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"systems biology"

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28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/06/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Predicting anatomic therapeutic chemical classification codes using tiered learning.

BMC Bioinformatics. 2017 Jun 07;18(Suppl 8):266

Authors: Olson T, Singh R

Abstract
BACKGROUND: The low success rate and high cost of drug discovery requires the development of new paradigms to identify molecules of therapeutic value. The Anatomical Therapeutic Chemical (ATC) Code System is a World Health Organization (WHO) proposed classification that assigns multi-level codes to compounds based on their therapeutic, pharmacological and chemical characteristics as well as the in-vivo sites(s) of activity. The ability to predict ATC codes of compounds can assist in creation of high-quality chemical libraries for drug screening and in applications such as drug repositioning. We propose a machine learning architecture called tiered learning for prediction of ATC codes that relies on the prediction results of the higher levels of the ATC code to simplify the predictions of the lower levels.
RESULTS: The proposed approach was validated using a number of compounds in both cross-validation and test setting. The validation experiments compared chemical descriptors, initialization methods and classification algorithms. The prediction accuracy obtained with tiered learning was found to be either comparable or better than that of established methods. Additionally, the experiments demonstrated the generalizability of the tiered learning architecture, in that its use was found to improve prediction rates for a majority of machine learning algorithms when compared to their stand-alone application.
CONCLUSION: The basis of our approach lies in the observation that anatomical-therapeutic biological activity of certain types typically precludes activities of many other types. Thus, there exists a characteristic distribution of the ATC codes, which can be leveraged to limit the search-space of possible codes that can be ascribed at a particular level once the codes at the preceding levels are known. Tiered learning utilizes this observation to constrain the learning space for ATC codes at a particular level based on the ATC code at higher levels. This simplifies the prediction and allows for improved accuracy.

PMID: 28617230 [PubMed - in process]

Drug repositioning for enzyme modulator based on human metabolite-likeness.

BMC Bioinformatics. 2017 May 31;18(Suppl 7):226

Authors: Lee YH, Choi H, Park S, Lee B, Yi GS

Abstract
BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs.
METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness.
RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence.
CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.

PMID: 28617219 [PubMed - in process]

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits.

PLoS One. 2017;12(6):e0179020

Authors: Pinsonneault JK, Frater JT, Kompa B, Mascarenhas R, Wang D, Sadee W

Abstract
Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36), and in the 3'UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12-33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders.

PMID: 28617822 [PubMed - in process]

[The association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk and rapid progression of multiple sclerosis].

Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(2. Vyp. 2):10-13

Authors: Nochevnaya OM, Pereverzeva OV, Sokolova EA, Phillipenko ML, Zamyatina SV, Palaschenko AS, Zhdanova ES, Elchaninova SA, Smagina IV

Abstract
AIM: To evaluate the association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk of multiple sclerosis and its progression dynamics.
MATERIAL AND METHODS: A case-control study included 100 patients with recurrent multiple sclerosis (MS), Russians from the Altai Territory, and 100 healthy volunteers. Real-time polymerase chain reaction was used to genotype the 1377G>A polymorphism in the promoter of the FAS/APO-1 (rs2234767) gene. Association of this polymorphism with the risk of multiple sclerosis and its progression was evaluated.
RESULTS: The G/А genotype and the А-allele were associated with the increased risk of multiple sclerosis. The G/А genotype and the А-allele were associated with the risk of high progression rate of the disease. The G/G genotype and the G-allele had a protective effect.
CONCLUSION: Predisposition to MS as well as to high progression rate are associated with the FAS/APO-1*G/А gene in Russians living in the Altai Territory. Further research is required to make the conclusion.

PMID: 28617356 [PubMed - in process]

Specific Genes Associated with Adverse Events of Methylphenidate Use in the Pediatric Population: A Systematic Literature Review.

