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The position of heritage hotels in place making narratives is not secure, given the challenges of new local developments and larger international forces. This research examines Singapore’s iconic luxury heritage hotel, Raffles Singapore, against the relatively new hotels, The Fullerton Hotel Singapore and Marina Bay Sands, to identify the nexus between the island city-state’s historical and contemporary position in the changing hospitality landscape, specifically addressing the concept of place making as a dynamic narrative. Applying sentiment analysis, 454 hotel guest reviews on internationally recognized travel websites were examined. The findings suggest that the dominance of a luxury heritage hotel in the narratives of place making can shift over time, subject to postmodern architectural developments in the hotel landscape and competition from other luxury heritage hotels with iconic and location histories. A key contribution to the hospitality discipline is the measurement of a luxury heritage hotel’s staying power through continuous place making amid glocal challenges. The significance of the findings should alert hospitality practitioners specializing in marketing to potential shifts arising from continuing new competitive narratives in place making.

This study explores two different destination membership card models with the aim of developing a comprehensive framework for understanding this aspect of elite travel. Through a comparative analysis of the different types of destination membership cards, we develop a model that situates tourism knowledge and suggests areas of further research in this under-explored area. Two important destination membership card models are identified: state supported and private sector based. The state-supported agent offers privileged membership, consolidates resources, and creates exclusive experiences. Conversely, the private-sector-based agent tends to amass the resources offered by destination businesses to create exclusive services and provide special access to resources. Both types are significant agents that channel and empower travellers in the high-end segment, thereby creating further differentiation in products and services in the context of market segmentation. Der vorliegende Artikel widmet sich dem bisher wenig betrachteten Bereich von „Destination Membership Cards“ im Segment der Luxusreisenden. Den Kern des Beitrages stellt eine vergleichende Analyse der beiden zentralen Betreibermodelle derartiger Angebote, namlich den staatlich geforderten beziehungsweise den privatwirtschaftlich organisierten Mitgliedsangeboten, dar. Stark verkurzt, lassen sich fur staatlich unterstutzte Initiativen die Ziele einer privilegierten Mitgliedschaft, der Konsolidierung von Ressourcen und die Schaffung exklusiver Erlebnisse konstatieren. Umgekehrt tendieren Initiativen im privaten Sektor dazu, die von den Zielunternehmen angebotenen Ressourcen anzuhaufen, um exklusive Dienste und einen besonderen Zugang zu Ressourcen zu schaffen. Beide Ansatze stellen interessante Instrumente dar, das Segment der High-End-Reisenden zu starken und zukunftig starker zu beeinflussen. Daruber hinaus fuhren sie zu einer zunehmenden Differenzierung von Produkten und Dienstleistungen und damit zu einer starkeren Marktsegmentierung.

Despite luxury brands’ efforts to incorporate sustainable development into their branding and product design, studies have shown inconclusive evidence about consumers’ reaction towards such efforts. This study investigates how consumption values (i.e. the need for exclusivity, conformity, and hedonism) affect consumers’ acceptance of luxury brands’ sustainable efforts. It adopts a cross-cultural framework by analysing two countries, namely China and the UK, which differ substantially in some of Hofstede’s cultural dimensions, namely power distance, individualism, and indulgence. Using the structural equation modelling in analysing 677 survey responses from actual luxury goods’ consumers in the two countries, we suggest that hedonic needs drive consumers’ purchase intentions in China and the UK. We find that the need for exclusivity in sustainable luxury items is negatively related to consumers’ purchase intentions in China, while the need for conformity is positively related. In contrast, these effects are reversed in the UK. Our study implies the need to align the marketing of sustainable luxury with consumption values of consumers to reflect the cultural differences. In theorizing sustainable luxury research, this study provides a deeper understanding of value perceptions pertaining to luxury product consumption and sustainability. Supplementary Information The online version contains supplementary material available at 10.1057/s41262-020-00228-0.

The importance of traditional architecture and planning of Kanchipuram is expressed through a set of objective and subjective map based indicators. The analysis is done at the block level. The results brings out values expressing the epitome of the traditional architecture and planning. The paper presents the map based analysis of the traditional core. The map based analysis perceives changes in the tissues of the study area. The paper emphasizes the importance of social activities as a key to good urban life. The importance of social activities in par with physical component holding it is also presented. A subjective note on climatic considerations at the block level is given based on observations. To compliment conservation measures, a feasibility study to revamp vernacular elements in the modern facades of the city is probed. Stated preference survey method was adopted for the feasibility study. Emphasis is given to public participation and professional involvement in the process of planning and implementing conservation measures. The measures shall realize economic development and life processes. Further certain morale ethics involved in the process methods of planning is discussed. Though the changes are high; the city upholds bright quos towards conservation pertaining to acceptance of traditional aspects and the urge for socialization.

