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Publication A mixed flavonoid-fish oil supplement induces immune-enhancing and anti-inflammatory transcriptomic changes in adult obese and overweight women—A randomized controlled trial(2016) Cialdella-Kam, L; Nieman, D.C; Knab, A.M; Shanely, R.A; Meaney, M.P; Jin, F; Sha, W; Ghosh, S; DUKE-NUS MEDICAL SCHOOLFlavonoids and fish oils have anti-inflammatory and immune-modulating influences. The purpose of this study was to determine if a mixed flavonoid-fish oil supplement (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg epigallocatechin (EGCG) from green tea extract, 400 mg n3-PUFAs (omega-3 polyunsaturated fatty acid) (220 mg eicosapentaenoic acid (EPA) and 180 mg docosahexaenoic acid (DHA)) from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 µg folic acid) would reduce complications associated with obesity; that is, reduce inflammatory and oxidative stress markers and alter genomic profiles in overweight women. Overweight and obese women (n = 48; age = 40–70 years) were assigned to Q-Mix or placebo groups using randomized double-blinded placebo-controlled procedures. Overnight fasted blood samples were collected at 0 and 10 weeks and analyzed for cytokines, C-reactive protein (CRP), F2-isoprostanes, and whole-blood-derived mRNA, which was assessed using Affymetrix HuGene-1_1 ST arrays. Statistical analysis included two-way ANOVA models for blood analytes and gene expression and pathway and network enrichment methods for gene expression. Plasma levels increased with Q-Mix supplementation by 388% for quercetin, 95% for EPA, 18% for DHA, and 20% for docosapentaenoic acid (DPA). Q-Mix did not alter plasma levels for CRP (p = 0.268), F2-isoprostanes (p = 0.273), and cytokines (p > 0.05). Gene set enrichment analysis revealed upregulation of pathways in Q-Mix vs. placebo related to interferon-induced antiviral mechanism (false discovery rate, FDR < 0.001). Overrepresentation analysis further disclosed an inhibition of phagocytosis-related inflammatory pathways in Q-Mix vs. placebo. Thus, a 10-week Q-Mix supplementation elicited a significant rise in plasma quercetin, EPA, DHA, and DPA, as well as stimulated an antiviral and inflammation whole-blood transcriptomic response in overweight women. © 2016 by the authors; licensee MDPI, Basel, Switzerland.Publication Comparative proteomics reveals human pluripotent stem cell-derived limbal epithelial stem cells are similar to native ocular surface epithelial cells(2015) Mikhailova, A; Jylhä, A; Rieck, J; Nättinen, J; Ilmarinen, T; Veréb, Z; Aapola, U; Beuerman, R; Petrovski, G; Uusitalo, H; Skottman, H; DUKE-NUS MEDICAL SCHOOLLimbal epithelial stem cells (LESCs) are tissue-specific stem cells responsible for renewing the corneal epithelium. Acute trauma or chronic disease affecting LESCs may disrupt corneal epithelial renewal, causing vision threatening and painful ocular surface disorders, collectively referred to as LESC deficiency (LESCD). These disorders cannot be treated with traditional corneal transplantation and therefore alternative cell sources for successful cell-based therapy are needed. LESCs derived from human pluripotent stem cells (hPSCs) are a prospective source for ocular surface reconstruction, yet critical evaluation of these cells is crucial before considering clinical applications. In order to quantitatively evaluate hPSC-derived LESCs, we compared protein expression in native human corneal cells to that in hPSC-derived LESCs using isobaric tag for relative and absolute quantitation (iTRAQ) technology. We identified 860 unique proteins present in all samples, including proteins involved in cell cycling, proliferation, differentiation and apoptosis, various LESC niche components, and limbal and corneal epithelial markers. Protein expression profiles were nearly identical in LESCs derived from two different hPSC lines, indicating that the differentiation protocol is reproducible, yielding homogeneous cell populations. Their protein expression profile suggests that hPSC-derived LESCs are similar to the human ocular surface epithelial cells, and possess LESC-like characteristics.Publication Age at natural menopause and risk of type 2 diabetes: a prospective cohort study(Springer Verlag, 2017) Muka, T; Asllanaj, E; Avazverdi, N; Jaspers, L; Stringa, N; Milic, J; Ligthart, S; Ikram, M.A; Laven, J.S.E; Kavousi, M; Dehghan, A; Franco, O.H; DUKE-NUS MEDICAL SCHOOLAims/hypothesis: In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators. Methods: We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study. Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40 years; early, 40–44 years; normal, 45–55 years; and late menopause, >55 years [reference]). Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens. Results: During a median follow-up of 9.2 years, we identified 348 individuals with incident type 2 diabetes. After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause (ptrend <0.001). The HR for type 2 diabetes per 1 year older at menopause was 0.96 (95% CI 0.94, 0.98). Further adjustment for BMI, glycaemic traits, metabolic risk factors, C-reactive protein, endogenous sex hormone levels or shared genetic factors did not affect this association. Conclusions/interpretation: Early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women. © 2017, The Author(s).Publication Recovery of methamphetamine associated cardiomyopathy predicted by late gadolinium enhanced cardiovascular magnetic resonance(2009) Lopez, J.E; Yeo, K; Caputo, G; Buonocore, M; Schaefer, S; DUKE-NUS MEDICAL SCHOOLMethamphetamine is known to cause a cardiomyopathy which may be reversible with appropriate medical therapy and cessation of use. Late gadolinium enhancement cardiovascular magnetic resonance (CMR) has been shown to identify fibrosis in ischemic and non-ischemic cardiomyopathies. We present a case of severe methamphetamine-associated cardiomyopathy in which cardiac function recovered after 6 months. Evaluation by CMR using late gadolinium enhancement was notable for an absence of enhancement, suggesting an absence of irreversible myocyte injury and a good prognosis. CMR may be useful to predict recovery in toxin-associated non-ischemic cardiomyopathies. © 2009 Lopez et al; licensee BioMed Central Ltd.Publication Monochromatic pupillometry in unilateral glaucoma discloses no adaptive changes subserved by the ipRGCs(2014) Nissen, C; Sander, B; Milea, D; Kolko, M; Herbst, K; Hamard, P; Lund-Andersen, H; DUKE-NUS MEDICAL SCHOOLPurpose: To detect signs of a possible adaptive mechanism of the intrinsically photosensitive ganglion cells in unilateral glaucoma. Method: Eleven patients with unilateral glaucoma, classified by automated perimetry (glaucoma: mean deviation < 0), were studied by monochromatic pupillometry, employing red (660 nm) or blue (470 nm) light, and by optical coherence tomography of the peripapillary retinal nerve fiber layer. The main outcome measure in pupillometry, the area under the curve (AUC), i.e., the product of pupillary contraction amplitude and time, was determined during and after light exposure in glaucomatous and unafflicted fellow eyes and compared to the AUCs of a healthy, age-matched control group. Results: The AUC to stimulation with blue light was significantly reduced in glaucomatous eyes, both during and after stimulus, compared with that of fellow, unafflicted eyes (p ≤ 0.014). The AUC to red light stimulation was reduced during (p = 0.035), but not after (p ≥ 0.072), exposure in glaucomatous eyes. In the unafflicted fellow eyes, the pupillary response to blue light did not differ from that of healthy controls. Conclusion: The pupillary response to blue light was decreased in the glaucomatous eyes of unilateral glaucoma. No difference was detected between the pupillary light response of the unafflicted fellow eyes and that of a healthy, age-matched control group. Thus no sign of an adaptive mechanism was detected, neither in the glaucomatous nor in the unafflicted fellow eyes, and consequently glaucoma appears to differ from non-arteritic anterior ischemic optic neuropathy. © 2014 Nissen, Sander, Milea, Kolko, Herbst, Hamard and Lund-Andersen.Publication Differentially Expressed miRNAs in Hepatocellular Carcinoma Target Genes in the Genetic Information Processing and Metabolism Pathways(2016) Thurnherr, T; Mah, W.