bluuebunny/crossref_metadata_2025_split huggingface dataset:
2299-PUB: PNPLA3 I148M Involved in Mechanism of Variability in Antilipogenesis Response to Exenatide
Authors: CHEN YUNZHI , LIANG HUA , XU FEN 
Published: June 2020

Background: GLP-1 receptor agonist, such as exenatide, has been proven to attenuate nonalcoholic fatty liver disease (NAFLD) in vivo and in vitro. Its potential mechanism remains elusive. PNPLA3 is a major susceptibility gene for NAFLD and its I148M polymorphism increases the risk of all disorders of NAFLD spectrum. However, whether genetic variation contributes to variability in exenatide response is still unclear.
Methods: Wild type (I148I) PNPLA3 knockin cells were constructed using HepG2 as a template which are homozygous for the PNPLA3I148M mutation by CRISPR/Cas 9 gene editing technique. Oil Red O staining combined with TG quantification were used to evaluate lipid accumulation. Western blot and RT-qPCR were conducted respectively to measure the protein and mRNA expression of lipid synthesis and inflammatory markers.
Results: Lipid deposition was increased in both wild type (I148I) and mutant (I148M) HepG2 cells treated with palmitoleic acid (PA), while mutant cells had a higher TG content than wild type cells. Exenatide treatment was showed to be more efficacious in mutant cells than in wild type cells on reducing the accumulation of TG. Exenatide-mediated inhibition of SREBP-1 and endoplasmic reticulum stress pathway, and activation of AMPK pathway, were more significant in mutatnt cells than in wild type cells.
Conclusion: PNPLA3 I148M might modify the treatment response to exenatide in NAFLD. This research would provide a novel insight for individualized exenatide treatment.

Disclosure
Y. Chen: None.
23-OR: EHR-Based Blood Glucose Alerts Improve Inpatient Glycemic Control at a Large Academic Medical Center
Authors: BAK LEIGH B. , FANDEL THOMAS M. , BOZZO JANIS E. , DEWITT MICHELLE L. , CHEN PING , PANDO RICHARD A. , FERRO LINDA , KAPLAN RORY , HENDRICKSON KARRIE C. , AMPORT STEPHANIE B. , SUSSMAN L. SCOTT , INZUCCHI SILVIO E. 
Published: June 2020

Hospital blood glucose (BG) management is a challenge. We implemented an electronic health record (EHR)-based system at our 1541-bed academic medical center (AMC), alerting when a patient (pt) experiences significant hyperglycemia (hyper; 2 BGs ≥300 mg/dL over 48 hours) or hypoglycemia (hypo; &lt;70 mg/dL). These Excursion Event Alerts (EEAs) fired to the clinician entering orders and provided links to insulin order sets and consult requests. The EEAs were launched on 14 non-ICU wards in mid-2019. We compared BG control during the 3 months prior to launch vs. the most recent 3 months. The control group consisted of 12 non-EEA wards. Our 1° outcome was the Quality Hyperglycemia Score-2 (QHS2), previously developed to assess/compare the overall BG quality on individual wards. QHS2 (scale, 0-100) incorporates 5 elements of BG management, crediting overall control as well as the minimization of significant fluctuations. After the intervention, there was a substantial 13.8% improvement in mean QHS2 (+9.36, p=0.029), comprised of more pt-days in target (+4.3%, p=0.024) and a trend for less pt-days with severe hyper (-2%, p=0.09), with no change in hypoglycemia. In contrast, there was no change in QHS2 on control wards. We conclude that a glycemic alert system was associated with improved BG control at our large AMC, suggesting that a simple EHR-based intervention can favorably impact hospital diabetes management.

