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Article ; Online: Implementing automation in deep brain stimulation: has the time come?

Bonizzato, Marco / Fasano, Alfonso

The Lancet. Digital health

2022 Volume 5, Issue 2, Page(s) e52–e53

MeSH term(s)	Deep Brain Stimulation ; Automation
Language	English
Publishing date	2022-12-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ISSN	2589-7500
ISSN (online)	2589-7500
DOI	10.1016/S2589-7500(22)00229-1
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Article ; Online: Cognitive, behavioral, and psychological manifestations of COVID-19 in post-acute rehabilitation setting: preliminary data of an observational study.

Bonizzato, Silvia / Ghiggia, Ada / Ferraro, Francesco / Galante, Emanuela

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology

2021 Volume 43, Issue 1, Page(s) 51–58

Abstract: Psychological, emotional, and behavioral domains could be altered in COVID-19 patients and measurement of variables within these domains seems to be mandatory. Neuropsychological assessment could detect possible cognitive impairment caused by COVID-19 ... ...

Abstract	Psychological, emotional, and behavioral domains could be altered in COVID-19 patients and measurement of variables within these domains seems to be mandatory. Neuropsychological assessment could detect possible cognitive impairment caused by COVID-19 and the choice of appropriate tools is an important question. Aim of this exploratory study was to verify the effectiveness of an assessment model for patients with COVID-19. Twelve patients were enrolled and tested with Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Anxiety and Depression Short Scale (AD-R), and the Neuropsychiatry Inventory (NPI), at the time of their entrance (T0) and discharge (T1) from a rehabilitative unit. Moreover, a follow-up evaluation after 3 months (T2) has been conducted on eight patients. Results showed that at baseline (T0), 58.3% of the patients reported a score below cut-off at MMSE and 50% at MoCA. Although a significant amelioration was found only in NPI scores, a qualitative improvement has been detected at all tests, except for MoCA scores, in the T0-T1 trend analysis. A one-way repeated measures analysis of variance showed a significant variation in AD-R depression score, considering the three-assessment time (T0, T1, and T2). The evaluation and tracking over time of the impact of COVID-19 on cognitive, psychological, and behavioral domains has relevant implications for rehabilitation and long-term assistance needs planning. The choice of assessment tools should consider patients vulnerability and match the best compromise among briefness, sensitivity, and specificity.
MeSH term(s)	COVID-19 ; Cognition ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/etiology ; Humans ; Mental Status and Dementia Tests ; Neuropsychological Tests ; Preliminary Data ; SARS-CoV-2
Language	English
Publishing date	2021-10-12
Publishing country	Italy
Document type	Journal Article ; Observational Study
ZDB-ID	2016546-8
ISSN	1590-3478 ; 1590-1874
ISSN (online)	1590-3478
ISSN	1590-1874
DOI	10.1007/s10072-021-05653-w
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Article ; Online: CirComPara: A Multi-Method Comparative Bioinformatics Pipeline to Detect and Study circRNAs from RNA-seq Data.

Gaffo, Enrico / Bonizzato, Annagiulia / Kronnie, Geertruy Te / Bortoluzzi, Stefania

Non-coding RNA

2017 Volume 3, Issue 1

Abstract: Circular RNAs (circRNAs) are generated by backsplicing of immature RNA forming covalently closed loops of intron/exon RNA molecules. Pervasiveness, evolutionary conservation, massive and regulated expression, and posttranscriptional regulatory roles of ... ...