The article attempts to investigate the impact of Madurai’s urban expansion on the River Vaigai at the confluence of six channels draining into the river from the urban watershed and at the causeways. Impervious surface cover (ISC) has impacted the river. Water samples were collected during 2017 in 15 stations in the urban stretch and two stations in the peri-urban stretch. Physical characteristics, namely, temperature, colour, odour and taste, and the intensity of chemical parameters, namely, pH, calcium, nitrates, total dissolved solids (TDS), total hardness (TH) and carbon dioxide demand (COD), were estimated. These estimations show that anomalous concentrations of physiochemical parameters in the river are much higher than the permissible standards prescribed by the Bureau of Indian Standards (BIS). The causeway recorded greater variations in TDS levels between the upstream and downstream zone. The study identifies two realities: first, variance in the intensity of physiochemical properties in the urban and peri-urban stretch and second, the impact of causeways on the flow characteristics of the river.

News frames influence destination reputation. Research primarily focuses on social media impact relative to destination reputation. Newspaper reporting is a major source of information which remains a study area underexplored when assessing news media framing. This study fills the gap by analyzing how newspapers from tourist generating countries such as China, USA, and Australia portrayed reputable destinations like New Zealand's and Singapore's efforts to mitigate the COVID-19 pandemic. The ProQuest library database was used to collect 192 newspaper articles. The software Qualtrics Text iQ and Leximancer were used to track sentiments, identify themes and concepts correlating with literature on tourism crisis management. Responses to the COVID-19 pandemic yields a negatively lower sentiment value for New Zealand, than Singapore's higher sentiment value. The contribution lies in the relationship concept emphasizing shifts in destination reputation corollary to crisis management, and to account for reputation fluctuations in media framework theory.

The luxury tourism industry immediately conjures up thoughts of exclusivity, with access to it confined to a small and elite group of travelers often located within their own social bubble. Our systematic literature review seeks to understand how tourism scholarship has addressed the issue of luxury travel based on social media pronouncements and the areas of concentration in which earlier studies have been conducted. Literature was sourced using the following key terms “luxury tourism”, “elite travel”, “social media”, and “sustainability” in various combinations using the OneSearch online platform, the Proquest Database, and Google Scholar. Only peer-reviewed journals were used for the critical analysis. Three main thematic areas were identified and reviewed: (1) the role of social media in luxury tourism; (2) the behavioral attributes of luxury travelers’ when using social media; and (3) the methodologies employed in the extant literature, given the limitations of accessing specific data for the luxury tourism market. The selected period for the journals and articles reviewed was the last ten years, from March 2010 to March 2020. NVivo version 12 was used to decipher the themes and focus areas as well as quantify the significance of social media to luxury tourism. Drawing from these literature review outcomes, the study explores future research areas and issues that require new theoretical and methodological frameworks to further our understanding of the intersection between social media and the luxury tourism business.

Approximately US$3.5 billion is spent annually as a result of adverse drug events (ADEs) [1], responsible for approximately a third of rehospitalizations and resulting in more than 700,000 annual emergency department visits by Medicare patients [2]. A substantial opportunity exists to reduce these iatrogenic events by taking a comprehensive and, when warranted, pharmacogenetics-guided approach to medication management based on the use of sophisticated clinical decision support (CDS) tools.

Kumbakonam, a historical town, addresses new challenges and changes. The visibility and significance of the town and its heritage settings are decaying due to the process of physical transformation. Thus, this paper intends to highlight the imageability of the Kumbakonam heritage settings that still survive in the town and reflect its characteristic elements. The findings reveal that the town of Kumbakonam is being confronted with the pressure of development and changes to its skyline and its urban fabric/facade elements. Moreover, this confrontation is accompanied by meagre changes in how towns conserve and promote their heritage settings against the haphazard development. The findings suggest that the heritage settings of the town contribute to the imageability of places. In this regard, the conservation strategies should be introduced to revive the imageability of the town, as the image of the town is distinct only when its heritage settings are conserved.

This study was aimed to identify miRNAs of corpus luteum (CL) in buffaloes during pregnancy. For this study, CL (n=2) were collected from gravid uteri of buffalo and RNA was isolated. Following this, the purity and integrity of RNA was checked and used for deep sequencing using Illumina Hiseq 2500 platform. The reads’ quality was checked prior to in silico analyses viz. identification of conserved, novel and target of miRNAs. In this study, out of identified miRNAs (3018), 3013 were known and 5 were novel miRNAs on alignment with reference genomes. In addition, prediction of putative target genes for identified abundant miRNAs revealed several genes viz. HOX, KLF4, NCOR2, CDKN2Z, MAPK7, COX2, PPARA, PTEN, ASS3A, ELK1, CASP3, BCL211, MCL1, CCND2, Cyclin A2 and CDC25A during early pregnancy in buffalo. These predicted target genes have been associated with various cellular house-keeping processes including apoptosis. In conclusion, this study reports the identification of conserved and novel microRNAs (miRNAs) in CL during pregnancy in buffalo by deep sequencing.

