المؤلفون: Todero, Jenna¹, Douillet, Christelle², Shumway, Alexandria J.¹, Koller, Beverly H.³, Kanke, Matt¹, Phuong, Daryl J.¹, Stýblo, Miroslav², Sethupathy, Praveen¹ pr46@cornell.edu

المصدر: Environmental Health Perspectives. Dec2023, Vol. 131 Issue 12, p127021-1-127021-16. 16p.

مصطلحات موضوعية: *ARSENIC metabolism, *BIOLOGICAL models, *ANIMAL experimentation, *MANN Whitney U Test, *MICRORNA, *SEX distribution, *RATS, *PEARSON correlation (Statistics), *GENE expression, *DESCRIPTIVE statistics, *RESEARCH funding, *DATA analysis software, *ADIPOSE tissues, *PHENOTYPES

مستخلص: BACKGROUND: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leveraged this model to study sex differences in the context of iAs exposure. OBJECTIVES: The aim of this study was to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. METHODS: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and gonadal adipose depots were harvested for iAs quantification and sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and homeostatic model assessment for insulin resistance (HOMA-IR). RESULTS: We detected sex divergence in liver and adipose markers of diabetes (e.g., miR-34a, insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. DISCUSSION: Our study underscored the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings suggested that humanized males are at increased risk for metabolic dysfunction relative to humanized females in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence. [ABSTRACT FROM AUTHOR]

المؤلفون: Abuawad, Ahlam K.¹, Bozack, Anne K.^1,2, Navas-Acien, Ana¹, Goldsmith, Jeff³, Xinhua Liu³, Hall, Megan N.⁴, Ilievski, Vesna¹, Lomax-Luu, Angela M.¹, Parvez, Faruque¹, Shahriar, Hasan⁵, Uddin, Mohammad N.⁵, Islam, Tariqul⁵, Graziano, Joseph H.¹, Gamble, Mary V.¹ mvg7@cumc.columbia.edu

المصدر: Environmental Health Perspectives. Mar2023, Vol. 131 Issue 3, p037015-1-037015-11. 11p. 3 Charts, 3 Graphs, 1 Map.

مصطلحات موضوعية: *ARSENIC metabolism, *KRUSKAL-Wallis Test, *DIETARY supplements, *TREATMENT effectiveness, *METHYLATION, *FOLIC acid, *BANGLADESHIS, *CREATININE

مصطلحات جغرافية: BANGLADESH

مستخلص: BACKGROUND: Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs facilitates urinary excretion and is associated with reduced risk for Asrelated health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation. OBJECTIVE: Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI: MMAs/InAs) and secondary methylation index (SMI: DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status METHODS: In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms: a) PBO (푛=102), b) 400μg FA/d (400FA; 푛=153), c) 800 μg FA/d (800FA;푛=151), d) 3 g creatine/d (creatine; 푛=101), or e) 3 g creatine + 400 μg of FA=d (creatine + 400FA; 푛=103) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24 RESULTS: At baseline, 80.3% (푛= 489) of participants were folate sufficient (=9 nmol/L in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (geometric mean±geometric standard deviation) decreased from 3.55±1.89 μg/L at baseline to 2:73±1:74 at week 1. After 1 wk, the mean within-person increase in SMI for the creatine + 400FA group was greater than that of the PBO group (푝=0.05). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group [400FA: -10.4 (95%CI: -11.9, -8:75), 800FA: -9:54 (95% CI: -11.1, -7.97), creatine: -5.85 (95% CI: -8.59, -3.03), creatine + 400FA:-8.44 (95% CI: -9.95, -6.90), PBO: -2.02 (95% CI: -4.03, 0.04)], and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO [400FA: 12.8 (95% CI: 10.5, 15.2), 800FA: 11.3 (95% CI: 8.95, 13.8), creatine + 400FA: 7.45 (95% CI: 5.23, 9.71), PBO: -0:15 (95% CI: -2:85, 2.63)]. The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO(푝<0:05).Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI [-9.0% (95% CI: -3.5, -14.8)] and bDMAs [-5.9% (95% CI: -1.8, -10.2)], whereas PMI and bMMAs concentrations continued to decline [-7:16% (95% CI: -0.48, -14:3) and -3.1% (95% CI: -0.1, -6.2), respectively] for those who remained on 800FAsupplementation. CONCLUSIONS: FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. [ABSTRACT FROM AUTHOR]

المؤلفون: El-Ghiaty, Mahmoud A.¹ (AUTHOR) aelkadi@ualberta.ca, El-Kadi, Ayman O.S.¹ (AUTHOR)

المصدر: Annual Review of Pharmacology & Toxicology. Jan2023, Vol. 63 Issue 1, p341-358. 15p.