J Res Pharm Pract. 2017 Apr-Jun;6(2):65-72

Authors: Joensen B, Meyer M, Aagaard L

Abstract
The aim of this study was to review empirical studies examining associations between candidate genes and adverse events (AEs) from methylphenidate (MPH) use in children and adolescents. The PubMed, EMBASE, CINAHL, and Web of Science databases were searched from their inception until March 2017. We included empirically based articles on pharmacogenetic studies in 0-17-year-old patients that investigated associations between specific candidate genes, their polymorphisms, and reported AEs. We extracted information about study design, setting, type of AE reporter, studied genes and their polymorphisms, age and gender, administered doses, method of genotyping, outcome measures, and main findings. A total of nine articles reporting information about four double-blind, placebo-controlled, cross-over studies and five open-label cohort studies were eligible for inclusion. Studies were published from 2006 onward and included a total of 998 patients (3-17-year-olds) diagnosed with attention-deficit hyperactivity disorder (ADHD). Studies predominantly involved males and lasted from 1 to 12 weeks. Studies used polymerase chain reaction and single nucleotide polymorphism genotyping methodology. Reported AEs were significantly associated with the following genes: appetite reduction (CES1*G); buccal-lingual movements (T1065G); diastolic blood pressure (ADRA2A Mspl C/C-GC); emotionality (DAT1*9/9); irritability (SNAP25 T1065G); picking (DRD4*7/DRD4*4); social withdrawal (DRD4*7/DRD4*4); somatic complaints (DAT1*10/10); tics (5-HTTLRP*S/L*L/L; SNAP25 T1065G); sadness (CES1*rsl12443580); and vegetative symptoms (5-HTTLPR). In conclusion, only few MPH pediatric pharmacogenetic studies were located, and large between-study heterogeneity was found. Studies were of naturalistic design and of short duration. They included small patient samples, poorly standardized treatment regimens, and limited outcome assessments. In the future, more pharmacogenomic studies in ADHD are needed, preferably using randomized, controlled study designs and of longer duration (more than 6 months).

PMID: 28616427 [PubMed - in process]

Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma.

Mol Cancer Ther. 2016 Nov;15(11):2640-2652

Authors: Buondonno I, Gazzano E, Jean SR, Audrito V, Kopecka J, Fanelli M, Salaroglio IC, Costamagna C, Roato I, Mungo E, Hattinger CM, Deaglio S, Kelley SO, Serra M, Riganti C

Abstract
Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. A total of 40% to 45% of high-grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin (Dox), due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve Dox-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted Dox (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to Dox. Unlike Dox, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, and induced necrotic and immunogenic cell death in Dox-resistant/Pgp-overexpressing cells, fully reproducing the activities exerted by anthracyclines in drug-sensitive tumors. mtDox reduced tumor growth and cell proliferation, increased apoptosis, primed tumor cells for recognition by the host immune system, and was less cardiotoxic than Dox in preclinical models of drug-resistant osteosarcoma. The increase in Dox resistance was paralleled by a progressive upregulation of mitochondrial metabolism. By widely modulating the expression of mitochondria-related genes, mtDox decreased mitochondrial biogenesis, the import of proteins and metabolites within mitochondria, mitochondrial metabolism, and the synthesis of ATP. These events were paralleled by increased reactive oxygen species production, mitochondrial depolarization, and mitochondria-dependent apoptosis in resistant osteosarcoma cells, where Dox was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared with Dox that may be effective for the treatment of Dox-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies. Mol Cancer Ther; 15(11); 2640-52. ©2016 AACR.

PMID: 27466354 [PubMed - indexed for MEDLINE]

The Right Pill for You.

Sci Am. 2016 Sep 20;315(4):46-51

Authors: Maron DF

PMID: 27798591 [PubMed - indexed for MEDLINE]

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells.

Mol Cancer Ther. 2016 Oct;15(10):2399-2412

Authors: Santamaría Nuñez G, Robles CM, Giraudon C, Martínez-Leal JF, Compe E, Coin F, Aviles P, Galmarini CM, Egly JM

Abstract
We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. ©2016 AACR.

PMID: 27630271 [PubMed - indexed for MEDLINE]

Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.