Aim: The present study was designed to identify other noncoding RNAs (ncRNAs) in the corpus luteum (CL) during early pregnancy in buffalo. Materials and Methods: For this study, CL (n=2) from two buffalo gravid uteri, obtained from the slaughter house, was transported to laboratory after snap freezing in liquid nitrogen (−196°C). The stage of pregnancy was determined by measuring the crown-rump region of the fetus. This was followed by isolation of RNA and deep sequencing. Post-deep sequencing, the obtained reads were checked and aligned against various ncRNA databases (GtRNA, RFAM, and deep guide). Various parameters, namely, frequency of specific ncRNAs, length, mismatch, and genomic location target in several model species were deciphered. Results: Frequency of piwi-interacting RNAs (piwi-RNAs), having target location in rodents and human genomes, were significantly higher compared to other piwi-RNAs and ncRNAs. Ribosomal RNAs (rRNAs) deduced had nucleotides (nts) ranging from 17 to 50 nts, but the occurrence of small length rRNAs was more than lengthier fragments. The target on 16S rRNA species confirms the conservation of 16S rRNA across species. With respect to transfer RNA (tRNA), the abundantly occurring tRNAs were unique with no duplication. Small nucleolar RNAs (snoRNAs), identified in this study, showed a strong tendency for coding box C/D snoRNAs in comparison to H/ACA snoRNAs. Regulatory and evolutionary implications of these identified ncRNAs are yet to be delineated in many species, including buffaloes. Conclusion: This is the first report of identification of other ncRNAs in CL of early pregnancy in buffalo.

Application of ozone and Fenton’s reagent was investigated as a pre-treatment to improve the biodegradability of acid blue 113 (AB 113) dye used in the tanneries and subsequent treatment in aerobic reactor. Pre-ozonation of 5 min improved the BOD5/COD ratio of AB 113 dye from 0.029 to 0.296 due to the partial oxidation of the dye molecules and resulted in the reduction in COD of 22%, with the generation of biodegradable organics. Fenton’s oxidation as pre-treatment at the optimum dose of H2O2/COD ratio of 1.0 (w/w) and H2O2/Fe2+ ratio at 9.7 (w/w) resulted in 45% reduction of COD due to mineralization, with subsequent improvement in BOD5/COD ratio from 0.029 to 0.411. Combined process of ozonation and aerobic treatment resulted in 55% removal of COD and the treated effluent had a BOD5 and COD of 45 and 355 mg/L, respectively. Combined Fenton and aerobic treatment resulted in 82% removal of COD and 25 and 230 mg/L of BOD5 and COD was observed in the treated effluent. FT-IR results also supported th...

Human liver gene regulatory (Bayesian) network analysis was previously used to identify a cytochrome P450 (P450) gene subnetwork with Aldo-keto reductase 1D1 (AKR1D1) as a key regulatory driver of this subnetwork. This study assessed the biologic importance of AKR1D1 [a key enzyme in the synthesis of bile acids, ligand activators of farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), known transcriptional regulators of P450s] to hepatic P450 expression. Overexpression of AKR1D1 in primary human hepatocytes led to increased expression of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6. Conversely, AKR1D1 knockdown decreased expression of these P450s. We resequenced AKR1D1 from 98 donor livers and identified a 3'-untranslated region (UTR) (rs1872930) single nucleotide polymorphism (SNP) significantly associated with higher AKR1D1 mRNA expression. AKR1D1 3'-UTR-luciferase reporter studies showed that the variant allele resulted in higher luciferase activity, suggesting that the SNP increases AKR1D1 mRNA stability and/or translation efficiency. Consistent with AKR1D1's putative role as a driver of the P450 subnetwork, the AKR1D1 3'-UTR SNP was significantly associated with increased hepatic mRNA expression of multiple P450s (CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6) and CYP3A4, CYP2C8, CYP2C19, and CYP2B6 activities. After adjusting for multiple testing, the association remained significant for AKR1D1, CYP2C9, and CYP2C8 mRNA expression and CYP2C8 activity. These results provide new insights into the variation in expression and activity of P450s that can account for interindividual differences in drug metabolism/efficacy and adverse drug events. In conclusion, we provide the first experimental evidence supporting a role for AKR1D1 as a key genetic regulator of the P450 network.