Abstract	Circular RNAs (circRNAs) are generated by backsplicing of immature RNA forming covalently closed loops of intron/exon RNA molecules. Pervasiveness, evolutionary conservation, massive and regulated expression, and posttranscriptional regulatory roles of circRNAs in eukaryotes have been appreciated and described only recently. Moreover, being easily detectable disease markers, circRNAs undoubtedly represent a molecular class with high bearing on molecular pathobiology. CircRNAs can be detected from RNAseq data using appropriate computational methods to identify the sequence reads spanning backsplice junctions that do not colinearly map to the reference genome. To this end, several programs were developed and critical assessment of various strategies and tools suggested the combination of at least two methods as good practice to guarantee robust circRNA detection. Here,we present CirComPara (http://github.com/egaffo/CirComPara), an automated bioinformatics pipeline, to detect, quantify and annotate circRNAs from RNAseq data using in parallel four different methods for backsplice identification. CirComPara also provides quantification of linear RNAs and gene expression, ultimately comparing and correlating circRNA and gene/transcript expression level. We applied our method to RNAseqdata of monocyte and macrophage samples in relation to haploinsufficiency of the RNAbinding splicing factor Quaking (QKI). The biological relevance of the results, in terms of number, types and variations of circRNAs expressed, illustrates CirComPara potential to enlarge the knowledge of the transcriptome, adding details on the circRNAome, and facilitating further computational and experimental studies.
Language	English
Publishing date	2017-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2813993-8
ISSN	2311-553X ; 2311-553X
ISSN (online)	2311-553X
ISSN	2311-553X
DOI	10.3390/ncrna3010008
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Article ; Online: CircRNAs in hematopoiesis and hematological malignancies.

Bonizzato, A / Gaffo, E / Te Kronnie, G / Bortoluzzi, S

Blood cancer journal

2016 Volume 6, Issue 10, Page(s) e483

Abstract: Cell states in hematopoiesis are controlled by master regulators and by complex circuits of a growing family of RNA species impacting cell phenotype maintenance and plasticity. Circular RNAs (circRNAs) are rapidly gaining the status of particularly ... ...

Abstract	Cell states in hematopoiesis are controlled by master regulators and by complex circuits of a growing family of RNA species impacting cell phenotype maintenance and plasticity. Circular RNAs (circRNAs) are rapidly gaining the status of particularly stable transcriptome members with distinctive qualities. RNA-seq identified thousands of circRNAs with developmental stage- and tissue-specific expression corroborating earlier suggestions that circular isoforms are a natural feature of the cell expression program. CircRNAs are abundantly expressed also in the hematopoietic compartment. There are a number of studies on circRNAs in blood cells, a specific overview is however lacking. In this review we first present current insight in circRNA biogenesis discussing the relevance for hematopoiesis of the highly interleaved processes of splicing and circRNA biogenesis. Regarding molecular functions circRNAs modulate host gene expression, but also compete for binding of microRNAs, RNA-binding proteins or translation initiation and participate in regulatory circuits. We examine circRNA expression in the hematopoietic compartment and in hematologic malignancies and review the recent breakthrough study that identified pathogenic circRNAs derived from leukemia fusion genes. CircRNA high and regulated expression in blood cell types indicate that further studies are warranted to inform the position of these regulators in normal and malignant hematopoiesis.
Language	English
Publishing date	2016-10-14
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/bcj.2016.81
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Article ; Online: IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation.

Barresi, Valeria / Simbolo, Michele / Mafficini, Andrea / Martini, Maurizio / Calicchia, Martina / Piredda, Maria Liliana / Ciaparrone, Chiara / Bonizzato, Giada / Ammendola, Serena / Caffo, Maria / Pinna, Giampietro / Sala, Francesco / Lawlor, Rita Teresa / Ghimenton, Claudio / Scarpa, Aldo

Acta neuropathologica communications

2021 Volume 9, Issue 1, Page(s) 200

Abstract: Giant cell glioblastoma (GC-GBM) is a rare variant of IDH-wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH-wt and IDH-mutant GBM. The lack of an objective ... ...

