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Article ; Online: Querying Recombination Junctions of Replication-Competent Adeno-Associated Viruses in Gene Therapy Vector Preparations with Single Molecule, Real-Time Sequencing.

Yip, Mitchell / Chen, Jing / Zhi, Yan / Tran, Ngoc Tam / Namkung, Suk / Pastor, Eric / Gao, Guangping / Tai, Phillip W L

Viruses

2023 Volume 15, Issue 6

Abstract: Clinical-grade preparations of adeno-associated virus (AAV) vectors used for gene therapy typically undergo a series of diagnostics to determine titer, purity, homogeneity, and the presence of DNA contaminants. One type of contaminant that remains poorly ...

Abstract	Clinical-grade preparations of adeno-associated virus (AAV) vectors used for gene therapy typically undergo a series of diagnostics to determine titer, purity, homogeneity, and the presence of DNA contaminants. One type of contaminant that remains poorly investigated is replication-competent (rc)AAVs. rcAAVs form through recombination of DNA originating from production materials, yielding intact, replicative, and potentially infectious virus-like virions. They can be detected through the serial passaging of lysates from cells transduced by AAV vectors in the presence of wildtype adenovirus. Cellular lysates from the last passage are subjected to qPCR to detect the presence of the
MeSH term(s)	Dependovirus/genetics ; Genetic Vectors/genetics ; Plasmids ; Genome, Viral ; Genetic Therapy
Language	English
Publishing date	2023-05-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15061228
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Direct ITR-to-ITR Nanopore Sequencing of AAV Vector Genomes.

Namkung, Suk / Tran, Ngoc Tam / Manokaran, Sangeetha / He, Ran / Su, Qin / Xie, Jun / Gao, Guangping / Tai, Phillip W L

Human gene therapy

2022 Volume 33, Issue 21-22, Page(s) 1187–1196

Abstract: Recombinant adeno-associated viruses (rAAVs) are currently the most prominently investigated vector platform for human gene therapy. The rAAV capsid serves as a potent and efficient vehicle for delivering genetic payloads into the host cell, while the ... ...

Abstract	Recombinant adeno-associated viruses (rAAVs) are currently the most prominently investigated vector platform for human gene therapy. The rAAV capsid serves as a potent and efficient vehicle for delivering genetic payloads into the host cell, while the vector genome determines the function and effectiveness of these biotherapies. However, current production schemes yield vectors that may consist of heterogeneous populations, compromising their potencies. The development of next-generation sequencing methods within the past few years have helped investigators profile the diversity and relative abundances of heterogenous species in vector preparations. Specifically, long-read sequencing methods, like single molecule real-time (SMRT) sequencing, have been used to uncover truncations, chimeric genomes, and inverted terminal repeat (ITR) mutations in vectors. Unfortunately, these sequencing platforms may be inaccessible to investigators with limited resources, require large amounts of input material, or may require long wait times for sequencing and analyses. Recent advances with nanopore sequencing have helped to bridge the gap for quick and relatively inexpensive long-read sequencing needs. However, their limitations and sample biases are not well-defined for sequencing rAAV. In this study, we explored the capacity for nanopore sequencing to directly interrogate rAAV content to obtain full-length resolution of encapsidated genomes. We found that the nanopore platform can cover the entirety of rAAV genomes from ITR to ITR without the need for pre-fragmentation. However, the accuracy for base calling was low, resulting in a high degree of miscalled bases and false indels. These false indels led to read-length compression; thus, assessing heterogeneity based on read length is not advisable with current nanopore technologies. Nonetheless, nanopore sequencing was able to correctly identify truncation hotspots in single-strand and self-complementary vectors similar to SMRT sequencing. In summary, nanopore sequencing can serve as a rapid and low-cost alternative for proofing AAV vectors.
MeSH term(s)	Humans ; Genetic Vectors/genetics ; Nanopores ; Nanopore Sequencing ; Dependovirus/genetics ; Terminal Repeat Sequences
Language	English
Publishing date	2022-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2022.143
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Article ; Online: Human and Insect Cell-Produced Recombinant Adeno-Associated Viruses Show Differences in Genome Heterogeneity.

Tran, Ngoc Tam / Lecomte, Emilie / Saleun, Sylvie / Namkung, Suk / Robin, Cécile / Weber, Kristina / Devine, Eric / Blouin, Veronique / Adjali, Oumeya / Ayuso, Eduard / Gao, Guangping / Penaud-Budloo, Magalie / Tai, Phillip W L

Human gene therapy

2022 Volume 33, Issue 7-8, Page(s) 371–388

Abstract: In the past two decades, adeno-associated virus (AAV) vector manufacturing has made remarkable advancements to meet large-scale production demands for preclinical and clinical trials. In addition, AAV vectors have been extensively studied for their ... ...