The subarachnoid space, where cerebrospinal fluid (CSF) flows over the brain and spinal cord, is lined on one side by arachnoid barrier (AB) cells that form part of the blood-CSF barrier. However, despite the fact that drugs are administered into the CSF and CSF drug concentrations are used as a surrogate for brain drug concentration following systemic drug administration, the tight-junctioned AB cells have never been examined for whether they express drug transporters that would influence CSF and central nervous system drug disposition. Hence, we characterized drug transporter expression and function in AB cells. Immunohistochemical analysis showed P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in mouse AB cells but not other meningeal tissue. The Gene Expression Nervous System Atlas (GENSAT) database and the Allen Mouse Brain Atlas confirmed these observations. Microarray analysis of mouse and human arachnoidal tissue revealed expression of many drug transporters and some drug-metabolizing enzymes. Immortalized mouse AB cells express functional P-gp on the apical (dura-facing) membrane and BCRP on both apical and basal (CSF-facing) membranes. Thus, like blood-brain barrier cells and choroid plexus cells, AB cells highly express drug transport proteins and likely contribute to the blood-CSF drug permeation barrier.

Within the realms of tourism, there are a select group of inquisitive people eager to experience the mystery and mystique inspired by sites located off the beaten path and thus not frequented by domestic and international visitors. These sites attract curiosity and often demand a degree of bravery in or order to enter their liminal domains.Given these places are either hidden or closed to public view, this paper plumbs the experiences of non-mainstream organised university tours anddelves into detail of one particular failed tourist attraction, the Tang Dynasty, to expound on the idea that non-public domains are significant spaces of experiential learning. Tang Dynasty was a tourist attraction in the 1990s in Singapore.Despite ceasing operation in 1999, this failed attraction continues to attract visitors into spaces that I have deemed the ‘non-public domain.‘ In this context, I shall explore how a non-public domain site Inspires learning for defiant sojourners.

The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.

Variation within the melanocortin receptor 1 (MC1R) gene, that influences phenotypic traits and susceptibility to melanoma, is abundant across the populations. We assessed and compared the risk of melanoma in 2 European populations, German and Spanish, by genotyping MC1R variants through direct DNA sequencing from 1,185 melanoma cases and 1,582 controls. The presence of any variant in both populations was associated with a significantly increased risk of melanoma (odds ratio OR = 1.67, 95% confidence interval CI 1.40-1.99). The population attributable fractions (PAF) associated with the MC1R variants in both populations was over 25%. However, the results showed a statistically significant (p < 0.0001) higher frequency of MC1R variants in the German (70%) than in the Spanish population (60%). The red-hair colour (RHC) variants, though associated with increased risk in both populations, were more common in the German than in the Spanish population (p < 0.0001). Interestingly, non-RHC variants increased the disease risk in the Spanish (OR = 1.60, 95% CI 1.20-2.14) but not in the German population (OR = 1.07, 95% CI 0.80-1.44). Although RHC variants explained a major proportion of the observed PAF in the German population, in the Spanish population the major contributor to the PAF was the non-RHC V60L variant. We also observed reduced historic linkage disequilibrium between the variants V92M and T314T in the gene in German melanoma cases. In conclusion, our data underscored the unambiguous importance of the MC1R variants towards the population burden of melanoma. However, the variants that are associated with the disease differ between the investigated populations.

This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Biomarkers of individual susceptibility: field studiesBiomarker (including alleles if genetic): XPC(A>C;K939Q), XPD(A>C;K715Q), XPG(G>C;D1104H), APEX1(T>G;D148E), XRCC1(G>A;R399Q), XRCC3(C>T;T241M), NBS1(G>C;E185Q)Effect studied (phenotype/pathology):modulation of BCC riskTissue/biological material/sample size: BLOODMethod of analysis: PCRStudy design: case-controlStudy size: 529 subjects with BCC, 533 controlsImpact on outcome (including dose-response): XRCC3(C>T;T241M) decreased risk for BCC, PR 0.66, CI95%, 0.51-0.86, P=0.002NBS1(G>C;E185Q) increased risk for BCC in men OR1.44, CI95%, 1.1-1.88, P=0.008, not in women OR0.96, CI95%, 0.74-1024, P=0.76All other polymorphisms no correlation found with risk. KEYWORDS CLASSIFICATION: adverse effects;Adolescent;Adult;Aged;Aged,80 and over;biomarkers of individual susceptibility: field studies;cancer epidemiology;Carcinoma,Basal Cell;Case-Control Studies;Cell Cycle;Cell Cycle Proteins;Child;Child,Preschool;DNA Repair;epidemiology;Female;genetics;Genetic Predisposition to Disease;Genotype;Germany;Humans;Hungary;Male;Middle Aged;Neoplasm Proteins;Nuclear Proteins;Odds Ratio;Polymorphism,Single Nucleotide;Proteins;Research;Risk Factors;Romania;Skin Neoplasms;Slovakia;Ultraviolet Rays. In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.