Abstract	Giant cell glioblastoma (GC-GBM) is a rare variant of IDH-wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH-wt and IDH-mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30-49% (15 cases) or ≥ 50% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content (< 50% or ≥ 50%). Most cases (82% and 51.2%) had impairment in TP53/MDM2 and PTEN/PI3K pathways, but a high proportion also featured TERT promoter mutations (61.5%) and RB1 (25.6%) or NF1 (25.6%) alterations. EGFR amplification was detected in 18% cases in association with a shorter overall survival (P = 0.004). Sixteen (41%) cases had a TMB > 10 mut/Mb, including two (5%) that harbored MSI and one with a POLE mutation. The frequency of RB1 and NF1 alterations and TMB counts were significantly higher compared to 567 IDH wild type (P < 0.0001; P = 0.0003; P < 0.0001) and 26 IDH-mutant (P < 0.0001; P = 0.0227; P < 0.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of TP53/MDM2 and PTEN/PI3K pathways, and additionally characterized by frequent RB1 alterations and hypermutation and by EGFR amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Female ; Glioblastoma/genetics ; Glioblastoma/pathology ; Humans ; Isocitrate Dehydrogenase/genetics ; Male ; Middle Aged ; Mutation ; Neurofibromin 1/genetics ; Retinoblastoma Binding Proteins/genetics ; Ubiquitin-Protein Ligases/genetics ; Young Adult
Chemical Substances	NF1 protein, human ; Neurofibromin 1 ; RB1 protein, human ; Retinoblastoma Binding Proteins ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2021-12-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-021-01304-5
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Article ; Online: Monolayer Graphene Coating of Intracortical Probes for Long-Lasting Neural Activity Monitoring.

Bourrier, Antoine / Shkorbatova, Polina / Bonizzato, Marco / Rey, Elodie / Barraud, Quentin / Courtine, Gregoire / Othmen, Riadh / Reita, Valerie / Bouchiat, Vincent / Delacour, Cécile

Advanced healthcare materials

2019 Volume 8, Issue 18, Page(s) e1801331

Abstract: The invasiveness of intracortical interfaces currently used today is responsible for the formation of an intense immunoresponse and inflammatory reaction from neural cells and tissues. This leads to a high concentration of reactive glial cells around the ...

Abstract	The invasiveness of intracortical interfaces currently used today is responsible for the formation of an intense immunoresponse and inflammatory reaction from neural cells and tissues. This leads to a high concentration of reactive glial cells around the implant site, creating a physical barrier between the neurons and the recording channels. Such a rejection of foreign analog interfaces causes neural signals to fade from recordings which become flooded by background noise after a few weeks. Despite their invasiveness, those devices are required to track single neuron activity and decode fine sensory or motor commands. In particular, such quantitative and long-lasting recordings of individual neurons are crucial during a long time period (several months) to restore essential functions of the cortex, disrupted after injuries, stroke, or neurodegenerative diseases. To overcome this limitation, graphene and related materials have attracted numerous interests, as they gather in the same material many suitable properties for interfacing living matter, such as an exceptionally high neural affinity, diffusion barrier, and high physical robustness. In this work, the neural affinity of a graphene monolayer with numerous materials commonly used in neuroprostheses is compared, and its impact on the performance and durability of intracortical probes is investigated. For that purpose, an innovative coating method to wrap 3D intracortical probes with a continuous monolayer graphene is developed. Experimental evidence demonstrate the positive impact of graphene on the bioacceptance of conventional intracortical probes, in terms of detection efficiency and tissues responses, allowing real-time samplings of motor neuron activity during 5 weeks. Since continuous graphene coatings can easily be implemented on a wide range of 3D surfaces, this study further motivates the use of graphene and related materials as it could significantly contribute to reduce the current rejection of neural probes currently used in many research areas, from fundamental neurosciences to medicine and neuroprostheses.
MeSH term(s)	Animals ; Astrocytes/cytology ; Cell Adhesion ; Cell Count ; Cell Proliferation ; Cells, Cultured ; Coated Materials, Biocompatible/chemistry ; Electrochemistry ; Graphite/chemistry ; Mice, Transgenic ; Neurites/metabolism ; Neurons/cytology ; Neurons/physiology
Chemical Substances	Coated Materials, Biocompatible ; Graphite (7782-42-5)
Language	English
Publishing date	2019-08-12
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649576-4
ISSN	2192-2659 ; 2192-2640
ISSN (online)	2192-2659
ISSN	2192-2640
DOI	10.1002/adhm.201801331
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Article ; Online: Introducing a biomimetic coating for graphene neuroelectronics: toward

Bourrier, Antoine / Szarpak-Jankowska, Anna / Veliev, Farida / Olarte-Hernandez, Renato / Shkorbatova, Polina / Bonizzato, Marco / Rey, Elodie / Barraud, Quentin / Briançon-Marjollet, Anne / Auzely, Rachel / Courtine, Gregoire / Bouchiat, Vincent / Delacour, Cécile

Biomedical physics & engineering express

2020 Volume 7, Issue 1

Abstract: Electronic micro and nano-devices are suitable tools to monitor the activity of many individual neurons over mesoscale networks. However the inorganic materials currently used in microelectronics are barely accepted by neural cells and tissues, thus ... ...

