mitochondrial mass dramatically increased, while the inner structure was altered with lack of cristae. Mutant cardiac muscles showed decreased rates of oxygen consumption and ATP production, suggesting that Crif1 plays a critical role in the maintenance of both mitochondrial structure and respiration in cardiac muscles.
PMCID: PMC3537664  PMID: 23308255
Molecular Brain  2012;5:40.
Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function.
Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses.
These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus.
PMCID: PMC3541076  PMID: 23111145
Mind bomb-1; Notch; Synaptic plasticity; Memory; Hippocampus
PLoS ONE  2012;7(9):e44307.
Phosphorylation of histone H3 on Ser-10 is regarded as an epigenetic mitotic marker and is tightly correlated with chromosome condensation during both mitosis and meiosis. However, it was also reported that histone H3 Ser-10 phosphorylation occurs when cells are exposed to various death stimuli, suggesting a potential role in the regulation of apoptosis. Here we report that histone H3 Ser-10 phosphorylation is mediated by the pro-apoptotic kinase protein kinase C (PKC) δ during apoptosis. We observed that PKCδ robustly phosphorylates histone H3 on Ser-10 both in vitro and in vivo. Ectopic expression of catalytically active PKCδ efficiently induces condensed chromatin structure in the nucleus. We also discovered that activation of PKCδ is required for histone H3 Ser-10 phosphorylation after treatment with DNA damaging agents during apoptosis. Collectively, these findings suggest that PKCδ is the kinase responsible for histone H3 Ser-10 phosphoryation during apoptosis and thus contributes to chromatin condensation together with other apoptosis-related histone modifications. As a result, histone H3 Ser-10 phosphorylation can be designated a new ‘apoptotic histone code’ mediated by PKCδ.
PMCID: PMC3440438  PMID: 22984491
Biomedical Optics Express  2012;3(9):2288-2298.
Peripheral arterial disease (PAD) is the narrowing of arteries due to plaque accumulation in the vascular walls. This leads to insufficient blood supply to the extremities and can ultimately cause cell death. Currently available methods are ineffective in diagnosing PAD in patients with calcified arteries, such as those with diabetes. In this paper we investigate the potential of dynamic diffuse optical tomography (DDOT) as an alternative way to assess PAD in the lower extremities. DDOT is a non-invasive, non-ionizing imaging modality that uses near-infrared light to create spatio-temporal maps of oxy- and deoxy-hemoglobin in tissue. We present three case studies in which we used DDOT to visualize vascular perfusion of a healthy volunteer, a PAD patient and a diabetic PAD patient with calcified arteries. These preliminary results show significant differences in DDOT time-traces and images between all three cases, underscoring the potential of DDOT as a new diagnostic tool.
PMCID: PMC3447568  PMID: 23024920
(170.3880) Medical and biological imaging; (170.6960) Tomography
Molecular and Cellular Biology  2012;32(3):717-728.
The mouse PERIOD1 (mPER1) protein, along with other clock proteins, plays a crucial role in the maintenance of circadian rhythms. mPER1 also provides an important link between the circadian system and the cell cycle system. Here we show that the circadian expression of mPER1 is regulated by rhythmic translational control of mPer1 mRNA together with transcriptional modulation. This time-dependent translation was controlled by an internal ribosomal entry site (IRES) element in the 5′ untranslated region (5′-UTR) of mPer1 mRNA along with the trans-acting factor mouse heterogeneous nuclear ribonucleoprotein Q (mhnRNP Q). Knockdown of mhnRNP Q caused a decrease in mPER1 levels and a slight delay in mPER1 expression without changing mRNA levels. The rate of IRES-mediated translation exhibits phase-dependent characteristics through rhythmic interactions between mPer1 mRNA and mhnRNP Q. Here, we demonstrate 5′-UTR-mediated rhythmic mPer1 translation and provide evidence for posttranscriptional regulation of the circadian rhythmicity of core clock genes.
PMCID: PMC3266596  PMID: 22124155
Nucleic Acids Research  2012;40(17):8499-8518.
The telomere integrity is maintained via replication machinery, telomere associated proteins and telomerase. Many telomere associated proteins are regulated in a cell cycle-dependent manner. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a single-stranded oligonucleotide binding protein, is thought to play a pivotal role in telomere maintenance. Here, we identified hnRNP A1 as a novel substrate for vaccinia-related kinase 1 (VRK1), a cell cycle regulating kinase. Phosphorylation by VRK1 potentiates the binding of hnRNP A1 to telomeric ssDNA and telomerase RNA in vitro and enhances its function for telomerase reaction. VRK1 deficiency induces a shortening of telomeres with an abnormal telomere arrangement and activation of DNA-damage signaling in mouse male germ cells. Together, our data suggest that VRK1 is required for telomere maintenance via phosphorylation of hnRNP A1, which regulates proteins associated with the telomere and telomerase RNA.