Determination of allele frequency in pooled DNA samples is a powerful and efficient tool for large-scale association studies. In this study, we tested and compared three PCR-based methods for accuracy, reproducibility, cost, and convenience. The methods compared were: (i) real-time PCR with allele-specific primers, (ii) real-time PCR with allele-specific TaqMan® probes, and (iii) quantitative sequencing. Allele frequencies of three single nucleotide polymorphisms in three different genes were estimated from pooled DNA. The pools were made of genomic DNA samples from 96 cases with basal cell carcinoma of the skin and 96 healthy controls with known genotypes. In this study, the allele frequency estimation made by real-time PCR with allele-specific primers had the smallest median deviation (MD) from the real allele frequency with 1.12% (absolute percentage points) and was also the cheapest method. However, this method required the most time for optimization and showed the highest variation between replicates (SD = 6.47%). Quantitative sequencing, the simplest method, was found to have intermediate accuracies (MD = 1.44%, SD = 4.2%). Real-time PCR with TaqMan probes, a convenient but very expensive method, had an MD of 1.47% and the lowest variation between replicates (SD = 3.18%).

Barbara Watson Andaya, Susan Blackburn, Love, sex and power; Women in Southeast Asia. Clayton VIC: Monash Asia Institute, 2001, iv + 144 pp. [Monash papers on Southeast Asia 55.] -Kathryn Gay Anderson, Juliette Koning ,Women and households in Indonesia; Cultural notions and social practices. Richmond, Surrey: Curzon, 2000, xiii + 354 pp. [Nordic Institute of Asian studies, studies in Asian topics 27.], Marleen Nolten, Janet Rodenburg (eds) -Greg Bankoff, Takeshi Kawanaka, Power in a Philippine city. Chiba: Institute of developing economies, 2002, 118 pp. [IDE Occasional papers series 38.] -René van den Berg, John Lynch ,The Oceanic languages. Richmond, Surrey: Curzon, 2002, xvii + 924 pp., Malcolm Ross, Terry Crowley (eds) -H.J.M. Claessen, Douglas Oliver, Polynesia in early historic times. Honolulu: Bess Press, 2002, 305 pp. -Harold Crouch, Andrew Rosser, The politics of economic liberalisation in Indonesia; State, market and power. Richmond, Surrey: Curzon, 2002, xv + 232 pp. -Hans Hägerdal, Arend de Roever, De jacht op sandelhout; De VOC en de tweedeling van Timor in de zeventiende eeuw. Zutphen: Walburg Pers, 2002, 383 pp. -Fiona Harris, Lorraine V. Aragon ,Structuralism's transformations; Order and revision in Indonesian and Malaysian societies; Paper written in honor of Clark E. Cunningham. Tempe AZ: Arizona State University Press, 1999, lxii + 402 pp., Susan D. Russell (eds) -David Henley, Christiaan Heersink, Dependence on green gold: A socio-economic history of the Indonesian coconut island Selayar. Leiden: KITlV Press, 1999, xviii + 371 pp. [Verhandelingen 184.] -David Hicks, James T. Siegel ,Southeast Asia over three generations; Essays presented to Benedict R.O'G. Anderson 2003, 398 pp. Ithaca NY: Cornell University Southeast Asia program. [Studies on Southeast Asia 36.], Audrey R. Kahin (eds) -Janny de Jong, L. de Jong, The collapse of a colonial society; The Dutch in Indonesia during the second world war. With an introduction by Jeroen Kemperman. Leiden: KITLV Press, 2002, 570 pp. [Verhandelingen 206.] -Gerry van Klinken, Grayson Lloyd ,Indonesia today; Challenges of history. Singapore: Institute of Southeast Asian studies, 2001, 359 pp., Shannon Smith (eds) -Johanna van Reenen, Frédéric Durand, Timor Lorosa'e, pays au carrefour de l'Asie et du Pacifique; Un atlas géo-historique. Marne-la-Vallée: Presses Universitaires de Marne-la-Vallée, 2002, 208 pp. -William R. Roff, Mona Abaza, Debates on Islam and knowledge in Malaysia and Egypt; Shifting worlds. London: RoutledgeCurzon, 2002, xix + 304 pp. -Mariëtte van Selm, Chr. van Fraassen ,G.E. Rumphius, De Ambonse eilanden onder de VOC, zoals opgetekend in 'De Ambonse landbeschrijving'. Utrecht: Landelijk Steunpunt Educatie Molukkers, 2002, 254 pp., H. Straver (eds) -K. Thirumaran, Prema-Chandra Athukorala, Crisis and recovery in Malaysia; The role of capital controls. Cheltenham: Elgar, 2001, xii + 159 pp. -K. Thirumaran, John Hilley, Malaysia; Mahathirism, hegemony and the new opposition. London: Zed books, 2001, xiii + 305 pp. -Reina van der Wiel, Damien Kingsbury ,Foreign devils and other journalists. Clayton VIC: Monash Asia Institute, 2000, vi + 277 pp. [Monash papers on Southeast Asia 52.], Eric Loo, Patricia Payne (eds) -Jennifer Fraser, Philip Yampolsky, Music of Indonesia. Washington DC: Smithsonian Folkways recordings, 1991-2000, 20 compact discs plus a CD of selections from the series, Discover Indonesia. All with accompanying booklets. -Robert Wessing, Nicola Tannenbaum ,Founders' cults in Southeast Asia; Ancestors, polity, and identity. New Haven CT: Yale University Southeast Asian studies, 2003, xi + 373 pp. [Yale Southeast Asia studies Monograph 52.], Cornelia Ann Kammerer (eds) -Robert Wessing, Henri Chambert-Loir ,The potent dead; Ancestors, saints and heroes in contemporary Indonesia. Crows Nest, New South Wales: Allen and Unwin, Honolulu: University of Hawai'i Press, 2002, xxvi + 243 pp. [Southeast Asia publications series.], Anthony Reid (eds)