Transpl Infect Dis. 2017 Jun 15;:

Authors: Parize P, Boussaud V, Poinsignon V, Sitterlé E, Botterel F, Lefeuvre S, Guillemain R, Dannaoui E, Billaud EM

Abstract
BACKGROUND: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT.
METHODS: Here we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period.
RESULTS: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive.
CONCLUSIONS: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed. This article is protected by copyright. All rights reserved.

PMID: 28618155 [PubMed - as supplied by publisher]

Patients with Cystic Fibrosis and a G551D or Homozygous F508del Mutation: Similar Lung Function Decline.

Am J Respir Crit Care Med. 2017 Jun 15;195(12):1673-1676

Authors: Sawicki GS, McKone EF, Millar SJ, Pasta DJ, Konstan MW, Lubarsky B, Wagener JS

PMID: 28617084 [PubMed - in process]

Cystic fibrosis prevalence among a group of high-risk children in the main referral children hospital in Iran.

J Educ Health Promot. 2017;6:54

Authors: Modaresi MR, Faghinia J, Reisi M, Keivanfar M, Navaie S, Seyyedi J, Baharzade F

Abstract
BACKGROUND: Knowledge about cystic fibrosis (CF) in Iran is very limited. The objective of this study was to determine the prevalence of CF among a group of high-risk children with suggestive clinical features in the main referral hospital in Iran.
MATERIALS AND METHODS: This study children consisted of 505 patients who had presented with one or more of the following symptoms: chronic or recurrent respiratory symptoms, gastrointestinal symptoms as rectal prolapse, steatorrhea, hepatobiliary disease as prolonged jaundice, failure to thrive, hyperglycemia and glycosuria, hypochloremic metabolic alkalosis, hypoprothrombinemia, anemia or edema, and positive family history of CF. Patients were screened using pilocarpine iontophoresis to collect sweat and chemical analysis of its chloride content with classic Gibson and Cooke technique.
RESULTS: Of 505 patients, 89 (17.6%) had positive sweat chloride screening test. Five (1%) patients had required cystic fibrosis transmembrane conductive regulator protein mutation analysis to confirm CF.
CONCLUSION: Our findings suggest that in Iran, CF is more common than what previously anticipated. Larger studies are warranted to identify the incidence, molecular basis, and clinical pattern of CF in the Iranian population.

PMID: 28616421 [PubMed - in process]

Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis.

Sci Rep. 2017 Jun 14;7(1):3517

Authors: Perniss A, Preiss K, Nier M, Althaus M

Abstract
Hydrogen sulfide (H2S) has been recognized as a signalling molecule which affects the activity of ion channels and transporters in epithelial cells. The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial anion channel and a key regulator of electrolyte and fluid homeostasis. In this study, we investigated the regulation of CFTR by H2S. Human CFTR was heterologously expressed in Xenopus oocytes and its activity was electrophysiologically measured by microelectrode recordings. The H2S-forming sulphur salt Na2S as well as the slow-releasing H2S-liberating compound GYY4137 increased transmembrane currents of CFTR-expressing oocytes. Na2S had no effect on native, non-injected oocytes. The effect of Na2S was blocked by the CFTR inhibitor CFTR_inh172, the adenylyl cyclase inhibitor MDL 12330A, and the protein kinase A antagonist cAMPS-Rp. Na2S potentiated CFTR stimulation by forskolin, but not that by IBMX. Na2S enhanced CFTR stimulation by membrane-permeable 8Br-cAMP under inhibition of adenylyl cyclase-mediated cAMP production by MDL 12330A. These data indicate that H2S activates CFTR in Xenopus oocytes by inhibiting phosphodiesterase activity and subsequent stimulation of CFTR by cAMP-dependent protein kinase A. In epithelia, an increased CFTR activity may correspond to a pro-secretory response to H2S which may be endogenously produced by the epithelium or H2S-generating microflora.

PMID: 28615646 [PubMed - in process]

CFTR protects against vascular inflammation and atherogenesis in apolipoprotein E-deficient mice.