Disclosure
L.B. Bak: None. T.M. Fandel: None. J.E. Bozzo: None. M.L. DeWitt: None. P. Chen: None. R.A. Pando: None. L. Ferro: None. R. Kaplan: None. K.C. Hendrickson: None. S.B. Amport: None. L. Sussman: None. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics.
230-OR: Personalized Nutrition for Prediabetes by Prediction of Glycemic Responses
Authors: BEN-YACOV ORLY , GODNEVA ANASTASIA , SEGAL ERAN 
Published: June 2020

Prediabetes is a leading risk factor for the development of type 2 diabetes mellitus (T2DM) and its metabolic complications. Current practice for prevention of diabetes includes weight loss-targeting dietary and lifestyle modifications but has had limited success. Alternative approaches, such as dietary interventions that directly target blood glucose levels for prevention of T2DM, are not well established and have been much less studied. In particular, postprandial (post-meal) glucose responses (PPGR) are a major determinant of glycemic control, but dietary methods for controlling PPGRs are rare and show limited efficacy. We previously recruited a population-based cohort of 900 people in which we continuously tracked blood glucose and obtained clinical and gut microbiota measurements. Our data of ∼50,000 PPGRs revealed that different people have vastly different responses to the same meal. We devised a machine learning algorithm based on clinical and microbiome features that accurately predicted personalized PPGRs to any food combination. Here, we sought to evaluate the long-term clinical efficacy of a dietary intervention based on our algorithm in prediabetes, and test the hypothesis that a dietary treatment that targets meal PPGR can lead to long-term improvements in glycemic control and other metabolic outcomes, as compared to a standard Mediterranean-style diet. To this end, we conducted a 6-month randomized controlled diet intervention trial (RCT) followed by a 6-month post-intervention follow-up program, and randomly assigned 225 adults with prediabetes to receive a Mediterranean-style (Med) diet or a Personalized Postprandial-targeting (PPT) diet. At 6 months, mean daily time of glucose levels above 140 mg/dl changed by -29% and -65% in the Med diet and PPT diet, respectively (p=3.4x10-10). Mean HbA1c% levels changed by -0.08% and -0.16% in the Med diet and PPT diet, respectively (p=6.9x10-3). The favorable effects of the ’PPT diet’ on glycemic control persisted also at one year follow up.

Disclosure
O. Ben-Yacov: None. A. Godneva: None. E. Segal: Consultant; Self; DayTwo.
238-OR: Once-Weekly Basal Insulin Icodec Offers Comparable Efficacy and Safety vs. Once-Daily Insulin Glargine U100 in Insulin-Naïve Patients with T2D Inadequately Controlled on OADS
Authors: ROSENSTOCK JULIO , KJAERSGAARD MAIKEN I.S. , MOLLER DANIEL , HANSEN MELISSA VOIGT , GOLDENBERG RONALD 
Published: June 2020

Insulin icodec* (icodec) is a novel basal insulin analog with a terminal half-life of ∼196 hours in development as the first once-weekly insulin. This 26-week, randomized, double-blind, double-dummy, treat-to-target, phase 2 trial investigated the efficacy and safety of once-weekly icodec vs. once-daily insulin glargine U100 (IGlar U100) in insulin-naïve patients with T2D inadequately controlled (A1C 7.0-9.5%) with metformin ± DPP-4i. Starting doses were 70 U weekly and 10 U daily, respectively, with weekly titration to a pre-breakfast SMBG target of 70-108 mg/dL. Primary endpoint was change in A1C from baseline to week 26. Secondary endpoints included change in FPG from baseline to week 26 and hypoglycemic episodes. Participants (n = 247) were randomized 1:1 to icodec (n = 125) or IGlar U100 (n = 122). Baseline characteristics appeared similar in both groups; mean age was 59.6 years, diabetes duration 9.7 years, BMI 31.3 kg/m2 and FPG 181 mg/dL. Mean baseline A1C was 8.1% (icodec) and 8.0% (IGlar U100). At week 26, estimated mean A1C was 6.69% for icodec and 6.87% for IGlar U100 (estimated mean change from baseline: -1.33% and -1.15%-points, respectively). There was no statistically significant treatment difference for change in A1C from baseline to week 26 (-0.18%, 95% CI, -0.38; 0.02). Estimated mean FPG at week 26 was 123 mg/dL (icodec) and 127 mg/dL (IGlar U100). Observed rates of level 2 (&lt;54 mg/dL) + 3 (severe) hypoglycemia were low (60.55 and 52.36 events per 100 patient years of exposure for icodec and IGlar U100, respectively) and were comparable (p = 0.85). There were no unexpected safety findings.
In conclusion, icodec is the first once-weekly insulin with similar glucose-lowering effects and safety profile to once-daily IGlar U100. Icodec could improve treatment acceptance and facilitate T2D management in patients needing basal insulin. *Proposed INN.