Human liver gene regulatory network analysis identified a cytochrome P450 subnetwork with AKR1D1 as its key regulatory driver. This study assessed the biologic importance of AKR1D1 [key enzyme in s...

Background In polypharmacy patients under home health management, pharmacogenetic testing coupled with guidance from a clinical decision support tool (CDST) on reducing drug, gene, and cumulative interaction risk may provide valuable insights in prescription drug treatment, reducing re-hospitalization and emergency department (ED) visits. We assessed the clinical impact of pharmacogenetic profiling integrating binary and cumulative drug and gene interaction warnings on home health polypharmacy patients. Methods and findings This prospective, open-label, randomized controlled trial was conducted at one hospital-based home health agency between February 2015 and February 2016. Recruitment came from patient referrals to home health at hospital discharge. Eligible patients were aged 50 years and older and taking or initiating treatment with medications with potential or significant drug-gene-based interactions. Subjects (n = 110) were randomized to pharmacogenetic profiling (n = 57). The study pharmacist reviewed drug-drug, drug-gene, and cumulative drug and/or gene interactions using the YouScript® CDST to provide drug therapy recommendations to clinicians. The control group (n = 53) received treatment as usual including pharmacist guided medication management using a standard drug information resource. The primary outcome measure was the number of re-hospitalizations and ED visits at 30 and 60 days after discharge from the hospital. The mean number of re-hospitalizations per patient in the tested vs. untested group was 0.25 vs. 0.38 at 30 days (relative risk (RR), 0.65; 95% confidence interval (CI), 0.32–1.28; P = 0.21) and 0.33 vs. 0.70 at 60 days following enrollment (RR, 0.48; 95% CI, 0.27–0.82; P = 0.007). The mean number of ED visits per patient in the tested vs. untested group was 0.25 vs. 0.40 at 30 days (RR, 0.62; 95% CI, 0.31–1.21; P = 0.16) and 0.39 vs. 0.66 at 60 days (RR, 0.58; 95% CI, 0.34–0.99; P = 0.045). Differences in composite outcomes at 60 days (exploratory endpoints) were also found. Of the total 124 drug therapy recommendations passed on to clinicians, 96 (77%) were followed. These findings should be verified with additional prospective confirmatory studies involving real-world applications in larger populations to broaden acceptance in routine clinical practice. Conclusions Pharmacogenetic testing of polypharmacy patients aged 50 and older, supported by an appropriate CDST, considerably reduced re-hospitalizations and ED visits at 60 days following enrollment resulting in potential health resource utilization savings and improved healthcare. Trial registration ClinicalTrials.gov NCT02378220

Aim: Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians. Materials & methods: CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects. Results: Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27–2.40) for area under the concentration time curve (AUC)0–12 h, 1.58 (1.03–2.42) for C0, and 0.53 (0.31–0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027). Conclusion: Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure. Original submitted 15 June 2010; Revision submitted 5 July 2011