مصطلحات موضوعية: *ARSENIC metabolism, *ARSENIC, *ARSENIC poisoning, *METHYLATION, *HEALTH impact assessment, *MOLECULAR structure, *ENVIRONMENTAL exposure

مستخلص: Arsenic is a naturally occurring hazardous element that is environmentally ubiquitous in various chemical forms. Upon exposure, the human body initiates an elimination pathway of progressive methylation into relatively less bioreactive and more easily excretable pentavalent methylated forms. Given its association with decreasing the internal burden of arsenic with ensuing attenuation of its related toxicities, biomethylation has been applauded for decades as a pure route of arsenic detoxification. However, the emergence of detectable trivalent species with profound toxicity has opened a long-standing debate regarding whether arsenic methylation is a detoxifying or bioactivating mechanism. In this review, we approach the topic of arsenic metabolism from both perspectives to create a complete picture of its potential role in the mitigation or aggravation of various arsenic-related pathologies. [ABSTRACT FROM AUTHOR]

المؤلفون: Han Li, Fuping Ye, Zhenyang Li, Xiaoshan Peng, Lu Wu, Qizhan Liu

المصدر: Environment International, Vol 190, Iss , Pp 108824- (2024)

مصطلحات موضوعية: Gut microbiome, Arsenic metabolism, Arsenic-binding protein, Methionine synthase, Liver injury, Environmental sciences, GE1-350

الوصف: The drivers of changes in gut microbiota under arsenic exposure and the mechanism by which microbiota affect arsenic metabolism are still unclear. Here, C57BL/6 mice were exposed to 0, 5, or 10 ppm NaAsO2 in drinking water for 6 months. The results showed that arsenic exposure induced liver injury and increased the abundance of folic acid (FA)/vitamin B12 (VB12)- and butyrate-synthesizing microbiota. Statistical analysis and in vitro cultures showed that microbiota were altered to meet the demand for FA/VB12 by arsenic metabolism and to resist the toxicity of unmetabolized arsenic. However, at higher arsenic levels, changes of these microbiota were inconsistent. A 3D molecular simulation showed that arsenic bound to methionine synthase (MTR), which was confirmed by SEC-UV-DAD (1 μM recombinant human MTR was purified with 0 or 2 μM NaAsO2 at room temperature for 1 h) and fluorescence-labeled arsenic co-localization (primary hepatocytes were exposed to 0, 0.5, or 1 μM ReAsH-EDT2 for 24 h) in non-cellular and cellular systems. Mechanistically, the arsenic-MTR interaction in the liver interferes with the utilization of FA/VB12, which increases arsenic retention and thus results in a substantial increase in the abundance of butyrate-synthesizing microbiota compared to FA/VB12-synthesizing microbiota. By exposing C57BL/6J mice to 0 or 10 ppm NaAsO2 with or without FA (6 mg/L) and VB12 (50 μg/L) supplementation in their drinking water for 6 months, we constructed an FA/VB12 intervention mouse model and found that FA/VB12 supplementation blocked the disturbance of gut microbiota, restored MTR levels, promoted arsenic metabolism, and alleviated liver injury. We demonstrate that the change of gut microbiota is a response to arsenic metabolism, a process influenced by the arsenic-MTR interaction. This study provides new insights for understanding the relationship between gut microbiota and arsenic metabolism and present therapeutic targets for arseniasis.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0160412024004100Test; https://doaj.org/toc/0160-4120Test

الوصول الحر: https://doaj.org/article/8af3ff774dd44f1a843dd764cea03d1fTest

المؤلفون: States, J. Christopher¹ jcstates@louisville.edu, Barchowsky, Aaron²

المصدر: Environmental Health Perspectives. Dec2023, Vol. 131 Issue 12, p121308-1-121308-2. 2p.

مصطلحات موضوعية: *ARSENIC metabolism, *BIOLOGICAL models, *MICRORNA, *GENE expression, *ADIPOSE tissues, *PHENOTYPES

مستخلص: In the article, the authors discuss the roles of transgenerational transmission and sex in improving the susceptibility to chronic diseases and the link of arsenic exposure to cancer, cardiovascular disease, diabetes mellitus, and neurological dysfunction. Other topics include the use of humanized AS3MT mouse model in assessing arsenic-promoted disease etiology, and the efforts to resolve the mouse-to-human comparisons.

