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1.
Emerg Infect Dis ; 25(3): 482-488, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30789126

RESUMO

The clinical phenotype of zoonotic tuberculosis and its contribution to the global burden of disease are poorly understood and probably underestimated. This shortcoming is partly because of the inability of currently available laboratory and in silico tools to accurately identify all subspecies of the Mycobacterium tuberculosis complex (MTBC). We present SNPs to Identify TB (SNP-IT), a single-nucleotide polymorphism-based tool to identify all members of MTBC, including animal clades. By applying SNP-IT to a collection of clinical genomes from a UK reference laboratory, we detected an unexpectedly high number of M. orygis isolates. M. orygis is seen at a similar rate to M. bovis, yet M. orygis cases have not been previously described in the United Kingdom. From an international perspective, it is possible that M. orygis is an underestimated zoonosis. Accurate identification will enable study of the clinical phenotype, host range, and transmission mechanisms of all subspecies of MTBC in greater detail.


Assuntos
Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/epidemiologia , Tuberculose/microbiologia , Animais , Antituberculosos/farmacologia , Biologia Computacional/métodos , DNA Bacteriano , Farmacorresistência Bacteriana , Marcadores Genéticos , Humanos , Tipagem Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Prevalência , Zoonoses/epidemiologia , Zoonoses/microbiologia
2.
Nat Biotechnol ; 37(2): 152-159, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30718882

RESUMO

Exponentially increasing amounts of unprocessed bacterial and viral genomic sequence data are stored in the global archives. The ability to query these data for sequence search terms would facilitate both basic research and applications such as real-time genomic epidemiology and surveillance. However, this is not possible with current methods. To solve this problem, we combine knowledge of microbial population genomics with computational methods devised for web search to produce a searchable data structure named BItsliced Genomic Signature Index (BIGSI). We indexed the entire global corpus of 447,833 bacterial and viral whole-genome sequence datasets using four orders of magnitude less storage than previous methods. We applied our BIGSI search function to rapidly find resistance genes MCR-1, MCR-2, and MCR-3, determine the host-range of 2,827 plasmids, and quantify antibiotic resistance in archived datasets. Our index can grow incrementally as new (unprocessed or assembled) sequence datasets are deposited and can scale to millions of datasets.


Assuntos
Biologia Computacional/métodos , Farmacorresistência Bacteriana/genética , Genoma Bacteriano , Genoma Viral , Algoritmos , Mapeamento Cromossômico , Bases de Dados Factuais , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Reações Falso-Positivas , Genômica , Genótipo , Proteínas de Membrana/genética , Modelos Estatísticos , Epidemiologia Molecular , Mycobacterium/genética , Filogenia , Plasmídeos/genética , Linguagens de Programação , Salmonella/genética , Análise de Sequência de DNA , Staphylococcus/genética , Streptococcus/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética
3.
Wellcome Open Res ; 4: 191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32055708

RESUMO

Two billion people are infected with Mycobacterium tuberculosis, leading to 10 million new cases of active tuberculosis and 1.5 million deaths annually. Universal access to drug susceptibility testing (DST) has become a World Health Organization priority. We previously developed a software tool, Mykrobe predictor, which provided offline species identification and drug resistance predictions for M. tuberculosis from whole genome sequencing (WGS) data. Performance was insufficient to support the use of WGS as an alternative to conventional phenotype-based DST, due to mutation catalogue limitations.  Here we present a new tool, Mykrobe, which provides the same functionality based on a new software implementation. Improvements include i) an updated mutation catalogue giving greater sensitivity to detect pyrazinamide resistance, ii) support for user-defined resistance catalogues, iii) improved identification of non-tuberculous mycobacterial species, and iv) an updated statistical model for Oxford Nanopore Technologies sequencing data. Mykrobe is released under MIT license at https://github.com/mykrobe-tools/mykrobe. We incorporate mutation catalogues from the CRyPTIC consortium et al. (2018) and from Walker et al. (2015), and make improvements based on performance on an initial set of 3206 and an independent set of 5845 M. tuberculosis Illumina sequences. To give estimates of error rates, we use a prospectively collected dataset of 4362 M. tuberculosis isolates. Using culture based DST as the reference, we estimate Mykrobe to be 100%, 95%, 82%, 99% sensitive and 99%, 100%, 99%, 99% specific for rifampicin, isoniazid, pyrazinamide and ethambutol resistance prediction respectively. We benchmark against four other tools on 10207 (=5845+4362) samples, and also show that Mykrobe gives concordant results with nanopore data.  We measure the ability of Mykrobe-based DST to guide personalized therapeutic regimen design in the context of complex drug susceptibility profiles, showing 94% concordance of implied regimen with that driven by phenotypic DST, higher than all other benchmarked tools.