Biosci Rep. 2017 Jun 14;:

Authors: Li Z, Shen Z, Xue H, Cheng S, Ji Q, Liu Y, Yang X

Abstract
Atherosclerosis is a chronic inflammatory disease of the vascular wall. Dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to result in inflammatory responses in cystic fibrosis (CF) patients. However, little is known about the role of CFTR in vascular inflammation and atherogenesis. Our results showed that CFTR was dominantly expressed in macrophages of atherosclerotic plaque and reduced in aorta and aortic sinus from atherosclerotic apolipoprotein E-deficient (apoE-/-) mice. In vivo administration of CFTR adenovirus (Ad-CFTR) with apoE-/- mice fed high-fat diet improved plaque stability by decreasing lipid accumulation and necrotic area and increasing smooth muscle cell content and collagen. The Ad-CFTR-treated mice also displayed reduced proinflammatory cytokines levels in aorta and peritoneal macrophages, whereas the anti-inflammatory M2 macrophage markers were increased. Confocal microscopy revealed that the infiltration of T-lymphocytes, neutrophils and macrophages in aortic sinus was markedly attenuated in Ad-CFTR-treated apoE-/- mice. Moreover, in vitro experiments showed that overexpression of CFTR inhibited ox-LDL-induced the migration of peritoneal macrophages. Finally, it was observed that CFTR upregulation suppressed NFκB and MAPKs activity induced by ox-LDL. Inhibition of JNK or ERK abrogated CFTR downregulation-induced NFκB activation, whereas NFκB inhibitor had no effects on JNK or ERK activation. Taken together, these results demonstrate that CFTR prevents inflammation and atherogenesis via inhibiting NFκB and MAPKs activation. Our data suggest that CFTR may present a potential therapeutic target for the treatment of vascular inflammation and development of atherosclerotic disease.

PMID: 28615349 [PubMed - as supplied by publisher]

Ease of use of tobramycin inhalation powder compared with nebulized tobramycin and colistimethate sodium: a crossover study in cystic fibrosis patients with pulmonary Pseudomonas aeruginosa infection.

Ther Adv Respir Dis. 2017 Jul;11(7):249-260

Authors: Greenwood J, Schwarz C, Sommerwerck U, Nash EF, Tamm M, Cao W, Mastoridis P, Debonnett L, Hamed K

Abstract
BACKGROUND: This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF).
METHODS: A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ⩾6 years with forced expiratory volume in 1 second (FEV1) ⩾25% to ⩽90% predicted. Patients were assigned to one of the three treatment arms in Cycle 1; all patients received TIP in Cycle 2. Each cycle consisted of 28 days on and 28 days off the treatment.
RESULTS: A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP ( n = 14); COLI/TIP ( n = 28); TIP/TIP ( n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP ( p = 0.0112) and COLI/TIP ( p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT® questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity.
CONCLUSION: The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile.

PMID: 28614995 [PubMed - in process]

Preimplantation genetic screening.

J Med Screen. 2017 Jan 01;:969141317691797

Authors: Harper JC

Abstract
Preimplantation genetic diagnosis was first successfully performed in 1989 as an alternative to prenatal diagnosis for couples at risk of transmitting a genetic or chromosomal abnormality, such as cystic fibrosis, to their child. From embryos generated in vitro, biopsied cells are genetically tested. From the mid-1990s, this technology has been employed as an embryo selection tool for patients undergoing in vitro fertilisation, screening as many chromosomes as possible, in the hope that selecting chromosomally normal embryos will lead to higher implantation and decreased miscarriage rates. This procedure, preimplantation genetic screening, was initially performed using fluorescent in situ hybridisation, but 11 randomised controlled trials of screening using this technique showed no improvement in in vitro fertilisation delivery rates. Progress in genetic testing has led to the introduction of array comparative genomic hybridisation, quantitative polymerase chain reaction, and next generation sequencing for preimplantation genetic screening, and three small randomised controlled trials of preimplantation genetic screening using these new techniques indicate a modest benefit. Other trials are still in progress but, regardless of their results, preimplantation genetic screening is now being offered globally. In the near future, it is likely that sequencing will be used to screen the full genetic code of the embryo.

PMID: 28614992 [PubMed - as supplied by publisher]