Serum Urate Concentrations and the Risk of Hyperuricemia

Serum Urate Concentrations and the Risk of Hyperuricemia Common UCP2 variants contribute to serum urate concentrations and the risk of hyperuricemia Luyu Yang, Zheng Dong, Jingru zhou, Yanyun Ma, Weilin Pu, Dongbao Zhao, Hongjun He, Hengdong Ji, Yajun Yang, Xiaofeng Wang, Xia Xu, Yafei Pang, Hejian Zou,  Li Jin,  Chengde Yang*, Jiucun Wang* *Corresponding author These authors equally contributed to this study.   Abstract Elevated serum urate, which is regulated at multiple levels including genetic variants, is a risk factor for gout and other metabolic diseases. This study aimed to investigate the association between UCP2 variants and serum urate as well as hyperuricemia in a Chinese population. In total, 4332 individuals were genotyped for two common UCP2 variants, -866G/A and Ala55Val. These loci were not associated either serum urate level or with a risk of hyperuricemia in the total group of subjects. However, in females, -866G/A and Ala55Val were associated with a lower serum urate (P = 0.006 and 0.014à ¯Ã‚ ¼Ã…’seperately) and played a protective role against hyperuricemia (OR = 0.80, P = 0.018; OR = 0.79, P = 0.016). These associations were not observed in the males. After further stratification, the two loci were associated with serum urate in overweight, but not underweight females. The haplotype A-T (-866G/A-Ala55Val) was a protective factor for hyperuricemia in the female subgroup (OR = 0.80, P=0.017). This present study identified a novel gene, UCP2, that influences the serum urate concentration and the risk of hyperuricemia, and the degree of association varies with gender and BMI levels.   Introduction Uric acid is the final product of purine oxidation in humans. Elevated serum urate, or hyperuricemia, has long been recognized as an independent risk factor for gout [1-2]. There is a renewed interest in hyperuricemia and its association with a number of other clinical disorders including hypertension, atherosclerosis, cardiovascular disease, chronic kidney diseases, and abdominal obesity, glucose intolerance, insulin resistance, and dyslipidemia, which are often subsumed under the term metabolic syndrome [3]. Serum urate is balanced between uric acid production in the liver and its disposal via the kidney and gut [4]. The occurrence of hyperuricemia could be caused by disruptions in any part of this metabolic process. Both genetic and environmental factors, such as gender and body mass index (BMI), have a strong effect on the risk of hyperuricemia [3]. Among those factors, the attribution of genetic factors is estimated to be as high as 73% [5]. Recent genome-wide association studies (GWAS) have identified 28 loci associated with serum urate concentration [6]. However, only approximately 7% of the variation in serum urate concentration could be explained by those reported loci, suggesting the missing heritability remained to be explored [6]. Human uncoupling proteins (UCPs) are mitochondrial transporters present in the inner membrane of mitochondria [7]. UCPs are capable of uncoupling ATP production from mitochondrial respiration by causing proton leak and preventing mitochondrial hyperpolarization and the formation of reactive oxygen species (ROS) [8]. Among the five identified UCPs, UCP2 is widely expressed in almost all mammalian tissues including white adipose tissue, liver, kidney, pancreatic islets, macrophages and retinal endothelial cells, indicating its involvement in a variety of physiologic or pathologic events [9-12]. Two of the most common polymorphisms of this gene, -866G/A (rs659366) in the promoter and Ala55Val (rs660339) in codon 55, were identified as being associated with different phenotypes [7, 12], including obesity, insulin resistance, type 2 diabetes mellitus (T2D), low-density lipoprotein (LDL) particle size, coronary incidence and other metabolic disorders [9-10, 13-21]. Given the involvement of UCP2 and hyperuricemia in a variety of metabolic disorders, we selected the two common loci -866G/A and Ala55Val to explore the association between genetic UCP2 variants and hyperuricemia in a Chinese population, offering a new diagnostic or therapeutic target for hyperuricemia. Results There was no  association between SNPs and serum urate The two loci were proven in Hardy-Weinberg equilibrium (-866G/A: P = 0.990; Ala55Val: P = 0.690). For -866G/A, AA, AG, and GG genotypes accounted for 21.6%, 49.9%, and 28.6% of hyperuricemic patients, respectively; in healthy controls, the distribution was 21.2%, 49.6%, and 29.3%, respectively. As shown in Table 1, the -866G/A polymorphism was not found to be associated with serum urate (AA/GG: Beta = -0.008, P = 0.644; AG/GG:Beta = -0.012, P = 0.474) or with the risk of hyperuricemia (AA/GG: OR = 1.05, P = 0.603; AG/GG:OR = 1.03, P = 0.667). For Ala55Val, the TT, TC, and CC genotype distribution was 21.5%, 50.5% and 28.0% in hyperuricemic patients, respectively, and the distribution was 21.5%, 49.8% and 28.6% in healthy controls, respectively. No association was observed between Ala55Val polymorphism and serum urate (TT/CC: Beta = -0.013, P = 0.460; TC/CC:Beta = -0.017, P = 0.324). There was no difference in the distribution of the genotypes or alleles among hyperuricemic patients a nd healthy controls (TT/CC: OR = 1.02, P = 0.824; TC/CC:OR = 1.04, P = 0.652). Therefore, no statistically solid evidence supported the genetic effect of -866G/A and Ala55Val on serum urate or the risk of hyperuricemia in the total group of subjects. UCP2 variants were associated withserum urate andhyperuricemia in female subgroups As shown in Table 1, we stratified all subjects into male and female subgroups to further explore the gender-related genetic effects of the two polymorphisms. In the male subgroups, there were no significant associations between the two loci and serum urate or the risk of hyperuricemia (all P > 