المؤلفون: Verma, Akshat^1,2 (AUTHOR), Murugan, Prem Anand³ (AUTHOR), Chinnasamy, Hariharan Vedi³ (AUTHOR), Singh, Abhas^1,2 (AUTHOR), Matheshwaran, Saravanan^3,4,5 (AUTHOR)

المصدر: BioMed Research International. 3/10/2022, p1-19. 19p.

مصطلحات موضوعية: *ARSENIC metabolism, *SEQUENCE analysis, *DNA, *CITROBACTER, *NUCLEIC acid hybridization, *AQUATIC microbiology, *WATER pollution, *GENOMICS, *MEMBRANE transport proteins, *MICROBIAL virulence, *DRUG resistance in microorganisms

مصطلحات جغرافية: INDIA

مستخلص: Whole-genome sequencing (WGS) data of a bacterial strain IITK SM2 isolated from an aquifer located in the middle Indo-Gangetic plain is reported here, along with its physiological, morphological, biochemical, and redox-transformation characteristics in the presence of dissolved arsenic (As). The aquifer exhibits oxidizing conditions relative to As speciation. Analyses based on 16S rRNA and recN sequences indicate that IITK SM2 was clustered with C. youngae NCTC 13708T and C. pasteuri NCTC UMH17T. However, WGS analyses using the digital DNA-DNA hybridization and Rapid Annotations using Subsystems Technology suggest that IITK SM2 belongs to a strain of C. youngae. This strain can effectively reduce As(V) to As(III) but cannot oxidize As(III) to As(V). It exhibited high resistance to As(V) [32,000 mg L-1] and As(III) [1,100 mg L-1], along with certain other heavy metals typically found in contaminated groundwater. WGS analysis also indicates the presence of As-metabolizing genes such as arsC, arsB, arsA, arsD, arsR, and arsH in this strain. Although these genes have been identified in several As(V)-reducers, the clustering of these genes in the forms of arsACBADR, arsCBRH, and an independent arsC gene has not been observed in any other Citrobacter species or other selected As(V)-reducing strains of Enterobacteriaceae family. Moreover, there were differences in the number of genes corresponding to membrane transporters, virulence and defense, motility, protein metabolism, phages, prophages, and transposable elements in IITK SM2 when compared to other strains. This genomic dataset will facilitate subsequent molecular and biochemical analyses of strain IITK SM2 to identify the reasons for high arsenic resistance in Citrobacter youngae and understand its role in As mobilization in middle Indo-Gangetic plain aquifers. [ABSTRACT FROM AUTHOR]

المؤلفون: Kuo, Chin-Chi, Balakrishnan, Poojitha, Gribble, Matthew O, Best, Lyle G, Goessler, Walter, Umans, Jason G, Navas-Acien, Ana

مصطلحات موضوعية: Pollution and Contamination, Epidemiology, Environmental Sciences, Public Health, Health Sciences, Clinical Research, Cancer, Foodborne Illness, Aetiology, 2.2 Factors relating to the physical environment, Cardiovascular, Good Health and Well Being, Aged, Arsenic, Arsenicals, Environmental Exposure, Female, Humans, Male, Middle Aged, Neoplasms, Prospective Studies, American Indians, Arsenic species, Arsenic methylation, Arsenic metabolism, Mortality, Cardiovascular disease, Strong Heart Study

الوصف: The effect of low-moderate levels of arsenic exposure and of arsenic metabolism on mortality remains uncertain. We used data from a prospective cohort study in 3600 men and women aged 45 to 75 years living in Arizona, Oklahoma, and North and South Dakota. The biomarker of inorganic arsenic exposure was the sum of urine inorganic (iAs), monomethylated (MMA) and dimethylated (DMA) arsenic compounds (ƩAs) at baseline. The proportions of urine iAs, MMA and DMA over the ƩiAs, expressed as iAs%, MMA%, and DMA%, respectively, were used as biomarkers of arsenic metabolism. Arsenic exposure and arsenic metabolism were associated with all-cause, cardiovascular, and cancer mortality. For each interquartile range (IQR) increase in ƩAs (12.5 μg/L, overall range 0.7-194.1 μg/L), the adjusted hazard ratios (aHRs) were 1.28 (95% CI 1.16-1.41) for all-cause mortality, 1.28 (1.08-1.52) for cardiovascular mortality and 1.15 (0.92-1.44) for cancer mortality. The aHR for mortality for each IQR increase in MMA%, when iAs% is decreasing, was 1.52 (95% CI 1.16-1.99) for cardiovascular disease, 0.73 (0.55-0.98) for cancer, and 1.03 (0.90-1.19) for all-cause mortality. These findings at low-moderate levels of arsenic exposure highlight the need to implement public health measures to protect populations from involuntary arsenic exposure and for research to advance the biological and clinical understanding of arsenic-related health effects in general populations.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0c31j4g7Test