-C; Lei, Z; Jin, Y; Rozen, S.G; Lee, C.G; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOL; BIOCHEMISTRYTo date, studies of the roles of microRNAs (miRNAs) in hepatocellular carcinoma (HCC) have either focused on specific individual miRNAs and a small number of suspected targets or simply reported a list of differentially expressed miRNAs based on expression profiling. Here, we seek a more in-depth understanding of the roles of miRNAs and their targets in HCC by integrating the miRNA and messenger RNA (mRNA) expression profiles of tumorous and adjacent non-tumorous liver tissues of 100 HCC patients. We assessed the levels of 829 mature miRNAs, of which 32 were significantly differentially expressed. Statistical analysis indicates that six of these miRNAs regulate a significant proportion of their in silico predicted target mRNAs. Three of these miRNAs (miR-26a, miR-122, and miR-130a) were down-regulated in HCC, and their up-regulated gene targets are primarily associated with aberrant cell proliferation that involves DNA replication, transcription and nucleotide metabolism. The other three miRNAs (miR-21, miR-93, and miR-221) were up-regulated in HCC, and their down-regulated gene targets are primarily involved in metabolism and immune system processes. We further found evidence for a coordinated miRNA-induced regulation of important cellular processes, a finding to be considered when designing therapeutic applications based on miRNAs. © 2016, Nature Publishing Group. All rights reserved.Publication Tracheal Hemangioma: The "cherry" in the Trachea(Hindawi Limited, 2016) Hsu, A.A.L; Takano, A.M.P; DUKE-NUS MEDICAL SCHOOL[No abstract available]Publication Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E(2014) Saadat, K.A.S.M; Murakami, Y; Tan, X; Nomura, Y; Yasukawa, T; Okada, E; Ikeda, Y; Yanagi, Y; DUKE-NUS MEDICAL SCHOOLIn this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules. © 2014 The Authors.Publication Conformational changes in intact dengue virus reveal serotype-specific expansion(Nature Publishing Group, 2017) Lim, X.-X; Chandramohan, A; Lim, X.Y.E; Bag, N; Sharma, K.K; Wirawan, M; Wohland, T; Lok, S.-M; Anand, G.S; BIOLOGY; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOL; BIOCHEMISTRYDengue virus serotype 2 (DENV2) alone undergoes structural expansion at 37 °C (associated with host entry), despite high sequence and structural homology among the four known serotypes. The basis for this differential expansion across strains and serotypes is unknown and necessitates mapping of the dynamics of dengue whole viral particles to describe their coordinated motions and conformational changes when exposed to host-like environments. Here we capture the dynamics of intact viral particles of two serotypes, DENV1 and DENV2, by amide hydrogen/deuterium exchange mass spectrometry (HDXMS) and time resolved Förster Resonance Energy Transfer. Our results show temperature-dependent dynamics hotspots on DENV2 and DENV1 particles with DENV1 showing expansion at 40 °C but not at 37 °C. HDXMS measurement of virion dynamics in solution offers a powerful approach to identify potential epitopes, map virus-antibody complex structure and dynamics, and test effects of multiple host-specific perturbations on viruses and virus-antibody complexes. © The Author(s) 2017.Publication Regulation of white and brown adipocyte differentiation by RhoGAP DLC1(2017) Sim C.K.; Kim S.-Y.; Brunmeir R.; Zhang Q.; Li H.; Dharmasegaran D.; Leong C.; Lim Y.Y.; Han W.; Xu F.; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOL; BIOCHEMISTRYAdipose tissues constitute an important component of metabolism, the dysfunction of which can cause obesity and type II diabetes. Here we show that differentiation of white and brown adipocytes requires Deleted in Liver Cancer 1 (DLC1), a Rho GTPase Activating Protein (RhoGAP) previously studied for its function in liver cancer. We identified Dlc1 as a superenhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPAR?, the master regulator of adipogenesis. We further observed that Dlc1 expression increases during differentiation, and knockdown of Dlc1 by siRNA in white adipocytes reduces the formation of lipid droplets and the expression of fat marker genes. Moreover, knockdown of Dlc1 in brown adipocytes reduces expression of brown fat-specific genes and diminishes mitochondrial respiration. Dlc1-/- knockout mouse embryonic fibroblasts show a complete inability to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), suggesting the involvement of Rho pathway in DLC1-regulated adipocyte differentiation. Furthermore, PPAR? binds to the promoter of Dlc1 gene to regulate its expression during both white and brown adipocyte differentiation. These results identify DLC1 as an activator of white and brown adipocyte differentiation, and provide a molecular link between PPAR? and Rho pathways. © 2017 Sim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.