0.025). However, some nominal significant associations were found between -866G/A and the hyperuricemia risk (genotype AA: OR = 1.26, P = 0.038; allele A: OR = 1.12, P = 0.035), indicating a possible risky effect of the -866G/A variant on hyperuricemia incidence in males. A significant association was found between SNPs and serum urate and hyperuricemia in the female subgroups. The -866G/A genotypes were associated with a lower serum urate (AA/GG: Beta = -0.078, P = 0.015; AG/GG: Beta = -0.104, P = 0.001) and a decreased risk of hyperuricemia (AG/GG: OR = 0.71, P = 0.025). The subjects carrying allele A had a lower serum urate and a decreased risk of hyperuricemia (A/G: Beta = -0.054, P = 0.006; OR = 0.80, P = 0.018). For Ala55Val, genotype TT carriers showed a lower serum urate (TT/CC: Beta = -0.075, P = 0.022) and a decreased risk of hyperuricemia (TT/CC: OR = 0.64, P = 0.020). Genotype TC carriers only had a lower serum urate (TC/CC: Beta = -0.082, P = 0.012) but no decreased risk of hyperuricemia (TC/CC: OR = 0.77, P = 0.093). Allele T was associated with a lower serum urate (T/C: Beta = -0.049, P = 0.016) and a decreased risk of hyperuricemia (T/C: OR = 0.79, P = 0.016). Further analysis of associationin females  with different BMI levels Further analysis was performed regarding the genetic effect of UCP2 variants on serum urate and the risk of hyperuricemia among females with different BMI levels (Table 2). The majority of the females enrolled were stratified into normal- or overweight group (Table 2). In the underweight subgroup, whose sample size was limited after stratification, no significant association was observed between the two loci and serum urate or hyperuricemia risk (all P > 0.025, Table 2). In the normal weight subgroup, -866G/A genotype AA+AG carriers were associated with a lower serum urate (AA+AG/GG: Beta = -0.095, P = 0.022) but not with a decreased risk of hyperuricemia (AA+AG/GG: OR = 0.65, P = 0.076). However, the Ala55Val genotypes or alleles showed no statistical association with serum urate (TT+TC/CC: Beta = -0.070, P = 0.091; T/C: Beta = -0.047, P = 0.106) or hyperuricemia (TT+TC/CC: OR = 0.72, P = 0.173; T/C: OR = 0.72, P = 0.051). In the overweight subgroup, the genotypes of both loci were associated a lower serum urate (AA+AG/GG: Beta = -0.138, P = 0.001; TT+TC/CC: Beta = -0.130, P = 0.003) and a significant, or at least marginal, decreased risk of hyperuricemia (AA+AG/GG: OR = 0.62, P = 0.015; TT+TC/CC: OR = 0.74, P = 0.027). However, the alleles of the loci were associated with a lower serum urate level (A/G: Beta = -0.072, P = 0.019; T/C: Beta = -0.072, P = 0.019) but not with a decreased risk of hyperuricemia (A/G: OR = 0.75, P = 0.036; T/C: OR = 0.74, P = 0.027). Our results suggested a stronger effect of UCP2 variants on overweight females than on normal weight females (Table 2). Association between haplotypes and risk of hyperuricemia As listed in Table 3, the haplotypes of the two loci were estimated in the total group of subjects and after stratification by gender. The -866G/A and Ala55Val variants were in strong linkage disequilibrium (D = 0.974, r2 = 0.936). The wild type haplotype G-C (-866G/A-Ala55Val) was applied as the reference one. Haplotype A-T made up for the most frequent one, while single mutation at -866G/A or Ala55Val each accounted for less than 1 percent (Table 3). In the total group of subjects, no haplotypes were correlated with susceptibility of hyperuricemia. In the female subgroups, haplotype A-T (-866G/A-Ala55Val) was associated with a decreased risk of hyperuricemia; however, this association was null in males. No further significant associations between hyperuricemia and other two rare haplotypes were found in our study, partly due to the limited size of the rare haplotypes carriers (Table 3). These results correlated with the association between genotypes or alleles and hyperuricemia (Ta ble 1). Discussion Uncoupling protein 2 (UCP2) is present in the inner mitochondrial membrane and mainly decreases the ATP level and ROS produced by electron transport; therefore, UCP2 is involved in a board range of pathological processes. In the present study, we first focused on the relationship between UCP2 variants and serum urate and hyperuricemia, potentially examining the scope of the loci related to hyperuricemia. The present study revealed no association between the two polymorphisms of UCP2 and serum urate or hyperuricemia in the total group of subjects. However, because serum urate is extensively influenced by gender differences, we stratified the total group of subjects and determined that -866G/A and Ala55Val were associated with serum urate and hyperuricemia in females [25-26]. Females with the -866G/A genotype AA+AG or allele A had lower serum urate and a decreased risk of hyperuricemia, indicating a protective role of -866G/A for hyperuricemia in females. The -866G/A variant is a functional polymorphism located in the promoter region and putatively changes the transcription factor binding sites [7]. The wild type G allele in -866G/A was associated with lower UCP2 mRNA expression [19, 27]. Increased UCP2 mRNA expression from the A allele was translated into an increased amount of UCP2 protein, with corresponding induced proton leak, decreased ATP/ADP ratio and enhanced elimination of ROS [10, 19]. Hypermethylation in the promoter region could affect the binding of transcripation factors, causing aberrant gene expression. Consistent with our expectations, we found a typical CpG island in the UCP2 promoter region, which included the locus of the -866G/A variant, using information from the University of California-Santa Cruz (UCSC; Santa Cruz, CA, USA) database (http://genome.ucsc.edu/cgi-bin/hgGateway). We believe the UCP2 promoter variant -866G/A could shape this CpG island and protect the UCP2 promoter region from DNA methylation, unco vering a novel underlying mechanism that