4.
N Engl J Med ; 379(15): 1403-1415, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30280646

RESUMO

BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Genoma Bacteriano , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico , Sequenciamento Completo do Genoma , Antituberculosos/uso terapêutico , Etambutol/farmacologia , Genótipo , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Fenótipo , Pirazinamida/farmacologia , Rifampina/farmacologia , Tuberculose/microbiologia
5.
J Clin Microbiol ; 56(9)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29925638

RESUMO

In principle, whole-genome sequencing (WGS) can predict phenotypic resistance directly from a genotype, replacing laboratory-based tests. However, the contribution of different bioinformatics methods to genotype-phenotype discrepancies has not been systematically explored to date. We compared three WGS-based bioinformatics methods (Genefinder [read based], Mykrobe [de Bruijn graph based], and Typewriter [BLAST based]) for predicting the presence/absence of 83 different resistance determinants and virulence genes and overall antimicrobial susceptibility in 1,379 Staphylococcus aureus isolates previously characterized by standard laboratory methods (disc diffusion, broth and/or agar dilution, and PCR). In total, 99.5% (113,830/114,457) of individual resistance-determinant/virulence gene predictions were identical between all three methods, with only 627 (0.5%) discordant predictions, demonstrating high overall agreement (Fleiss' kappa = 0.98, P < 0.0001). Discrepancies when identified were in only one of the three methods for all genes except the cassette recombinase, ccrC(b). The genotypic antimicrobial susceptibility prediction matched the laboratory phenotype in 98.3% (14,224/14,464) of cases (2,720 [18.8%] resistant, 11,504 [79.5%] susceptible). There was greater disagreement between the laboratory phenotypes and the combined genotypic predictions (97 [0.7%] phenotypically susceptible, but all bioinformatic methods reported resistance; 89 [0.6%] phenotypically resistant, but all bioinformatics methods reported susceptible) than within the three bioinformatics methods (54 [0.4%] cases, 16 phenotypically resistant, 38 phenotypically susceptible). However, in 36/54 (67%) cases, the consensus genotype matched the laboratory phenotype. In this study, the choice between these three specific bioinformatic methods to identify resistance determinants or other genes in S. aureus did not prove critical, with all demonstrating high concordance with each other and phenotypic/molecular methods. However, each has some limitations; therefore, consensus methods provide some assurance.


Assuntos
Biologia Computacional/métodos , Farmacorresistência Bacteriana/genética , Genoma Bacteriano/genética , Staphylococcus aureus/genética , Fatores de Virulência/genética , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Fenótipo , Sensibilidade e Especificidade , Análise de Sequência de DNA , Software , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação
6.
Nat Commun ; 9(1): 1179, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29563494

RESUMO

Colistin represents one of the few available drugs for treating infections caused by carbapenem-resistant Enterobacteriaceae. As such, the recent plasmid-mediated spread of the colistin resistance gene mcr-1 poses a significant public health threat, requiring global monitoring and surveillance. Here, we characterize the global distribution of mcr-1 using a data set of 457 mcr-1-positive sequenced isolates. We find mcr-1 in various plasmid types but identify an immediate background common to all mcr-1 sequences. Our analyses establish that all mcr-1 elements in circulation descend from the same initial mobilization of mcr-1 by an ISApl1 transposon in the mid 2000s (2002-2008; 95% highest posterior density), followed by a marked demographic expansion, which led to its current global distribution. Our results provide the first systematic phylogenetic analysis of the origin and spread of mcr-1, and emphasize the importance of understanding the movement of antibiotic resistance genes across multiple levels of genomic organization.


Assuntos
Colistina/farmacologia , Elementos de DNA Transponíveis , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Enterobacteriaceae/epidemiologia , Enterobacteriaceae/genética , Proteínas de Escherichia coli/genética , Genoma Bacteriano , América/epidemiologia , Antibacterianos/farmacologia , Ásia/epidemiologia , Carbapenêmicos/farmacologia , Enterobacteriaceae/classificação , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/transmissão , Proteínas de Escherichia coli/metabolismo , Europa (Continente)/epidemiologia , Evolução Molecular , Expressão Gênica , Transferência Genética Horizontal , Humanos , Plasmídeos/química , Plasmídeos/metabolismo , Dinâmica Populacional
7.
J Med Microbiol ; 67(3): 347-357, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29458686