Disclosure
J. Rosenstock: None. M.I.S. Kjaersgaard: Employee; Self; Novo Nordisk A/S. D. Moller: Employee; Self; Novo Nordisk A/S. M. Voigt Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. R. Goldenberg: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Johnson & Johnson, Merck & Co., Inc., Novo Nordisk Inc., Sanofi.
24-LB: RIPK1 Activation Induces Necroptosis, Proinflammation, and Profibrosis in Kidney of STZ/HFD-Induced Diabetic Mice
Authors: CHEN QING , LONG YANG , GUO MAN , MA XIU M. , PU YUELI , XU YONG 
Published: June 2020

Diabetic kidney disease (DKD) is attributed largely to renal tubular interstitial fibrosis. However, the complex mechanism of renal tubular interstitial fibrosis in DKD pathogenesis remains unclear. Recently, necroptosis has emerged as an important cell death model in many pathological conditions, which is regulated through RIPK1/RIPK3 pathway. In this present study, we aimed to evaluate whether necroptosis is involved in the development of diabetic kidney disease, and to investigate the mechanisms involved. In the current study, the results of immunohistochemistry and Western blot showed that the ratio of p-RIPK1/RIPK1, p-RIPK3/RIPK3, p-MLKL/MLKL were significantly increased in the kidney of STZ/HFD induced diabetic mice. Additionally, the levels of serum MCP-1, and the expression of IL-1 β and TGF - β in kidney were increased in the diabetic mice. Moreover, Necrostatin-1, an inhibitor of RIPK1, can effectively decrease the ratio of p-RIPK1/RIPK1, p-RIPK3/RIPK3, p-MLKL/MLKL, the levels of serum MCP-1, and the expression of TGF-β and IL-1 β in kidney in the diabetic mice. Necrostatin-1 treatment also resulted in delayed progression of renal structural lesions and significantly improved the function of kidney. High glucose stimulation, which induced excessive ROS production, led to necrosis and increased phosphorylation of RIPK1, RIPK3 and MLKL in rat tubular epithelial cell NRK-52E cells. Moreover, NAC treatment, a ROS inhibitor, could partly reverse the effect of glucose on RIPK1, RIPK3, and MLKL.
In conclusion, RIPK1 activation may induce necroptosis, pro-inflammation and pro-fibrosis in kidney of STZ/HFD induced diabetic mice; High glucose induces RIPK1 -dependent necroptosis in NRK-52E cells; excessive ROS production mediate high glucose induced necroptosis.

Disclosure
Q. Chen: None. Y. Long: None. M. Guo: None. X.M. Ma: None. Y. Pu: None. Y. Xu: None.

Funding
Science and Technology Bureau of Luzhou (2016LZXNYD-G02)
241-LB: Positive Regulation of JAK/STAT at Signaling with SOCS3-Derived Cell-Permeable Binding Domain to ObR Induces Anti-obesity Effect
Authors: LEE KUYSOOK , JEON JISOOK , KIM SU JEONG , KANG HYEONTAE , KWAK JEONGHUN , CHOI YOUNGSIL , JO DAEWOONG 
Published: June 2020