المؤلفون: Dong, Ju¹ (AUTHOR) 290014@njucm.edu.cn, Wang, Ying¹ (AUTHOR), Qian, Qin¹ (AUTHOR), Wu, Juan¹ (AUTHOR), Yang, Dongqing¹ (AUTHOR), Liu, Deye² (AUTHOR)

المصدر: Journal of Ethnopharmacology. Oct2024, Vol. 333, pN.PAG-N.PAG. 1p.

مصطلحات موضوعية: *ARSENIC metabolism, *CHINESE medicine, *METHYLATION, *HIGH performance liquid chromatography, *NUCLEOSIDES, *GLUTATHIONE, *DESCRIPTIVE statistics, *PLANT extracts, *MUTAGENICITY testing, *MICE, *GENE expression, *MESSENGER RNA, *ARSENIC poisoning, *ANIMAL experimentation, *METABOLISM, *GLYCOSIDES, *DNA damage, *ARSENIC

مستخلص: Realgar (As 2 S 2 or As 4 S 4) is a traditional Chinese medicine (TCM) containing arsenic. Existing studies have shown that it has genotoxicity under long-term use with large doses. Niuhuang Jiedu (NHJD) is a Chinese medicine prescription containing realgar and seven other TCMs. Whether the multiple TCMs combination in NHJD can reduce the genotoxicity induced by realgar in equivalent doses is still unknown. To research the effect of NHJD on realgar's genotoxicity and the possible mechanism involved based on the arsenic methylation metabolic pathway. Six groups (control, realgar (0.8 g/kg), NHJD (12.48 g/kg), as well as Glycyrrhiza uralensis Fisch (GU), Scutellaria baicalensis Georg (SB), Rheum palmatum L (RP) plus equivalent doses of realgar, respectively) were set up. ICR mice were intragastric administered for 12 weeks. First, genotoxicology tests were conducted to evaluate the effect of NHJD, GU, SB, and RP on reducing realgar's genotoxicity. The inorganic arsenic (iAs), dimethyl arsenic acid (DMA), and monomethyl arsenic acid (MMA) were determined by HPLC-AFS, and the iAs%, MMA%, DMA%, primary methylation index (PMI), etc. Were calculated. Meanwhile, the S-adenosyl methionine (SAM) and arsenate reductase (ARR) levels, the arsenic (+3)methyltransferase (As 3 MT), purine-nucleoside phosphorylase (PNP) , glutathione S-transfer omega1 (GSTO1) gene expression were detected, aimed to explore the possible alleviation mechanisms of NHJD. The combination of multiple TCMs in NHJD decreased the levels of MN‰, SPA%, and DNA damage caused by realgar, with similar effects observed when SB, RP, and GU were used separately with realgar. Notably, the iAs% significantly decreased, while DMA% and PMI notably increased in the NHJD and realgar + SB (or RP) groups compared to the realgar-only group (P < 0.05). Increases in SAM and ARR levels were observed across various groups, but only the ARR increase in the NHJD group was statistically significant. Moreover, significant increases in As 3 MT mRNA and GSTO1 mRNA were noted in the NHJD group, and PNP mRNA levels significantly rose in the realgar + SB group. This study revealed that NHJD could attenuate the genotoxic effects of realgar. The botanicals SB, RP, and GU within NHJD may be key contributors to this effect. Enhancements in arsenic methylation capabilities through increased levels of SAM and ARR and elevated gene expressions of As 3 MT, PNP, and GSTO1 suggest potential mechanisms behind these findings. [Display omitted] • NHJD reduces the increment of MN‰, SPA%, and DNA damage caused by realgar. • NHJD increases arsenic methylation capacity compared to equivalent doses of realgar. • SAM and ARR proteins may play roles in NHJD's alleviating realgar genotoxicity. • As 3 MT, PNP, and GSTO1 genes may be involved in the detoxification mechanisms of NHJD. • Nine chemical compounds were identified in the prepared NHJD decoction. [ABSTRACT FROM AUTHOR]

المؤلفون: Zhao, Wan¹, Zhang, Qiumei², Chen, Xiongying³, Li, Yang¹, Li, Xiaohong³, Du, Boqi¹, Deng, Xiaoxiang¹, Ji, Feng⁴, Wang, Chuanyue³, Xiang, Yu-Tao⁵, Dong, Qi¹, Chen, Chuansheng⁶, Li, Jun¹ lijundp@bnu.edu.cn

المصدر: Psychological Medicine. Aug2021, Vol. 51 Issue 11, p1927-1932. 6p.