Abstract	In the past two decades, adeno-associated virus (AAV) vector manufacturing has made remarkable advancements to meet large-scale production demands for preclinical and clinical trials. In addition, AAV vectors have been extensively studied for their safety and efficacy. In particular, the presence of empty AAV capsids and particles containing "inaccurate" vector genomes in preparations has been a subject of concern. Several methods exist to separate empty capsids from full particles; but thus far, no single technique can produce vectors that are free of empty or partial (non-unit length) capsids. Unfortunately, the exact genome compositions of full, intermediate, and empty capsids remain largely unknown. In this work, we used AAV-genome population sequencing to explore the compositions of DNase-resistant, encapsidated vector genomes produced by two common production pipelines: plasmid transfection in human embryonic kidney cells (pTx/HEK293) and baculovirus expression vectors in
MeSH term(s)	Animals ; Baculoviridae/genetics ; Dependovirus/genetics ; Dependovirus/metabolism ; Genetic Vectors/genetics ; HEK293 Cells ; Humans ; Insecta/genetics
Language	English
Publishing date	2022-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2022.050
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Article: Prospects for dengue vaccines for travelers.

Lim, Sl-Ki / Lee, Yong Seok / Namkung, Suk / Lim, Jacqueline K / Yoon, In-Kyu

Clinical and experimental vaccine research

2016 Volume 5, Issue 2, Page(s) 89–100

Abstract: Travel-acquired dengue cases have been increasing as the overall global dengue burden has expanded. In Korea, imported dengue cases have been reported since 2000 when it first became a notifiable disease. During the first four months of 2016, three times ...

Abstract	Travel-acquired dengue cases have been increasing as the overall global dengue burden has expanded. In Korea, imported dengue cases have been reported since 2000 when it first became a notifiable disease. During the first four months of 2016, three times more dengue cases were reported in Korea than during the same period the previous year. A safe and efficacious vaccine for travelers would be beneficial to prevent dengue disease in individual travelers and potentially decrease the risk of virus spread to non-endemic areas. Here, we summarize the characteristics of dengue vaccines for travelers and review dengue vaccines currently licensed or in clinical development.
Language	English
Publishing date	2016-07-29
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	2684652-4
ISSN	2287-366X ; 2287-3651
ISSN (online)	2287-366X
ISSN	2287-3651
DOI	10.7774/cevr.2016.5.2.89
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Article ; Online: Epidemiology of dengue fever in Gabon: Results from a health facility-based fever surveillance in Lambaréné and its surroundings.

Lim, Jacqueline Kyungah / Fernandes, José Francisco / Yoon, In-Kyu / Lee, Jung-Seok / Mba, Regis Obiang / Lee, Kang Sung / Namkung, Suk / Yang, Jae Seung / Bae, So Hee / Lim, Sl-Ki / Lell, Bertrand / Esen, Meral / Loembe, Marguerite Massinga / Kremsner, Peter G / Alexander, Neal / Agnandji, Selidji Todagbe

PLoS neglected tropical diseases

2021 Volume 15, Issue 2, Page(s) e0008861

Abstract: Background: In Africa, information on dengue is limited to outbreak reports and focused on some countries with continuing transmission in West and East Africa. To estimate the proportion of dengue-positive cases among febrile patients and identify ... ...