Aim: Leptin, a hormone which regulates food intake and energy expenditure, is excessively expressed in obese patients. Leptin signaling is regulated by a negative feedback regulator, suppressor of cytokine signaling 3 (SOCS3) that competitively binds to the leptin receptor (ObR) and promotes leptin resistance. We hypothesized that an exogenously delivered SOCS3 binding domain (SH2) would compete with SOCS3 for binding to p-Tyr985ObR, and thereby maintain leptin-initiated JAK/STAT signaling.
Method: Cell-permeable, dominant-interfering ΔSOCS3 protein consists of the SOCS3 SH2 domain, a sequence optimized-advanced macromolecule transduction domain to deliver the protein into cells and tissues to facilitate soluble purification, biologically active proteins. Intracellular delivery of ΔSOCS3 was tested for the ability to enhance leptin signaling and sensitivity in diet-induced obese (DIO) mice.
Result: The cell-permeable ΔSOCS3 was delivered efficiently into cell types and tissues examined including the hypothalamus; thus, the protein appeared to cross the blood-brain barrier. CP-ΔSOCS3 competitively bound p-Tyr985ObR and blocked negative regulation by endogenous SOCS3 as assessed by increased levels of phospho-STAT3. DIO mice treated with CP-ΔSOCS3 showed 12.1% body weight loss in 14 days. In addition, fat volume (53.5%), food intake (29.2%), serum leptin (93.1%) and expression of SOCS3 mRNA were also decreased in CP-ΔSOCS3-treated compared to mice treated with diluent. In addition, treatment group showed a significant increase in STAT3 phosphorylation and pro-opiomelanocortin in the hypothalamus.
Conclusion: CP-ΔSOCS3 appeared to competitively suppress feedback inhibition of JAK/STAT signaling by endogenous SOCS3 thereby enhancing leptin sensitivity. This establishes the importance of SOCS3 in the biology of leptin signaling and resistance and suggests CP-ΔSOCS3 might be used as a mechanism-specific weight-loss therapy.

Disclosure
K. Lee: None. J. Jeon: None. S. Kim: None. H. Kang: None. J. Kwak: None. Y. Choi: None. D. Jo: None.
242-LB: The Obesity Paradox among Patients Hospitalized for Diabetes and Its Complications: Outcomes of the Nationwide Inpatient Sample
Authors: SHAKA HAFEEZ , PADILLA SORTO MARIA ELENA , GOMEZ TRISHA MARIE A. , EDIGIN EHIZOGIE , XU JING , YAP SARA ELIZABETH T. 
Published: June 2020

Background: Obesity has long been considered a risk factor for individual morbidity and mortality for numerous cardiopulmonary diseases. However, multiple studies have shown that patients who are overweight or obese according to BMI have better inpatient outcomes.
Objective: To demonstrate the effect of obesity on outcomes of patients admitted for diabetes with and without complications.
Method: Data were extracted from the Nationwide Inpatient Sample (NIS) Database for 2016 and 2017. The numbers in the database are weighted to optimize national estimates. Hospitalizations involving all adults with a principal diagnosis of type 1 and type 2 DM were included. This group was further categorized based on the presence of obesity, defined as BMI &gt;30, as a secondary diagnosis. The primary outcome was inpatient mortality and secondary outcomes were Length of stay (LOS) and Total hospital Charge (THC). Multivariate regression analysis was used to adjust for possible confounders.
Results: Around 1,031,009 hospitalizations had a principal diagnosis of DM types 1 and 2. This group had a prevalence of 15.67% of obesity as a secondary diagnosis. Inpatient mortality occurred in 6285 cases (0.61%). After accounting for age, sex, disease severity and type of diabetes, the adjusted odds ratio (aOR) for mortality in obese patients was 0.63 (95% CI: 0.526 - 0 .762, p&lt; 0.001) compared to non-obese patients. Obese patients however, had adjusted increase in THC of $560 (95% CI: -347 - 1467, p=0.226) and adjusted increase in LOS of 0.3 days (95% CI: 0.3 - 0.4, p&lt;0.001).
Conclusions: In patients hospitalized with a principal diagnosis of diabetes and its complications, obese patients had a statistically lower mortality rate. Hence, there seems to be growing evidence for the obesity paradox. More research needs to be done to determine the factors responsible for this recurrent phenomenon.