مصطلحات موضوعية: *BRAIN physiology, *ARSENIC metabolism, *MEMORY, *BRAIN, *IN vivo studies, *HUMAN genome, *TASK performance, *NEUROPLASTICITY, *MAGNETIC resonance imaging, *GENE expression, *PRE-tests & post-tests, *TRANSFERASES, *OXIDATION-reduction reaction

مستخلص: Background: The Arsenic (+3 oxidation state) methyltransferase (AS3MT) gene has been identified as a top risk gene for schizophrenia in several large-scale genome-wide association studies. A variable number tandem repeat (VNTR) of this gene is the most significant expression quantitative trait locus, but its role in brain activity in vivo is still unknown. Methods: We first performed a functional magnetic resonance imaging (fMRI) scan of 101 healthy subjects during a memory span task, trained all subjects on an adaptive memory span task for 1 month, and finally performed another fMRI scan after the training. After excluding subjects with excessive head movements for one or more scanning sessions, data from 93 subjects were included in the final analyses. Results: The VNTR was significantly associated with both baseline brain activation and training-induced changes in multiple regions including the prefrontal cortex and the anterior and posterior cingulate cortex. Additionally, it was associated with baseline brain activation in the striatum and the parietal cortex. All these results were corrected based on the family-wise error rate method across the whole brain at the peak level. Conclusions: This study sheds light on the role of AS3MT gene variants in neural plasticity related to memory span training. [ABSTRACT FROM AUTHOR]

المؤلفون: Scannell Bryan, Molly¹, Sofer, Tamar^2,3, Afshar, Majid⁴, Mossavar-Rahmani, Yasmin⁵, Hosgood, H. Dean⁵, Punjabi, Naresh M.⁶, Zeng, Donglin⁷, Daviglus, Martha L.¹, Argos, Maria⁸ argos@uic.edu

المصدر: Scientific Reports. 6/29/2021, Vol. 11 Issue 1, p1-11. 11p.

مصطلحات موضوعية: *MENDEL'S law, *ARSENIC metabolism, *PULMONARY function tests, *PUBLIC health, *SPIROMETRY

مستخلص: Arsenic exposure has been linked to poor pulmonary function, and inefficient arsenic metabolizers may be at increased risk. Dietary rice has recently been identified as a possible substantial route of exposure to arsenic, and it remains unknown whether it can provide a sufficient level of exposure to affect pulmonary function in inefficient metabolizers. Within 12,609 participants of HCHS/SOL, asthma diagnoses and spirometry-based measures of pulmonary function were assessed, and rice consumption was inferred from grain intake via a food frequency questionnaire. After stratifying by smoking history, the relationship between arsenic metabolism efficiency [percentages of inorganic arsenic (%iAs), monomethylarsenate (%MMA), and dimethylarsinate (%DMA) species in urine] and the measures of pulmonary function were estimated in a two-sample Mendelian randomization approach (genotype information from an Illumina HumanOmni2.5-8v1-1 array), focusing on participants with high inferred rice consumption. Among never-smoking high inferred consumers of rice (n = 1395), inefficient metabolism was associated with past asthma diagnosis and forced vital capacity below the lower limit of normal (LLN) (OR 1.40, p = 0.0212 and OR 1.42, p = 0.0072, respectively, for each percentage-point increase in %iAs; OR 1.26, p = 0.0240 and OR 1.24, p = 0.0193 for %MMA; OR 0.87, p = 0.0209 and OR 0.87, p = 0.0123 for the marker of efficient metabolism, %DMA). Among ever-smoking high inferred consumers of rice (n = 1127), inefficient metabolism was associated with peak expiratory flow below LLN (OR 1.54, p = 0.0108/percentage-point increase in %iAs, OR 1.37, p = 0.0097 for %MMA, and OR 0.83, p = 0.0093 for %DMA). Less efficient arsenic metabolism was associated with indicators of pulmonary dysfunction among those with high inferred rice consumption, suggesting that reductions in dietary arsenic could improve respiratory health. [ABSTRACT FROM AUTHOR]