determines -866G/A increases UCP2 transcription. Uric acid accumulation is caused by the acceleration of ATP degradation to AMP, a precursor of uric acid, and UCP2 could decrease the ATP level and lower redundant AMP for uric acid formation [7, 28]. Moreover, an elevation of serum urate concentration occurs as a physiologic response to increased oxidative stress [31]. Because the ROS level could be down-regulated by UCP2, a counter-regulatory increase of serum urate as an antioxidant defense is less urgent. Therefore, the -866G/A variant in the promoter region might serve as a protective factor through a higher UCP2 mRNA level and increased translation of the UCP2 protein, which might regulate ROS and modify the ATP/ADP ratio. The other locus, Ala55Val, is a missense variant in exon 4 and is associated with an altered degree of uncoupling [7]. In our study, a protective effect for hyperuricemia and lower serum urate were observed in genotype TT and allele T in the female subgroups. However, the genetic effect of the Ala55Val variant was less clear. Several researchers identified an association of Ala55Val with the BMI level and type 2 diabetes mellitus (T2D), with controversial conclusions within cohorts, and few functional studies were performed [14, 32-33]. Similar to -866G/A, the protective role of the Ala55Val variant for hyperuricemia might also be attributed to altered UCP2 transcription. In the male subgroups, a less statistically significant but possible effect of -866G/A and Ala55Val was observed for hyperuricemia risk and higher serum urate. Similar gender-associated genetic effects of UCP2 variants were more or less observed for diseases other than hyperuricemia [7]. For example, Heidema et al. suggested a genetic effect of UCP2 on weight gain was regulated through different mechanism in males and females [34]. Lee, et al. demonstrated that the association between UCP2 variants and BMI was more apparent among female subjects [35]. Cheurfa et al. confirmed the association of UCP2 variants with coronary artery diseases in males but not females [36]. In the present study, we found UCP2 variants -866G/A and Ala55Val had a stronger effect on females with hyperuricemia. One possible explanation for the gender-associated genetic effects of UCP2 might be a regulation role of sex hormones such as estrogen. Estrogen was reported to repress UCP2 in a breast cancer cell line and papillary thyroid cancer cells [37-38]. Taken together, these results suggest the UCP2 protein level was down-regulated by estrogen in females but reversed by the variants of -866G/A and Ala55Val, providing a plausible explanation for the specific protective effects of UCP2 variants on females [37]. Genetic effects on hyperuricemia and obesity have been widely recognized [3]. In the present study, we found that -866G/A and Ala55Val were associated with lower serum urate and a decreased risk of hyperuricemia in overweight, but not underweight, females (Table 2). The relative small sample size might limit the correlation analysis in the underweight group. However, we did observe females with higher BMI level were more likely to benefit from the protective genetic effect of -866G/A and Ala55Val, where the association was significant between the two SNPs and serum urate level of risk of hyperuricemia. In the contrast, among the normal weight females, -866G/A, but not Ala55Val, showed a significant association with a low risk of hyperuricemia, indicating a less contribution from the protective effect of UCP2 variants than seen in overweight females. It was also implied from our results that the [tw1]functional à ¢Ã‹â€ Ã¢â‚¬â„¢866G>A promoter variant displayed a stronger effect. The interactions between obesity, uric acid and UCP2 were complicated. BMI has long been viewed as an essential factor influencing uric acid [3]. UCP2 transcription was activated by fatty acids [16]. A recent meta-analysis revealed that UCP2 -866G/A and Ala55Val are associated with a risk of obesity [32]. Subtle intermediary obesity related phenotypes such as elevated triglycerides, total cholesterol concentrations, increased the risk of dyslipidemia and circulating leptin levels were also observed to be correlated with UCP2 variants [40]. Based on these results, we assumed lipid metabolism material such as fatty acids participated in and enhanced the genetic effect of UCP2 variants on serum urate regulation, explaining the stronger genetic effect of UCP2 variants on females with higher BMI levels observed in the present study. The -866G/A and Ala55Val variants were in strong linkage disequilibrium (D = 0.974, r2 = 0.936). The haplotype frequency analysis revealed that variants of the two loci were more in co-variant haplotype A-T (-866G/A-Ala55Val) compared with the single variant forms of G-T or A-C (Table 3). Haplotype A-T was associated with a decreased risk of hyperuricemia only in females, which was consistent with the genotype or alleles results. However, the small size of the two rare haplotypes might limit the power of association analysis with hyperuricemia risk to a certain extent. The susceptibility of hyperuricemia in the two rare haplotype carriers required validation in a larger cohort. Conclusion The present study identified a novel gene, UCP2, with two loci, -866G/A and Ala55Val; this gene influenced the serum urate concentrations and the risk of hyperuricemia in females. The associations of those loci were affected by gender and BMI. This study supported the potential involvement of this gene in the prevention, prediction and treatment of hyperuricemia. Materials and methods Experimental design A total of 4332 subjects were enrolled from the Taizhou Longitudinal Study [22] and included 1387 hyperuricemic patients and 2945 healthy controls. The associations of common UCP2 variants with serum urate and hyperuricemia were tested by linear regression and logistic regression