Single-nucleotide polymorphisms in different DNA-repair genes are reported to modulate risk of various cancers including melanoma. We genotyped DNA from 1186 melanoma patients and 1280 healthy controls for 13 different polymorphisms in eight DNA-repair genes. Data analyses showed that none of the polymorphisms except T241M XRCC3 was associated with an increased risk for cutaneous melanoma. Carriers of the variant alleles were associated with a decreased risk (OR 0.83; 95% CI, 0.79-0.98). Three additional polymorphisms together with T241M XRCC3 that tagged the entire gene region and the neighbouring genes KLC1, ZFYVE21 and PPP1R13B were not associated with the disease risk; neither were the inferred haplotypes. Imputation showed association of comparable magnitude with 11 non-genotyped neighbouring polymorphisms. Finally, the combination of results for all polymorphisms genotyped in the present study with published data suggests that none of the investigated polymorphisms was associated with melanoma susceptibility. We conclude that 13 non-synonymous polymorphisms in eight DNA-repair genes that are frequently investigated with respect to modulation of cancer risk in populations are not associated with susceptibility to cutaneous melanoma. (C) 2010 Elsevier B.V. All rights reserved.

The CYP3A locus encodes hepatic enzymes that metabolize many clinically used drugs. However, there is marked interindividual variability in enzyme expression and clearance of drugs metabolized by these enzymes. We utilized comparative genomics and computational prediction of transcriptional factor binding sites to evaluate regions within CYP3A that were most likely to contribute to this variation. We then used a haplotype tagging single-nucleotide polymorphisms (htSNPs) approach to evaluate the entire locus with the fewest number of maximally informative SNPs. We investigated the association between these htSNPs and in vivo CYP3A enzyme activity using a single-point IV midazolam clearance assay. We found associations between the midazolam phenotype and age, diagnosis of hypertension and one htSNP (141689) located upstream of CYP3A4. 141689 lies near the xenobiotic responsive enhancer module (XREM) regulatory region of CYP3A4. Cell-based studies show increased transcriptional activation with the minor allele at 141689, in agreement with the in vivo association study findings. This study marks the first systematic evaluation of coding and noncoding variation that may contribute to CYP3A phenotypic variability.

A 19-base pair germline deletion in exon 2 of the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene (Leiden mutation) has been detected in Dutch families with familial melanomas. The penetrance of CDKN2A mutations varies widely and is influenced by environmental and unrelated genetic factors such as variants in the MC1R gene.We describe a 25-year-old German woman who developed 8 invasive melanomas and 6 in situ melanomas after radiation therapy and polychemotherapy for Hodgkin lymphoma. Genetic testing revealed a constitutional CDKN2A Leiden mutation in the proband and her sister, mother, and mother's sister. The proband also carried high-risk MC1R variant alleles R151C and R160W, which she had inherited from her father and her mother, respectively. The less affected mutation carrier sister did not have high-risk MC1R variant alleles. Analysis of DNA from paraffin-embedded tissues showed loss of heterozygosity at CDKN2A loci in all 3 melanomas studied but not in Hodgkin lymphoma. The pedigree revealed several types of cancers on both sides of the family, but no Dutch ancestors were found. No mutations in the CDK4, B-raf, and N-ras genes were detected either in the germline or in tumors from the patient.This study shows the variability of the penetrance of the CDKN2A Leiden mutation within the same family, which could be due to genetic or exogenous factors.

BACKGROUND: There is a wide variation in susceptibility to health effects of arsenic, which, in part, may be due to differences in arsenic metabolism. Arsenic is metabolized by reduction and methylation reactions, catalyzed by reductases and methyltransferases. OBJECTIVES: Our goal in this study was to elucidate the influence of various demographic and genetic factors on the metabolism of arsenic. METHODS: We studied 415 individuals from Hungary, Romania, and Slovakia by measuring arsenic metabolites in urine using liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). We performed genotyping of arsenic (+III) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), and methylene-tetrahydrofolate reductase (MTHFR). RESULTS: The results show that the M287T (T-->C) polymorphism in the AS3MT gene, the A222V (C-->T) polymorphism in the MTHFR gene, body mass index, and sex are major factors that influence arsenic metabolism in this population, with a median of 8.0 microg/L arsenic in urine. Females < 60 years of age had, in general, higher methylation efficiency than males, indicating an influence of sex steroids. That might also explain the observed better methylation in overweight or obese women, compared with normal weight men. The influence of the M287T (T-->C) polymorphism in the AS3MT gene on the methylation capacity was much more pronounced in men than in women. CONCLUSIONS: The factors investigated explained almost 20% of the variation seen in the metabolism of arsenic among men and only around 4% of the variation among women. The rest of the variation is probably explained by other methyltransferases backing up the methylation of arsenic.