Abstract	Background: In Africa, information on dengue is limited to outbreak reports and focused on some countries with continuing transmission in West and East Africa. To estimate the proportion of dengue-positive cases among febrile patients and identify clinical indicators of dengue cases, we conducted passive facility-based fever surveillance in a catchment area population of 70,000 residents of Lambaréné and its surroundings in Gabon. Methods: Non-malarial febrile patients with current fever or history of fever (≤7 days) between 1 and 55 years of age, were enrolled at Albert Schweitzer Hospital (ASH). Acute (visit 1, day of enrollment) and convalescent blood samples were collected between 10 and 21 days after enrollment. Acute/convalescent samples were tested with IgM/IgG ELISA, and a selected subset of acute samples with RT-PCR. Results: Among 682 non-malarial febrile patients enrolled, 119 (17.4%) were identified as dengue-positive (94 dengue-confirmed and 25 dengue-probable cases). Of these dengue-positive cases, 14 were confirmed with PCR, and based on serotyping, two infections were identified to be DENV-2 and two were DENV-3. The majority of our enrolled patients were <25 years of age and close to 80% of our dengue-positive cases were <15 years of age. In adjusted analyses, retro-orbital pain and abdominal pain were 2.7 and 1.6 times more frequently found among dengue-positive cases, compared to non-dengue cases. Conclusion: Lambaréné is not considered dengue-endemic. However, one in six non-malarial febrile episodes was found to be dengue-positive in the study period. Dengue should be considered more frequently in clinicians' diagnosis among non-malarial febrile patients in Lambaréné. Given the lack of data on dengue in Gabon, additional prospective and longitudinal studies would help to further define the burden and patterns of dengue for improved case detection.
MeSH term(s)	Adolescent ; Adult ; Antibodies, Viral/blood ; Child ; Child, Preschool ; Dengue/epidemiology ; Dengue/pathology ; Dengue Virus/classification ; Dengue Virus/genetics ; Dengue Virus/isolation & purification ; Disease Outbreaks ; Enzyme-Linked Immunosorbent Assay ; Epidemiological Monitoring ; Female ; Fever/epidemiology ; Fever/etiology ; Gabon/epidemiology ; Health Facilities ; Humans ; Immunoglobulin G/blood ; Immunoglobulin M/blood ; Infant ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Prospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Young Adult
Chemical Substances	Antibodies, Viral ; Immunoglobulin G ; Immunoglobulin M
Language	English
Publishing date	2021-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0008861
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Article ; Online: Molecular evidence for an old world origin of Galapagos and Caribbean band-winged grasshoppers (Acrididae: Oedipodinae: Sphingonotus).

Husemann, Martin / Habel, Jan Christian / Namkung, Suk / Hochkirch, Axel / Otte, Daniel / Danley, Patrick D

PloS one

2015 Volume 10, Issue 2, Page(s) e0118208

Abstract: Patterns of colonization and diversification on islands provide valuable insights into evolutionary processes. Due to their unique geographic position and well known history, the Galapagos Islands are an important model system for evolutionary studies. ... ...

Abstract	Patterns of colonization and diversification on islands provide valuable insights into evolutionary processes. Due to their unique geographic position and well known history, the Galapagos Islands are an important model system for evolutionary studies. Here we investigate the evolutionary history of a winged grasshopper genus to infer its origin and pattern of colonization in the Galapagos archipelago. The grasshopper genus Sphingonotus has radiated extensively in the Palaearctic and many species are endemic to islands. In the New World, the genus is largely replaced by the genus Trimerotropis. Oddly, in the Caribbean and on the Galapagos archipelago, two species of Sphingonotus are found, which has led to the suggestion that these might be the result of anthropogenic translocations from Europe. Here, we test this hypothesis using mitochondrial and nuclear DNA sequences from a broad sample of Sphingonotini and Trimerotropini species from the Old World and New World. The genetic data show two distinct genetic clusters representing the New World Trimerotropini and the Old World Sphingonotini. However, the Sphingonotus species from Galapagos and the Caribbean split basally within the Old World Sphingonotini lineage. The Galapagos and Caribbean species appear to be related to Old World taxa, but are not the result of recent anthropogenic translocations as revealed by divergence time estimates. Distinct genetic lineages occur on the four investigated Galapagos Islands, with deep splits among them compared to their relatives from the Palaearctic. A scenario of a past wider distribution of Sphingonotus in the New World with subsequent extinction on the mainland and replacement by Trimerotropis might explain the disjunct distribution.
MeSH term(s)	Animals ; Ecuador ; Electron Transport Complex IV/genetics ; Evolution, Molecular ; Grasshoppers/classification ; Grasshoppers/genetics ; Histones/genetics ; Phylogeny ; Phylogeography ; Sequence Analysis, DNA ; West Indies
Chemical Substances	Histones ; Electron Transport Complex IV (EC 1.9.3.1)
Language	English
Publishing date	2015-02-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0118208
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Article ; Online: A multi-country study of the economic burden of dengue fever based on patient-specific field surveys in Burkina Faso, Kenya, and Cambodia.