with or without gender stratification, respectively. A body mass index (BMI) subgroup was also used for further analysis. Participants All subjects were enrolled from Taizhou Longitudinal Study [22], of which 1387 individuals had serum urate level over 7 mg/dl and were treated as hyperuricemic patients, and 2945 individuals had normal serum urate (à ¢Ã¢â‚¬ °Ã‚ ¤ 7 mg/dl) and were treated as healthy controls [23]. The subjects were divided into subgroups (underweight: BMI à ¯Ã¢â€š ¬Ã‚ ¼ 18.5; normal weight: 18.50 à ¯Ã¢â‚¬Å¡Ã‚ £ BMI Genetic analysis Genetic analysis was carried out in accordance with the written informed consent and guideline offered by the Ethical Committees of the School of Life Science of Fudan University. For genetic analysis, peripheral blood was collected from all the individuals included in this study. Genomic DNA was extracted from whole blood using the QIAamp DNA Blood Mini kit (QIAGEN, Germany) and was stored at -20à ¢Ã¢â‚¬Å¾Ã†â€™. The DNA concentration and quality (including optical density (OD) 260/280 and 260/230 measurements) were determined using a Nanodrop Lite spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). Genotyping of -866G/A and Ala55Val in UCP2 were performed by SNPscan according to the manufacturers instructions. Statistical analysis The clinical characteristics were presented as the mean à ¯Ã¢â‚¬Å¡Ã‚ ± SD. Students t-test was used to test for a significant difference in the mean age, BMI and serum urate between hyperuricemic patients and healthy controls. The chi-square test was used to describe the gender distribution difference between hyperuricemic patients and healthy controls. The chi-square test was used to test Hardy-Weinberg equilibrium (HWE) of the two loci. We conducted a logistic regression analysis to calculate adjusted odd ratio (OR) with 95% confidence interval (95% CI) and P-values to describe the distribution of -866G/A and Ala55Val adjusted for age and gender between hyperuricemic patients and healthy controls. A linear regression was performed to calculate Beta and P-values to estimate the effect on serum urate in different genotypes and alleles. Genotype GG, allele G of -866G/A and genotype CC, allele C of Ala55Val were used as references, respectively. Stratification into subgroups was performed on the basis of gender and different BMI values for further analysis. Haplotype frequencies between the hyperuricemic patients and controls were estimated by OR (95% CI) and chi-square test. The haplotype of the most frequent (-866G/A-Ala55Val, G-C) was used as the reference. A 2-sided P-value less than 0.025 was considered statistically significant after multiple correlation by Bonferroni method. The PHASE program (V2.1) was used for haplotype frequencies estimation, and SPSS 19.0 was used for the statistical analysis. References 1. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143(7):499-516. 2.  Weaver AL. Epidemiology of gout. Cleve Clin J Med 2008;75 Suppl 5:S9-12. 3.  Billiet L, Doaty S, Katz JD, Velasquez MT. Review of hyperuricemia as new marker for metabolic syndrome. ISRN Rheumatol 2014;2014:852954. 4.  Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology (Bethesda) 2005;20:125-33. 5.  Kolz M, Johnson T, Sanna S, Teumer A, Vitart V, Perola M, et al.. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet 2009;5(6):e1000504. 6.  Kà ¶ttgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J, Hundertmark C, et al.. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nature Genetics 2012;45(2):145-154. 7.  Donadelli M, Dando I, Fiorini C, Palmieri M. UCP2, a mitochondrial protein regulated at multiple levels. In; 2014. p. 1171-90. 8.  Azzu V, Jastroch M, Divakaruni AS, Brand MD. The regulation and turnover of mitochondrial uncoupling proteins. Biochimica et Biophysica Acta (BBA) Bioenergetics 2010;1797(6-7):785-791. 9.  Dalgaard LT, Andersen G, Larsen LH, Sorensen TI, Andersen T, Drivsholm T, et al.. Mutational analysis of the UCP2 core promoter and relationships of variants with   obesity. Obes Res 2003;11(11):1420-7. 10. Dalgaard LT. Genetic Variance in Uncoupling Protein 2 in Relation to Obesity, Type 2 Diabetes, and Related Metabolic Traits: Focus on the Functional -866G>A Promoter Variant (rs659366). J Obes 2011;2011:340241. 11. Rousset S, Mozo J, Dujardin G, Emre Y, Masscheleyn S, Ricquier D, et al.. UCP2 is a mitochondrial transporter with an unusual very short half-life. FEBS Lett 2007;581(3):479-82. 12. Jarmuszkiewicz W, Woyda-Ploszczyca A. [Mitochondrial uncoupling proteins: regulation and physiological role]. Postepy Biochem 2008;54(2):179-87. 13. Yu X, Wieczorek S, Franke A, Yin H, Pierer M, Sina C, et al.. Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases. In; 2009. p. 601-5. 14. Rosmond R, Bouchard C, Bjorntorp P. Lack of association between the uncoupling protein-2 Ala55Val gene polymorphism and phenotypic features of the Metabolic Syndrome. Biochim Biophys Acta 2002;1588(2):103-5. 15.  Heidari J, Akrami SM, Heshmat R, Amiri P, Fakhrzadeh H, Pajouhi M. Association study of the -866G/A UCP2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population: a case control study. Arch Iran Med 2010;13(5):384-90. 16.  Emre Y, Nà ¼bel T. Uncoupling protein UCP2: When mitochondrial activity meets immunity. In; 2010. p. 1437-1442. 17. Toda C, Diano S. Mitochondrial UCP2 in the central regulation of metabolism. Best Pract Res Clin Endocrinol Metab 2014;28(5):757-64. 18. Shen Y, Wen Z, Wang N, Zheng Z, Liu K, Xia X, et al.. Investigation of variants in UCP2 in Chinese type 2 diabetes and diabetic retinopathy. PLoS One 2014;9(11):e112670. 19. Sesti G, Cardellini M, Marini MA, Frontoni S, DAdamo M, Del GS, et al.. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003;52(5):1280-3. 20.  Otaegui D, Saenz A, Ruiz-Martinez J, Olaskoaga J, Lopez DMA. UCP2 and mitochondrial haplogroups as a multiple sclerosis risk factor. In; 2007. p. 454-8. 21.  