RESUMO

PURPOSE: Speed of bloodstream infection diagnosis is vital to reduce morbidity and mortality. Whole genome sequencing (WGS) performed directly from liquid blood culture could provide single-assay species and antibiotic susceptibility prediction; however, high inhibitor and human cell/DNA concentrations limit pathogen recovery. We develop a method for the preparation of bacterial DNA for WGS-based diagnostics direct from liquid blood culture. METHODOLOGY: We evaluate three commercial DNA extraction kits: BiOstic Bacteraemia, Amplex Hyplex and MolYsis Plus. Differential centrifugation, filtration, selective lysis and solid-phase reversible immobilization bead clean-up are tested to improve human cells/DNA and inhibitor removal. Using WGS (Illumina/MinION), we assess human DNA removal, pathogen recovery, and predict species and antibiotic susceptibility inpositive blood cultures of 44 Gram-negative and 54 Staphylococcus species.Results/Key findings. BiOstic kit extractions yield the greatest mean DNA concentration, 94-301 ng µl-1, versus 0-2.5 ng µl-1 using Amplex and MolYsis kits. However, we note higher levels of inhibition (260/280 ratio 0.9-2.1) and human DNA (0.0-4.4×106 copies) in BiOstic extracts. Differential centrifugation (2000 g, 1 min) prior to BiOstic extraction reduces human DNA by 63-89 % with selective lysis minimizing by a further 62 %. Post-extraction bead clean-up lowers inhibition. Overall, 67 % of sequenced samples (Illumina MiSeq) contain <10 % human DNA, with >93 % concordance between WGS-based species and susceptibility predictions and clinical diagnosis. If >60 % of sequencing reads are human (7/98 samples) susceptibility prediction becomes compromised. Novel MinION-based WGS (n=9) currently gives rapid species identification but not susceptibility prediction. CONCLUSION: Our method for DNA preparation allows WGS-based diagnosis direct from blood culture bottles, providing species and antibiotic susceptibility prediction in a single assay.


Assuntos
Bacteriemia/diagnóstico , Hemocultura , DNA Bacteriano/isolamento & purificação , Genoma Bacteriano , Sequenciamento Completo do Genoma , Bacteriemia/microbiologia , Infecções Relacionadas a Cateter/diagnóstico , Infecções Relacionadas a Cateter/microbiologia , DNA Bacteriano/análise , DNA Bacteriano/genética , Escherichia coli/genética , Humanos , Testes de Sensibilidade Microbiana , Técnicas de Diagnóstico Molecular/métodos , Kit de Reagentes para Diagnóstico , Análise de Sequência de DNA/métodos , Staphylococcus aureus/genética
8.
J Clin Microbiol ; 56(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29167290

RESUMO

Use of whole-genome sequencing (WGS) for routine mycobacterial species identification and drug susceptibility testing (DST) is becoming a reality. We compared the performances of WGS and standard laboratory workflows prospectively, by parallel processing at a major mycobacterial reference service over the course of 1 year, for species identification, first-line Mycobacterium tuberculosis resistance prediction, and turnaround time. Among 2,039 isolates with line probe assay results for species identification, 74 (3.6%) failed sequencing or WGS species identification. Excluding these isolates, clinically important species were identified for 1,902 isolates, of which 1,825 (96.0%) were identified as the same species by WGS and the line probe assay. A total of 2,157 line probe test results for detection of resistance to the first-line drugs isoniazid and rifampin were available for 728 M. tuberculosis complex isolates. Excluding 216 (10.0%) cases where there were insufficient sequencing data for WGS to make a prediction, overall concordance was 99.3% (95% confidence interval [CI], 98.9 to 99.6%), sensitivity was 97.6% (91.7 to 99.7%), and specificity was 99.5% (99.0 to 99.7%). A total of 2,982 phenotypic DST results were available for 777 M. tuberculosis complex isolates. Of these, 356 (11.9%) had no WGS comparator due to insufficient sequencing data, and in 154 (5.2%) cases the WGS prediction was indeterminate due to discovery of novel, previously uncharacterized mutations. Excluding these data, overall concordance was 99.2% (98.7 to 99.5%), sensitivity was 94.2% (88.4 to 97.6%), and specificity was 99.4% (99.0 to 99.7%). Median processing times for the routine laboratory tests versus WGS were similar overall, i.e., 20 days (interquartile range [IQR], 15 to 31 days) and 21 days (15 to 29 days), respectively (P = 0.41). In conclusion, WGS predicts species and drug susceptibility with great accuracy, but work is needed to increase the proportion of predictions made.