Lee, Jung-Seok / Mogasale, Vittal / Lim, Jacqueline K / Ly, Sowath / Lee, Kang Sung / Sorn, Sopheak / Andia, Esther / Carabali, Mabel / Namkung, Suk / Lim, Sl-Ki / Ridde, Valéry / Njenga, Sammy M / Yaro, Seydou / Yoon, In-Kyu

PLoS neglected tropical diseases

2019 Volume 13, Issue 2, Page(s) e0007164

Abstract: Background: Dengue fever is a rapidly growing public health problem in many parts of the tropics and sub-tropics in the world. While there are existing studies on the economic burden of dengue fever in some of dengue-endemic countries, cost components ... ...

Abstract	Background: Dengue fever is a rapidly growing public health problem in many parts of the tropics and sub-tropics in the world. While there are existing studies on the economic burden of dengue fever in some of dengue-endemic countries, cost components are often not standardized, making cross-country comparisons challenging. Furthermore, no such studies have been available in Africa. Methods/principal findings: A patient-specific survey questionnaire was developed and applied in Burkina Faso, Kenya, and Cambodia in a standardized format. Multiple interviews were carried out in order to capture the entire cost incurred during the period of dengue illness. Both private (patient's out-of-pocket) and public (non-private) expenditure were accessed to understand how the economic burden of dengue is distributed between private and non-private payers. A substantial number of dengue-confirmed patients were identified in all three countries: 414 in Burkina Faso, 149 in Kenya, and 254 in Cambodia. The average cost of illness for dengue fever was $26 (95% CI $23-$29) and $134 (95% CI $119-$152) per inpatient in Burkina Faso and Cambodia, respectively. In the case of outpatients, the average economic burden per episode was $13 (95% CI $23-$29) in Burkina Faso and $23 (95% CI $19-$28) in Kenya. Compared to Cambodia, public contributions were trivial in Burkina Faso and Kenya, reflecting that a majority of medical costs had to be directly borne by patients in the two countries. Conclusions/significance: The cost of illness for dengue fever is significant in the three countries. In particular, the current study sheds light on the potential economic burden of the disease in Burkina Faso and Kenya where existing evidence is sparse in the context of dengue fever, and underscores the need to achieve Universal Health Coverage. Given the availability of the current (CYD-TDV) and second-generation dengue vaccines in the near future, our study outcomes can be used to guide decision makers in setting health policy priorities.
MeSH term(s)	Burkina Faso/epidemiology ; Cambodia/epidemiology ; Cost of Illness ; Dengue/economics ; Dengue/epidemiology ; Health Care Costs ; Humans ; Kenya/epidemiology ; Public Health/economics
Language	English
Publishing date	2019-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0007164
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Article ; Online: Estimating the Force of Infection for Dengue Virus Using Repeated Serosurveys, Ouagadougou, Burkina Faso.

Lim, Jacqueline K / Carabali, Mabel / Edwards, Tansy / Barro, Ahmed / Lee, Jung-Seok / Dahourou, Desire / Lee, Kang Sung / Nikiema, Teguewende / Shin, Mee Young / Bonnet, Emmanuel / Kagone, Therese / Kaba, Losseni / Namkung, Suk / Somé, Paul-André / Yang, Jae Seung / Ridde, Valéry / Yoon, In-Kyu / Alexander, Neal / Seydou, Yaro

Emerging infectious diseases

2020 Volume 27, Issue 1, Page(s) 130–139

Abstract: Because of limited data on dengue virus in Burkina Faso, we conducted 4 consecutive age-stratified longitudinal serologic surveys, ≈6 months apart, among persons 1-55 years of age, during June 2015-March 2017, which included a 2016 outbreak. The ... ...

Abstract	Because of limited data on dengue virus in Burkina Faso, we conducted 4 consecutive age-stratified longitudinal serologic surveys, ≈6 months apart, among persons 1-55 years of age, during June 2015-March 2017, which included a 2016 outbreak. The seroconversion rate before the serosurvey enrollment was estimated by binomial regression, taking age as the duration of exposure, and assuming constant force of infection (FOI) over age and calendar time. We calculated FOI between consecutive surveys and rate ratios for potentially associated characteristics based on seroconversion using the duration of intervals. Among 2,897 persons at enrollment, 66.3% were IgG-positive, and estimated annual FOI was 5.95%. Of 1,269 enrollees participating in all 4 serosurveys, 438 were IgG-negative at enrollment. The annualized FOI ranged from 10% to 20% (during the 2016 outbreak). Overall, we observed high FOI for dengue. These results could support decision-making about control and preventive measures for dengue.
MeSH term(s)	Burkina Faso/epidemiology ; Child, Preschool ; Dengue/epidemiology ; Dengue Virus ; Disease Outbreaks ; Humans ; Infant
Language	English
Publishing date	2020-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1380686-5
ISSN	1080-6059 ; 1080-6040
ISSN (online)	1080-6059
ISSN	1080-6040
DOI	10.3201/eid2701.191650
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Zs.A 4778: Show issues

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Article ; Online: Clinical and epidemiologic characteristics associated with dengue fever in Mombasa, Kenya.