Oktavianthi S, Trimarsanto H, Febinia CA, Suastika K, Saraswati MR, Dwipayana Pà ¦Ã¢â‚¬ ºÃ‚ ´AW, et al.. Uncoupling protein 2 gene polymorphisms are associated with obesity. Cardiovascular diabetology 2012;11(1):41. 22.  Wang X, Lu M, Qian J, Yang Y, Li S, Lu D, et al.. Rationales, design and recruitment of the Taizhou Longitudinal Study. BMC Public Health 2009;9:223. 23.  Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med 2008;75 Suppl 5:S5-8. 24.  WHO Global Database on Body Mass Index (BMI): an interactive surveillance tool for monitoring nutrition transition. Public Health Nutr. 2006; 9(5):658-. doi:10.1079/Phn2006967. ISI:000239972300019.. 25. Terkeltaub RA. Clinical practice. Gout. N Engl J Med 2003;349(17):1647-55. 26.  Neogi T. Clinical practice. Gout. N Engl J Med 2011;364(5):443-52.   Ã‚   27.  Lapice E, Pinelli M, Pisu E, Monticelli A, Gambino R, Pagano G, et al.. Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients. Cardiovasc Diabetol 2010;9:68. 28.  Richette P, Bardin T. Gout. Lancet 2010;375(9711):318-28. 29. Waring WS, Webb DJ, Maxwell SR. Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers. J Cardiovasc Pharmacol 2001;38(3):365-71. 30. Zhang M, Wang M, Zhao Z. Uncoupling protein 2 gene polymorphisms in association with overweight and obesity susceptibility: A meta-analysis. Meta Gene 2014;2:143-159. 31.Vogler S, Goedde R, Miterski B, Gold R, Kroner A, Koczan D, et al.. Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J Mol Med (Berl) 2005;83(10):806-11. 32.Heidema AG, Wang P, van Rossum CT, Feskens EJ, Boer JM, Bouwman FG, et al.. Sex-specific effects of CNTF, IL6 and UCP2 polymorphisms on weight gain. Physiol Behav 2010;99(1):1-7. 33.Lee YH, Kim W, Yu BC, Park BL, Kim LH, Shin HD. Association of the ins/del polymorphisms of uncoupling protein 2 (UCP2) with BMI   in a Korean population. Biochem Biophys Res Commun 2008;371(4):767-71. 34.Cheurfa N, Dubois-Laforgue D, Ferrarezi DA, Reis AF, Brenner GM, Bouche C, et al.. The common -866G>A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men. Diabetes 2008;57(4):1063-8. 35.Nadal-Serrano M, Sastre-Serra J, Pons DG, Miro AM, Oliver J, Roca P. The ERalpha/ERbeta ratio determines oxidative stress in breast cancer cell lines in response to 17beta-estradiol. J Cell Biochem 2012;113(10):3178-85. 36.Hima S, Sreeja S. Regulatory role of estrogen-induced reactive oxygen species in the modulatory function of UCP 2 in papillary thyroid cancer cells. IUBMB Life 2015. 37.Hamada T, Kotani K, Fujiwara S, Sano Y, Domichi M, Tsuzaki K, et al.. The UCP2-866 A/A genotype is associated with low density lipoprotein particle sizes in the general population. Med Sci Monit 2008;14(3):CR107-11. Acknowledgements This research was supported by grants from the Science and Technology Committee of Shanghai Municipality (11DJ1400100), International ST Cooperation Program of China (2013DFA30870), Ministry of Science and Technology (2011BAI09B00), and Program for 2012 Outstanding Medical Academic Leader for Hejian Zou. The computations involved in this study were supported by Fudan University High-End Computing Center. Author contributions statement

Malaria Life Cycle :: essays research papers

Page 1 of 6 Life Cycle of Malaria Page 2 of 6 Malaria is an ancient disease transmitted by the Anopheles mosquito that predates recorded history. Historically it was common in the swampy areas around Rome, and was believed that the tainted air in those locations made people very sick, the disease was therefore named malaria for the Latin root words bad air. Malaria is caused by small parasitic protozoa of the genus Plasmodium which infects both humans and mosquitoes in a cyclical process. It is carried by only by female mosquitoes residing in tropical and subtropical areas and is injected into unsuspecting human hosts by the bite of an infected mosquito. This particular Plasmodium is highly specific to infecting humans as we are the only vertebrates infected and the Anopheles mosquitoes are the vectors. (1). This papers main focus shall be the process by which a malarial plasmodium colonizes and infects a human host, the methods the body employs to control the infection and the continuous life cycle completed between the two hos ts. To understand any disease in humans one must first understand how it arrives into the body and what processes ensue. The following shall first describe the transmition of the disease and then the colonization that takes place. During a blood meal on a human a female mosquito must inject her saliva containing an anticoagulant agent to ensure and even flow of blood into the mouth (1). With the saliva comes malarial sporozoites which, within minutes of direct contact with the blood take an immediate route with the circulation of blood to the liver of the human (2). Research has indicated that once the sporozoites arrive in the livers sinusoidal cavities they stop their movement by using two major surface proteins, the circumsporozoite and the thormbospondin-related adhesive protein (3). Research Page 3 of 6 conducted by Pradel et al. suggests that the sporozoites use these surface proteins to attach to proteoglycans in the sinusoidal extracellular matrix to slow their travel through the liver and then bind to chondroiten and heparin sulfate proteoglycans on the Kupfer cells. The Kupfer cells then become the doorways through which the sporozoite leaves the circulatory system and enters the underlying hepatocytes. Once the sporozoites invade the hepatocytes they are protected from the immune system by a parasitophosphorous (4) vacuole that does not colocalize with the normal signals for acidifying organelles (2). Because the body doesn’t recognize the vacuole as a threat at this point it remains safely with in the hepatic cell where it will stay for 9-16 days and differentiate into haploid cells called schizont which contain nearly 30,000 compact cells called merozoites (1).