Disclosure
H. Shaka: None. M. Padilla Sorto: None. T.A. Gomez: None. E. Edigin: None. J. Xu: None. S.T. Yap: None.
243-LB: Enzymes for Dicarbonyl Detoxification Are Attenuated with Obesity by Mechanisms of Acetylation
Authors: MIRANDA EDWIN R. , SHADIOW JAMES , LOMBARD DAVID B. , LUDLOW ANDREW T. , HAUS JACOB M. 
Published: June 2020

Glyoxalase I (GLOI) is the primary enzyme for detoxifying the reactive dicarbonyl methylglyoxal. Pre-clinical models demonstrate that loss of GLOI promotes the development of diabetes in obesogenic conditions. To determine if GLOI is attenuated with human obesity, we compared GLOI expression in skeletal muscle biopsy samples from 5 obese (OB) and 15 age-matched lean, healthy individuals (LH). GLOI protein was ~50% lower (p&lt;0.05), whereas GLOI mRNA was ~2-fold higher in OB muscle (p&lt;0.001). The NRF2/Keap1 axis, which regulates GLOI transcription, was unperturbed by obesity. Given the NAD+-dependent deacetylase SIRT1 is capable of deacetylating GLOI which may prevent GLOI’s degradation, we measured the expression of SIRT1 as well as NAMPT and HIF1α which regulate NAD+ bioavailability. HIF1α mRNA was increased 3-fold (p=0.002) and NAMPT protein was ~50% lower (p=0.2) in OB muscle suggesting a pseudo-hypoxic environment which may attenuate NAD+ bioavailability. SIRT1 protein was ~50% lower in OB muscle (p=0.09). SIRT1 protein (r = 0.673, p = 0.003) and HIF1α transcripts (r = -0.487, p = 0.041) correlated with GLO1 protein expression. NAMPT inhibition in human primary myotubes increased GLOI acetylation (~50%) and GLO1 protein (~40%) both of which were rescued by treatment with the NAD+ precursor nicotinamide riboside. Silencing of NAMPT or SIRT1 also reduced GLOI protein by 50%. These data suggest that OB muscle may be in a pseudo-hypoxic state that limits NAD+ bioavailability and SIRT1 activity promoting GLO1 acetylation and degradation.

Disclosure
E.R. Miranda: None. J. Shadiow: None. D.B. Lombard: None. A.T. Ludlow: None. J.M. Haus: None.

Funding
National Institutes of Health (R01DK109948)
244-LB: Data-Driven Metabolic Subgrouping of Obesity by Machine Learning (ML)
Authors: LIN ZIWEI , HUI YOU , WU SHANDONG , QU SHEN 
Published: June 2020

Aim: Current clinical classification paradigms for obesity are unrefined and demand more precise classification.
Methods: Unsupervised ML is used to cluster patients with obesity on 2 independent cohorts at 1 institution: an outpatient (n=507) and an inpatient (n=229) cohort. The clustering is performed separately on the 2 cohorts, based on 4 physician expert-selected clinical variables (age, AUC of insulin, FSH, urine acid). Statistics of a lean cohort (n=702) are measured as control.
Results: The classification reveals 4 metabolic different obese clusters on each cohort (Fig 1). Jaccard similarity is 0.865 between the 2 cohorts’ clusters. MHO shows a moderate basal metabolic rate (BMR) with relative healthy hormone levels and glucometabolism. LMO shows the lowest BMR and hormone, oldest age, and most severe glucometabolism. Both HMO-T1 and HMO-T2 show the highest BMR and hormone, lowest glucose, highest incidents of hyperuricemia and female hyperandrogenemia. Moreover, higher urine acid and testosterone in female are observed in HMO-T1, while extremely high insulin secretion and low incidents of diabetes are seen in HMO-T2.
Conclusion: Clinical characteristics-separable subgroups of obesity can be autonomously identified by ML, where the sub-grouping is generalizable across 2 independent cohorts. This may provide interpretation of pathogenesis and enable more precise therapy decision-making for patients with obesity.

Disclosure
Z. Lin: None. Y. Hui: None. S. Wu: Other Relationship; Spouse/Partner; LifeVantage. S. Qu: None.