Assuntos
Farmacorresistência Bacteriana/genética , Genoma Bacteriano/genética , Tipagem Molecular/métodos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/microbiologia , Antituberculosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Estudos Prospectivos , Rifampina/farmacologia , Sensibilidade e Especificidade , Fatores de Tempo , Tuberculose/diagnóstico
9.
J Clin Microbiol ; 55(5): 1285-1298, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28275074

RESUMO

Routine full characterization of Mycobacterium tuberculosis is culture based, taking many weeks. Whole-genome sequencing (WGS) can generate antibiotic susceptibility profiles to inform treatment, augmented with strain information for global surveillance; such data could be transformative if provided at or near the point of care. We demonstrate a low-cost method of DNA extraction directly from patient samples for M. tuberculosis WGS. We initially evaluated the method by using the Illumina MiSeq sequencer (40 smear-positive respiratory samples obtained after routine clinical testing and 27 matched liquid cultures). M. tuberculosis was identified in all 39 samples from which DNA was successfully extracted. Sufficient data for antibiotic susceptibility prediction were obtained from 24 (62%) samples; all results were concordant with reference laboratory phenotypes. Phylogenetic placement was concordant between direct and cultured samples. With Illumina MiSeq/MiniSeq, the workflow from patient sample to results can be completed in 44/16 h at a reagent cost of £96/£198 per sample. We then employed a nonspecific PCR-based library preparation method for sequencing on an Oxford Nanopore Technologies MinION sequencer. We applied this to cultured Mycobacterium bovis strain BCG DNA and to combined culture-negative sputum DNA and BCG DNA. For flow cell version R9.4, the estimated turnaround time from patient to identification of BCG, detection of pyrazinamide resistance, and phylogenetic placement was 7.5 h, with full susceptibility results 5 h later. Antibiotic susceptibility predictions were fully concordant. A critical advantage of MinION is the ability to continue sequencing until sufficient coverage is obtained, providing a potential solution to the problem of variable amounts of M. tuberculosis DNA in direct samples.


Assuntos
Antituberculosos/uso terapêutico , Genoma Bacteriano/genética , Mycobacterium tuberculosis/genética , Análise de Sequência de DNA/métodos , Tuberculose Pulmonar/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/economia , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Sistemas Automatizados de Assistência Junto ao Leito , Pirazinamida/uso terapêutico , Fatores de Tempo , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia
11.
Nat Commun ; 6: 10063, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26686880

RESUMO

The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Genoma Bacteriano , Mycobacterium tuberculosis/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Tuberculose/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
12.
Lancet Infect Dis ; 15(10): 1193-1202, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26116186

RESUMO

BACKGROUND: Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drug-susceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistance-determining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all first-line and second-line drugs for tuberculosis. METHODS: Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identified from the drug-resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. FINDINGS: We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7-93·7) and 98·4% specificity (98·1-98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identified among mutations under selection pressure in non-candidate genes. INTERPRETATION: A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workflows, phasing out phenotypic drug-susceptibility testing while reporting drug resistance early. FUNDING: Wellcome Trust, National Institute of Health Research, Medical Research Council, and the European Union.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana , Técnicas de Genotipagem/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Análise de Sequência de DNA/métodos , Humanos , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/isolamento & purificação , Estudos Retrospectivos , Tuberculose/microbiologia
13.
Proc Natl Acad Sci U S A ; 108(45): 18233-7, 2011 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22006302

RESUMO

Replacing a magnetic atom by a spinless atom in a heavy-fermion compound generates a quantum state often referred to as a "Kondo-hole". No experimental imaging has been achieved of the atomic-scale electronic structure of a Kondo-hole, or of their destructive impact [Lawrence JM, et al. (1996) Phys Rev B 53:12559-12562] [Bauer ED, et al. (2011) Proc Natl Acad Sci. 108:6857-6861] on the hybridization process between conduction and localized electrons which generates the heavy-fermion state. Here we report visualization of the electronic structure at Kondo-holes created by substituting spinless thorium atoms for magnetic uranium atoms in the heavy-fermion system URu(2)Si(2). At each thorium atom, an electronic bound state is observed. Moreover, surrounding each thorium atom we find the unusual modulations of hybridization strength recently predicted to occur at Kondo-holes [Figgins J, Morr DK (2011) Phys Rev Lett 107:066401]. Then, by introducing the "hybridization gapmap" technique to heavy-fermion studies, we discover intense nanoscale heterogeneity of hybridization due to a combination of the randomness of Kondo-hole sites and the long-range nature of the hybridization oscillations. These observations provide direct insight into both the microscopic processes of heavy-fermion forming hybridization and the macroscopic effects of Kondo-hole doping.

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