George Orwell’s Nineteen Eighty-Four Essay

George Orwell’s Nineteen Eighty-Four is a dystopian novel which presents an exagerated version of a totalitarian regime which not only controlled everything but which also could not be removed by any means. Orwell’s novel drew attention, back in 1949 when the novel was published, upon how this world would look like if a totalitarian regime would truly take over. My aim for this essay is to analyze Orwell’s novel with respect to the marxist elements present in the novel and also to illustrate their impact upon the protagonist’s feelings. Marxism and especially Stalinism are present in Orwell’s novel through certain elements: countinuous surveillance, control of the mind, the cult of personality and a supposed â€Å"equality† between the Party’s members. Isaac Asimov, in his essay Review of 1984, considers Orwell as a writer with not much of an imagination, accusing him of not developing in the novel the actual communist actions which were happening in reality. â€Å"Orwell imagines Great Britain to have gone through a revolution similar to the Russian Revolution and to have gone through all the stages that Soviet development did. He can think of almost no variations on the theme. I believe, though, that Orwell was an extraordinary visionary who pictured a society chained in nothing but governmental controll, a society which cannot be defeated. A communist concept presented in the novel is that of the powerless individual and of the high disregard the Party had for individualism. Everybody must form a group with everybody – this is the recipe for power, according to any communism regime. In 1984, history is continuously rewritten and in this way, the population’s memories are restricted only to what appears in the remaining articles after rewriting; it can be seen as another way of mind control. Winston himself discovers that most of what the Party states is lies and towards the end of the novel, when Oceania suddenly becomes enemies with Eastasia, the country with which it had been allies all along, everybody is forced to conceive that they have â€Å"always been at war with Eastasia†. Ramesh K. writes in his essay Socio-Cultural Matrix in George Orwell’s Nineteen Eighty Four that â€Å"history is constantly rewritten to suit the current goals of the Party. Only the destruction of human memory will make it possible. Hence the Ministry of Truth (Minitru) modifies history perpetually to the tune of the ideals of the Party†. As a result of the rewriting of history is the loss of memories. Nobody remembers how life looked like â€Å"before† Big Brother, and yet nobody seems to find it as disturbing as Winston does. He barely remembers his family, and he suspects that most of his memories are only a product of his imagination. He has problems recalling maternal love; he sometimes feels guilty for his parents’ disappearance and he constantly regrets his childhood behavior. When regarding history, the only existing proof or better said, evidence, of such distant civilizations, ones before Big Brother, is written in censored books, created by the Party itself, with carefully selected details which attempt to illustrate how life is much better in the year of 1984, with the Ingsoc regime, then before the totalitarian era. Truth is continuously distorted and it can be regarded as close to extinction, since nobody has a correct notion of what is or is not true, anymore. Memories are vague and the ones vivid are imposed, influenced by the Party. The loss of memories the whole society experiences may also be a result of the continuous flow of new information which constantly contradicts the old one and which, in its turn, is recreated over and over again. The process of rewriting history is described in 1984: â€Å"This process of continuous alteration was applied not only to newspapers, but to books, periodicals, pamphlets, posters, leaflets, films, sound-tracks, cartoons, photographs – to every kind of literature or documentation which might conceivably hold any political or ideological significance† (Orwell, Part 1, Chapter 4, p. 1). The cult of personality has a huge influence on Orwell’s dystopia, as on any other totalitarian society. Big Brother has been associated by the critics with Stalin, while his political enemy, another alleged founder of the Party, Emmanuel Goldstein, was seen as the correspondent of Trotsky, Stalin’s enemy in the power struggle from the 1920s. Like Trotsky, Goldstein was deported and excluded from the Party. According to Isaac Asimov, Orwell’s â€Å"enemy was Stalin, and at the time that 1984 was published, Stalin ad ruled the Soviet Union in a ribbreaking bear hug for twenty-five years, had survived a terrible war in which his nation suffered enormous losses and yet was now stronger than ever. To Orwell, it must have seemed that neither time nor fortune could budge Stalin, but that he would live on forever with ever increasing strength. – And that was how Orwell pictured Big Brother†. Big Brother is regarded as immortal, the is no evidence of his actual existence, and even O’Brien hints to the fact that Big Brother is nothing more than the embodiment of the Party. In the fictional book written by Goldstein he states that â€Å"Nobody has ever seen Big Brother. He is a face on the hoardings, a voice on the telescreen. We may be reasonably sure that he will never die, and there is already considerable uncertainty as to when he was born. Big Brother is the guise in which the Party chooses to exhibit itself to the world† (Orwell, Part 2, Chapter 9, p. 262). Big Brother was everywhere: â€Å"On coins, on stamps, on the covers of books, on banners, on posters, and on the wrappings of a cigarette packet – everywhere. Always the eyes