Lim, Jacqueline Kyungah / Matendechero, Sultani Hadley / Alexander, Neal / Lee, Jung-Seok / Lee, Kang Sung / Namkung, Suk / Andia, Esther / Oyembo, Noah / Lim, Sl-Ki / Kanyi, Henry / Bae, So Hee / Yang, Jae Seung / Ochola, Mary A / Edwards, Tansy / Yoon, In-Kyu / Njenga, Sammy M

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

2020 Volume 100, Page(s) 207–215

Abstract: Objectives: Information on dengue in Africa is limited. To estimate the proportion of dengue-positive cases among febrile patients and describe clinical indicators of dengue, we conducted passive health facility-based fever surveillance in Mombasa, ... ...

Abstract	Objectives: Information on dengue in Africa is limited. To estimate the proportion of dengue-positive cases among febrile patients and describe clinical indicators of dengue, we conducted passive health facility-based fever surveillance in Mombasa, Kenya. Methods: Non-malarial febrile patients between one and 55 years were enrolled at three health facilities between March 2016 and May 2017. Acute and convalescent blood samples were collected with an interval of 10-21 days. Acute samples were tested with dengue RDT and a selected subset with RT-PCR, and acute/convalescent samples with IgM/IgG ELISA. Results: Among 482 enrollees, 295 (61.2%) were dengue-positive based on laboratory results. The surveillance covered the beginning of a dengue outbreak in April-May 2017, during which 73.9% of enrollees were dengue-positive. By contrast, during the non-outbreak period, 54.6% were dengue-positive. Dengue case status was positively associated with rash, fatigue, headache, retro-orbital pain, nausea/vomiting, nose bleeding, gum bleeding, loss of appetite, myalgia, and arthralgia. Dengue-positive cases in our study had mostly mild disease, with only two requiring observation, and no DHF. Conclusions: The clinical response was generally mild relative to what was observed in SE Asia and the Americas. Given the high level of DENV transmission in Mombasa, more data would be needed to further understand the disease burden and improve case detection for surveillance/monitoring of outbreaks.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Dengue/epidemiology ; Dengue/transmission ; Dengue/virology ; Dengue Virus/physiology ; Disease Outbreaks ; Enzyme-Linked Immunosorbent Assay ; Epidemiological Monitoring ; Female ; Health Facilities ; Humans ; Infant ; Kenya/epidemiology ; Male ; Middle Aged ; Young Adult
Language	English
Publishing date	2020-09-03
Publishing country	Canada
Document type	Journal Article
ZDB-ID	1331197-9
ISSN	1878-3511 ; 1201-9712
ISSN (online)	1878-3511
ISSN	1201-9712
DOI	10.1016/j.ijid.2020.08.074
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Zs.A 4516: Show issues

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Article ; Online: Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo.

Nature communications

2021 Volume 12, Issue 1, Page(s) 6267

Abstract: Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. Here, we ... ...

Abstract	Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs for segmental deletions, or a single sgRNA with a homology-directed repair (HDR) template. We also use anti-CRISPR proteins to enable production of vectors that self-inactivate via Nme2Cas9 cleavage. We further introduce a nanopore-based sequencing platform that is designed to profile rAAV genomes and serves as a quality control measure for vector homogeneity. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice by HDR-based correction of the disease allele. These results will enable the engineering of single-vector AAVs that can achieve diverse therapeutic genome editing outcomes.
MeSH term(s)	Animals ; CRISPR-Associated Protein 9/genetics ; CRISPR-Associated Protein 9/metabolism ; Dependovirus/genetics ; Dependovirus/metabolism ; Female ; Gene Editing/methods ; Genetic Therapy ; Genetic Vectors/genetics ; Genetic Vectors/metabolism ; Humans ; Male ; Mice ; Mucopolysaccharidosis II/genetics ; Mucopolysaccharidosis II/therapy ; Recombinational DNA Repair ; Tyrosinemias/genetics ; Tyrosinemias/therapy
Chemical Substances	CRISPR-Associated Protein 9 (EC 3.1.-)
Language	English
Publishing date	2021-11-01
Publishing country	England
Document type	Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-26518-y
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