PMCID: PMC3458570  PMID: 22740652
Scientific Reports  2012;2:468.
The Vaccinia-related kinase 1(VRK1), which is generally implicated in modulating cell cycle, plays important roles in mammalian gametogenesis. Female infertility in VRK1-deficient mice was reported to be caused by defective meiotic progression in oocyte at postovulatory stage. VRK1 roles in folliculogenesis, however, remain largely unknown. Here, accurate quantification of folliculogenesis is performed by a direct visualization of ‘intact’ ovary in 3-dimensions (3-D) using a synchrotron X-ray microtomography. In VRK1-deficient ovaries, the numbers of pre-antral and antral follicles are significantly reduced by 38% and 46%, respectively, comparing to control. The oocytes volumes in antral and Graffian follicles also decrease by 42% and 37% in the mutants, respectively, indicating defects in oocyte quality at preovulatory stage. Genetic analysis shows that gene expressions related to folliculogenesis are down-regulated in VRK1-deficient ovaries, implying defects in folliculogenesis. We suggest that VRK1 is required for both follicle development and oocyte growth in mammalian female reproduction system.
PMCID: PMC3384087  PMID: 22741057
PLoS ONE  2012;7(5):e37936.
The mouse PERIOD1 (mPER1) plays an important role in the maintenance of circadian rhythm. Translation of mPer1 is directed by both a cap-dependent process and cap-independent translation mediated by an internal ribosomal entry site (IRES) in the 5′ untranslated region (UTR). Here, we compared mPer1 IRES activity with other cellular IRESs. We also found critical region in mPer1 5′UTR for heterogeneous nuclear ribonucleoprotein Q (HNRNPQ) binding. Deletion of HNRNPQ binding region markedly decreased IRES activity and disrupted rhythmicity. A mathematical model also suggests that rhythmic IRES-dependent translation is a key process in mPER1 oscillation. The IRES-mediated translation of mPer1 will help define the post-transcriptional regulation of the core clock genes.
PMCID: PMC3360671  PMID: 22662251
The British Journal of Nutrition  2011;105(5):688-693.
High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C57BL/6 mice were pair-fed with four different amino acid-defined diets for 20 weeks: folate deplete (0 mg/kg diet); folate replete (2 mg/kg diet); folate supplemented (8 mg/kg diet); folate deplete (0 mg/kg diet) with thymidine supplementation (1·8 g/kg diet). Thymidylate synthesis from uracil requires folate, but synthesis from thymidine is folate independent. Liver folate concentrations were determined by the Lactobacillus casei assay. Uracil misincorporation into DNA was measured by a GC/MS method. Liver folate concentrations demonstrated a stepwise increase across the spectrum of dietary folate levels in both old (P=0·003) and young (P<0·001) mice. Uracil content in colonic DNA was paradoxically increased in parallel with increasing dietary folate among the young mice (P trend=0·033), but differences were not observed in the old mice. The mean values of uracil in liver DNA, in contrast, decreased with increasing dietary folate among the old mice, but it did not reach a statistically significant level (P<0·1). Compared with the folate-deplete group, thymidine supplementation reduced uracil misincorporation into the liver DNA of aged mice (P=0·026). The present study suggests that the effects of folate and thymidine supplementation on uracil misincorporation into DNA differ depending on age and tissue. Further studies are needed to clarify the significance of increased uracil misincorporation into colonic DNA of folate-supplemented young mice.
PMCID: PMC3259804  PMID: 21251336
Folate; Uracil; Thymidine; Colon; Liver; Mice
Korean Journal of Anesthesiology  2012;62(3):272-276.
Patients with cervical spine instability and limited range of motion are challenge to anesthesiologists. It is important to consider alternatetive methods for securing the airway while maintaining neutral position and minimizing neck motion, because these patients are at increased risk for tracheal intubation failure and neurologic injury during airway management or position change. We experienced two cases that patients had cervical spine instability and severe limited range of motion due to the fusion of the entire cervical spine. One patient was a 6-year-old girl weighing 12.7 kg and had Klippel-Feil syndrome with Arnold-Chiari malformation, the other was a 24-year-old female weighing 31 kg and had juvenile rheumatoid arthritis. We successfully performed the intubation by using the fiberoptic intubation though a laryngeal mask airway in these two cases.
PMCID: PMC3315659  PMID: 22474556
Arnorl-Chiari malformation; Difficult airway; Fiberoptic intubation; Juvenile rheumatoid arthritis; Klippel-Feil syndrome; Laryngeal mask airway

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