watching you and the voice enveloping you. Asleep or awake, working or eating, indoors or out of doors, in the bath or in bed—no escape. Nothing was your own except the few cubic centimetres inside your skull† (Orwell, Part 1, Chapter 2, p. 34). In such a strict society, Winston attempts rebelling against the Party and also falling in love. Once he meets Julia, his double life takes form and he finds himself in a continuous seek for freedom. The relationship between Winston and Julia is, of course, sentenced to permanent influences on behalf of the Party. They attempt to rebell against it but their rebellion is nothing but a narrowed one, with no actual influence upon the Party. In a world where everything, with no exception, has been adapted to completely new rules, where history is continuously modified and the truth is contorsed over and over again, not even love or friendship remain the same. Winston and Julia are supposed to be in love and moreover, they are supposed to be not only friends, but allies in their fight against the system, but in 1984, in this parallel version of totalitarianism Orwell created, friendship and love would always be darkened by the other’s real identity. An example for how love is reduced can be found in the episode when Julia attempts to dress up for Winston, when renting the room above the antiquities shop, a room which does not have a telescreen. She hardly manages to become feminin by using a very bad smelling perfume – which brings about awful memories to Winston – and by wearing ugly – and yet different from the Party’s uniform – clothes. It seems like no one has the ability of being romantic any longer, and even more important, no one has the means of being so. In 1984, no possible love relationship can be imagined and the idea of making love is something strictly forbidden, because making love – and this is something the Party knows very well – makes people happy, and when people are happy, they no longer care for every bad thing that happens in their every day life in the context of a totalitarian society. Julia explained to Winston the Party’s conception: â€Å"When you make love you’re using up energy; and afterwards you feel happy and don’t give a damn for anything. They can’t bear you to feel like that. They want you to be bursting with energy all the time. All this marching up and down and cheering and waving flags is simply sex gone sour. If you’re happy inside yourself, why should you get excited about Big Brother and the Three-Year Plans and the Two Minutes Hate and all the rest of their bloody rot? † (Orwell, Part 2, Chapter 3, p. 167). In the eyes of the Party, there’s no such thing as love or friendship, and even the existing feelings can only be pointed towards Big Brother, the totalitarian leader who can only be seen on the posters all over the city, which show Big Brother’s portrait and a terrifying slogan: â€Å"Big Brother is watching you†. According to Isaac Asimov â€Å"the great Orwellian contribution to future technology is that the television set is two-way, and that the people who are forced to hear and see the television screen can themselves be heard and seen at all times and are under constant supervision even while sleeping or in the bathroom. Hence, the meaning of the phrase ‘Big Brother is watching you’. † Love, as already discussed, is distorted, reduced to physical needs (not even physical pleasure). But, as it is easy to notice, throughout the novel, love remains the Party’s greatest enemy against which they are already fighting through manipulating the children – yet only achieving the destruction of parental love. I consider that children betraying their parents are a symbol and nonetheless, an illustration of what Orwell may have imagined about future generations who will do everything for the Party’s sake – even betray their own mothers and fathers. In my opinion, children when regarded as a symbol, are supposed to â€Å"bring the change into the world†. In 1984 they are the reversed, the opposite version of this concept: children will not change anything, from their point of view, the totalitarian society must and will remain as it is, with few corrections here and there in the history books, when actions and facts begin to contradict with others. â€Å"Nearly all children nowadays were horrible [†¦ ] they were systematically turned into ungovernable little savages, and yet this produced in them no tendency whatever to rebel against the discipline of the Party. On the contrary, they adored the Party and everything connected with it. †¦ ]All their ferocity was turned outwards, against the enemies of the State, against foreigners, traitors, saboteurs, thought-criminals. It was almost normal for people over thirty to be frightened of their own children† (Orwell, Chapter 2, p. 31). As a conclusion, 1984 emphasizes not only on the impact of a totalitarian regime upon the society, but also on its impact upon the individual’s soul, feelings and thoughts. Winston and Julia’s rebellion may be described as an abstract one, because they do not really achieve anything. Oliver Substance, in his essay The Tendency of Man: Nineteen Eighty-Four, states that â€Å"to truly be a rebel, all of one’s actions need to be rebellious, not just the one’s involving the basic human urges. Rebels need plans, or else they end up the same way as every other would-be rebel: in Room 101. † The impact upon the reader has no limit, since the novel leaves so much space for interpretation and continuation. Finally, I would like to end my essay with the following quote from the novel: â€Å"If you can FEEL that staying human is worth while, even when it can’t have any result whatever, you’ve beaten them† (Orwell, Part 2, Chapter 7, p. 210).