In melanoma, the RAS/RAF/MEK/ERK signalling pathway is an area of great interest, because it regulates tumor cell proliferation and survival. A varying mutation rate has been reported for B-RAF and N-RAS, which has been largely attributed to the differential source of tumor DNA analyzed, e.g., fixed tumor tissues or in vitro propagated melanoma cells. Notably, this variation also interfered with interpreting the impact of these mutations on the clinical course of the disease. Consequently, we investigated the mutational profile of B-RAF and N-RAS in biopsies and corresponding cell lines from metastatic tumor lesions of 109 melanoma patients (AJCC stage III/IV), and its respective impact on survival. 97 tissue biopsies and 105 biopsy-derived cell lines were screened for B-RAF and N-RAS mutations by PCR single strand conformation polymorphism and DNA sequencing. Mutations were correlated with patient survival data obtained within a median follow-up time of 31 months. B-RAF mutations were detected in 55% tissues and 51% cell lines, N-RAS mutations in 23% tissues and 25% cell lines, respectively. There was strong concordance between the mutational status of tissues and corresponding cell lines, showing a differing status for B-RAF in only 5% and N-RAS in only 6%, respectively. Patients with tumors carrying mutated B-RAF showed an impaired median survival (8.0 versus 11.8 months, p = 0.055, tissues; 7.1 versus 9.3 months, p = 0.068, cell lines), whereas patients with N-RAS-mutated tumors presented with a favorable prognosis (median survival 12.5 versus 7.9 months, p = 0.084, tissues; 15.4 versus 6.8 months, p = 0.0008, cell lines), each in comparison with wildtype gene status. Multivariate analysis qualified N-RAS (p = 0.006) but not B-RAF mutation status as an independent prognostic factor of overall survival. Our findings demonstrate that B-RAF and N-RAS mutations are well preserved during short term in vitro propagation and, most importantly, differentially impact the outcome of melanoma patients.

The endothelin signaling pathway plays a crucial role in melanocyte differentiation and migration. In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM). The coding region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 patients (11%), but only two were found in four control subjects (3%, odds ratio [OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which had previously been shown to lead to loss of function. In multivariable logistic regression analysis including skin type, eye and hair color, number of nevi, and dorsal lentigines (freckles), the association between EDNRB mutations and MM risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = .03). Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.

In a recent report on the role of the 5,10-methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms in childhood acute lymphoblastic leukemia (ALL), Krajinovic et al reported a reduced risk associated with a combination of genotypes.[1][1] On stratification of patients into those born

CYP3A4, an integral endoplasmic reticulum (ER)-anchored protein, is the major human liver cytochrome P450 enzyme responsible for the disposition of over 50% of clinically relevant drugs. Alterations of its protein turnover can influence drug metabolism, drug-drug interactions, and the bioavailability of chemotherapeutic drugs. Such CYP3A4 turnover occurs via a classical ER-associated degradation (ERAD) process involving ubiquitination by both UBC7/gp78 and UbcH5a/CHIP E2-E3 complexes for 26 S proteasomal targeting. These E3 ligases act sequentially and cooperatively in CYP3A4 ERAD because RNA interference knockdown of each in cultured hepatocytes results in the stabilization of a functionally active enzyme. We have documented that UBC7/gp78-mediated CYP3A4 ubiquitination requires protein phosphorylation by protein kinase (PK) A and PKC and identified three residues (Ser-478, Thr-264, and Ser-420) whose phosphorylation is required for intracellular CYP3A4 ERAD. We document herein that of these, Ser-478 plays a pivotal role in UBC7/gp78-mediated CYP3A4 ubiquitination, which is accelerated and enhanced on its mutation to the phosphomimetic Asp residue but attenuated on its Ala mutation. Intriguingly, CYP3A5, a polymorphically expressed human liver CYP3A4 isoform (containing Asp-478) is ubiquitinated but not degraded to a greater extent than CYP3A4 in HepG2 cells. This suggests that although Ser-478 phosphorylation is essential for UBC7/gp78-mediated CYP3A4 ubiquitination, it is not sufficient for its ERAD. Additionally, we now report that CYP3A4 protein phosphorylation by PKA and/or PKC at sites other than Ser-478, Thr-264, and Ser-420 also enhances UbcH5a/CHIP-mediated ubiquitination. Through proteomic analyses, we identify (i) 12 additional phosphorylation sites that may be involved in CHIP-CYP3A4 interactions and (ii) 8 previously unidentified CYP3A4 ubiquitination sites within spatially associated clusters of Asp/Glu and phosphorylatable Ser/Thr residues that may serve to engage each E2-E3 complex. Collectively, our findings underscore the interplay between protein phosphorylation and ubiquitination in ERAD and, to our knowledge, provide the very first example of gp78 substrate recognition via protein phosphorylation.