Funding
National Key R&D Program of China (2018YFC1314100); National Natural Science Foundation of China for Youth (81500687); Fundamental Research Funds for the Central Universities of Tongji University (22120190210)
244-OR: Single Nuclei Chromatin and Transcriptome Profiling across Human and Rat Skeletal Muscle Identifies Regulatory Elements, Genes, and Cell Types Associated with Diabetes GWAS Signals
Authors: PARKER STEPHEN ,   FUSION TISSUE SAMPLING GROUP
Published: June 2020

Skeletal muscle is the largest organ, by weight (&gt;40%), in the human body; insulin resistance in this and other peripheral tissues is a hallmark of type 2 diabetes (T2D). Recent genome wide association study (GWAS) results show significant enrichment for fasting insulin single nucleotide polymorphisms (SNPs) in skeletal muscle tissue chromatin-defined regulatory regions. The next steps towards mechanistic translation are identification of causal variants, the target genes these variants regulate, and the specific cell populations in which they function. To accomplish this, we optimized and performed single-nuclei resolution chromatin (snATAC-seq) and transcriptome (snRNA-seq) profiling across human and rat frozen skeletal muscle, collectively measuring ’omic profiles on 38,386 nuclei. We used integrative non-negative matrix factorization for data fusion across ’omics modalities and species, revealing seven distinct clusters that range in abundance from 58% to 2.1% of all nuclei. The clusters are consistent across independent human and rat samples and across ’omic modalities. We find heterogeneity in fasting insulin GWAS enrichment across snATAC peaks for the muscle cell types (2/7 significantly enriched), one of which is mesenchymal stem cells (∼4% of nuclei). We use genetically fine-mapped SNPs from the largest T2D GWAS and find the highest posterior probability 99% credible set SNP (rs702634) out of three at the ARL15 locus resides in a muscle mesenchymal stem cell-specific snATAC peak. We are nearly finished snRNA+snATAC profiling across 400 additional samples, which will enable muscle cell-specific e/chromQTL analyses and GWAS colocalization reports for the ADA meeting. This work represents a unique resource for the genetic signature of skeletal muscle biology at unprecedented epigenomic, transcriptomic, and cellular scales.

Disclosure
S. Parker: None.

Funding
American Diabetes Association (1-14-INI-07 to S.P.); National Institutes of Health (R01DK117960)
245-LB: Aberrant DNA Methylation as a Contributor to Obesity-Associated Vascular Dysfunction
Authors: ALI MOHAMED M. , HASSAN CHANDRA , MASRUR MARIO , BIANCO FRANCESCO , PHILLIPS SHANE A. , MAHMOUD ABEER M. 
Published: June 2020

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity-associated hypoxia in disturbing the methylation of genes involved in inflammation and vascular dysfunction and propose a mediating role of the hypoxia-inducible factor, HIF1α and the DNA hydroxymethylase, TET1.
Methods: We obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non-obese (NOB) adults having elective surgeries (n=36; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for vasoreactivity in response to increasing pressure gradients. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and promoter methylation/gene expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF-α, and IFNɣ were measured in the AT biopsy. Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound.
Results: Flow-induced dilation (FID) was 40-50% higher in NOB than OB adults across all pressure gradients (p&lt;0.05). NO production was higher, and ROS generation was lower in the OB arterioles compared to NOB. HIF1α and TET1 proteins were 2 to 4-fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID and NO and brachial artery FMD (r=0.82, 0.64, 0.91, respectively; p&lt;0.001) and positively with arteriolar ROS production (r=-0.71, p&lt;0.01). Global hydroxymethylation was observed in OB compared to NOB as well as DNA promoter hypomethylation and increased gene expression of the targeted adipocytokines.
Conclusion: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines in the hypoxic AT. A downstream target for this pathway could reside in endothelial cells of nearby arterioles and remote arteries resulting in vascular dysfunction.

Disclosure
M.M. Ali: None. C. Hassan: None. M. Masrur: None. F. Bianco: Consultant; Self; Intuitive, Medtronic. S.A. Phillips: None. A.M. Mahmoud: None.

Funding
National Institutes of Health (4R00HL140049, 031K99, HL14004901)