Supply Chain Management Essay example - 1672 Words

Supply Chain Management Supply chain management lets an organization get their products of raw goods to the place they are needed at the right time, the right place, and what exactly they have ordered, and at a reasonable cost. It moves from parts supplier to manufacturers to wholesale to retailer then consumer. Supply chain management plays an important role supplying the manufacturers all the way down to the consumer, so they can satisfy their customers, and to have good benefits for their company, if the supply chain management is managed good, they will have a good outcome for their company. Supply chain management does involve some factors; location of facilities of where the goods will be flowing from, production is another†¦show more content†¦The procedures of this chain that takes place in a good way or efficient way they will make their organization have a good outcome, and they will produce more customers. Many or most of the companies that produce raw materials, products, are affected by the supply chain management, once they have their supply chain going and the links of the chain are linked to one another, they have a good outcome for their organization or company it does take planning and implementing the applications to have a good flow going for your raw goods too, and materials to get where they need to be. It is affected anytime during their producing of the materials or products. There are mistakes in the supply chain management that can effect your supply chain management. From one source they do have top ten mistakes running your supply chain management, listing. Always viewing the supply chain as a chain believing that supply chain management is about managing a chain, but its planning the whole chain, not just linking, trying to achieve your business when your always doing business as usual when companies are to comfortable at where they are knowing there are going to be changes or they have to do some rearranging for their market, and being in their comfort zone, they have to face that their will be challenges amongShow MoreRelatedThe Supply Chain Management Of Supply Chains1372 Words   |  6 Pagesthe world. Supply chains are now very complex and flourishing in the global marketplace, but only constructed and managed correctly. My discipline is supply chain management. There are many different functions of the supply chain that make it what it is. Breaking this discipline down to specific job task is difficult because each process in a supply chain, no matter how complex is connected with at least one other process in the supply chain. There is no clear definition of a supply chain. A supplyRead MoreSupply Chain Management : Supply Chains1476 Words   |  6 Pages1.3 Supply Chain Supply chains encompass the companies and the business activities needed to design, make, deliver, and use a product or service. Businesses depend on their supply chains to provide them with what they need to survive and thrive. Every business fits into one or more supply chains and has a role to play in each of them. The pace of change and the uncertainty about how markets will evolve has made it increasingly important for companies to be aware of the supply chains they participateRead MoreSupply Chain Management Of Supply Chains1188 Words   |  5 Pagesthe supply chain, not just a simple competition between enterprises. In order to win the competition in the supply chain, which means it must be through the management of the supply chain. Currently supply chains become more integrated, more global, the high-speed development of information technology has become an important driving force. In this report will explore the development of supply chain management technologies and impor tant role. Supply chain and technologies role Supply chain is theRead MoreSupply Chain Management : Supply Chains Essay831 Words   |  4 Pagesto answer the question of what is supply chain management we must know what a supply chain is. According to (Mentzer et al., 2001, p. 1) â€Å"Supply chain is defined as the network of organisations which are involved in different processes that produce value either in the form of products or services delivered to consumers†. A supply chain is made up of suppliers, manufactures and distributors, a good way of looking at this is the supply chain pipeline. A supply chain is seen as an enabler, this is whyRead MoreSupply Of Supply Chain Management830 Words   |  4 PagesSupply Chain Management Goal of a supply chain. According to Defining the Supply Chain, there are 5 specific goals of supply chain management. They are as follows: 1. Achieve Efficient Fulfillment – â€Å"the purpose of supply chain management is to make inventory readily available in customer facing positions to fulfill demand. The fresh produce business adage â€Å"you can’t sell from an empty wagon† highlights this fundamental purpose of supply chain management†. (Defining the Supply Chain) OrganizationsRead MoreSupply Chain Management986 Words   |  4 Pagesthat are not faced by Dell? How should Ford deal with these challenges? 3. If you are Teri Takai, what would you recommend to senior executives? Tow what degree should Ford emulate Dell’s business model? Herman Miller: Innovation by Design? (Supply Chain Strategy) 1. What are the main elements of Herman Miller’s history, design philospophy, and corporate values? How have they influenced the company’s success? 2. What led Miller SQA to develop a new business model to serve its market? What isRead MoreSupply Chain Management12177 Words   |  49 PagesSUPPLY CHAIN UPPLY HAIN MANAGEMENT ANAGEMENT Report produced for the EC funded project INNOREGIO: dissemination of innovation and knowledge management techniques Sotiris Zigiaris, MSc, BPR engineer by BPR HELLAS SA J A N U A R Y 2 0 0 0 SUPPLY CHAIN MANAGEMENT 1 Contents 1 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.2 Description What is the Supply Chain Management (SCM) What is the importance of Supply Chain Management Supply Chain Management Today Supply Chain Management TomorrowRead MoreSupply Chain Management1730 Words   |  7 PagesSTARBUCKS IT SUPPLY CHAIN MANAGEMENT This is a case that illustrates several facets at once: Globalization Rapid Expansion, Supply Chain Management, ERP Implementation, and IT Infrastructure. This case takes place in 1997. Introduction You have to admire the enthusiasm of Starbucks employees. Store managers have been known to stuff sacks of coffee beans into their cars and race over to help out other stores running low. Exceptional customer service, but certainly no way to run a businessRead MoreSupply Chain Management Value Of Supply Chains1122 Words   |  5 PagesHeading: Supply Chain Management-Value of Supply Chain Introduction: Supply chain management is a complex undertaking that must involve more than one organization’s efforts to succeed. A tremendous amount of skill, time, and money must be present to build and develop relationships, discover and implement a strategy, and use the capabilities of the chain to build quality at an efficient financial rate. Allowing for these requirements, it leaves one to wonder whether supply chain management is a viableRead MoreSupply Of Supply Chain Management Essay2046 Words   |  9 PagesSupply Chain Management involves the process of managing, monitoring, controlling and constantly coordinating supply related activities among manufacturers, suppliers, wholesalers, retailer and the consumers. All this is done while integrating supply management with demand management, not only within but also across companies. Since all the processes involved in managing supply chain activities require a robust system in place, every company turns to technology for efficient and effective synchronization