Abstract	Electronic micro and nano-devices are suitable tools to monitor the activity of many individual neurons over mesoscale networks. However the inorganic materials currently used in microelectronics are barely accepted by neural cells and tissues, thus limiting both the sensor lifetime and efficiency. In particular, penetrating intracortical probes face high failure rate because of a wide immune response of cells and tissues. This adverse reaction called gliosis leads to the rejection of the implanted probe after few weeks and prevent long-lasting recordings of cortical neurons. Such acceptance issue impedes the realization of many neuro-rehabilitation projects. To overcome this, graphene and related carbon-based materials have attracted a lot of interest regarding their positive impact on the adhesion and regeneration of neurons, and their ability to provide high-sensitive electronic devices, such as graphene field effect transistor (G-FET). Such devices can also be implemented on numerous suitable substrates including soft substrates to match the mechanical compliance of cells and tissues, improving further the biocompatibility of the implants. Thus, using graphene as a coating and sensing device material could significantly enhance the acceptance of intracortical probes. However, such a thin monolayer of carbon atoms could be teared off during manipulation and insertion within the brain, and could also display degradation over time. In this work, we have investigated the ability to protect graphene with a natural, biocompatible and degradable polymeric film derivated from hyaluronic acid (HA). We demonstrate that HA-based coatings can be deposited over a wide range of substrates, including intracortical probes and graphene FET arrays without altering the underlying device material, its biocompatibility and sensitivity. Moreover, we show that this coating can be monitored
MeSH term(s)	Biomimetics ; Graphite ; Neurons/physiology ; Polymers ; Prostheses and Implants
Chemical Substances	Polymers ; Graphite (7782-42-5)
Language	English
Publishing date	2020-11-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2057-1976
ISSN (online)	2057-1976
DOI	10.1088/2057-1976/ab42d6
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Article ; Online: Clinical validation of a combinatorial PharmAcogeNomic approach in major Depressive disorder: an Observational prospective RAndomized, participant and rater-blinded, controlled trial (PANDORA trial).

Minelli, Alessandra / Barlati, Stefano / Vitali, Erika / Bignotti, Stefano / Dattilo, Vincenzo / Tura, Giovanni Battista / Maffioletti, Elisabetta / Giacopuzzi, Edoardo / Santoro, Vincenza / Perusi, Giulia / Cobelli, Chiara / Magri, Chiara / Bonizzato, Silvia / Bocchio-Chiavetto, Luisella / Spina, Edoardo / Vita, Antonio / Gennarelli, Massimo

Trials

2021 Volume 22, Issue 1, Page(s) 896

Abstract: Background: Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only ...

Abstract	Background: Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only approximately one third of patients respond to the first treatment because of the ineffectiveness or side effects of antidepressants. Precision medicine in psychiatry might offer clinicians the possibility to tailor treatment according to the best possible evidence of efficacy and tolerability for each subject. In this context, our study aims to carry out a clinical validation of a combinatorial pharmacogenomics (PGx) test in an Italian MDD patient cohort with advocacy license independence. Methods: Our study is a prospective participant- and rater-blinded, randomized, controlled clinical observational trial enrolling 300 MDD patients who are referred to psychiatric services to receive a new antidepressant due to the failure of their current treatment and/or the onset of adverse effects. Eligible participants are randomized to the TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, DNA is collected with a buccal brush. The primary outcome is the reduction in depressive symptomatology. The secondary outcomes involve a range of scales that assess MDD symptoms and social functioning outcomes. The assessment is performed at four timepoints: baseline and 4, 8, and 12 weeks. Discussion: This project represents the first randomized controlled clinical trial to investigate whether a non-commercial PGx test improves outcomes in an MDD naturalistic cohort. Moreover, the identification of new genetic variants associated with non-response or side effects will improve the efficacy of the test, leading to further cost-saving. Trial registration number: ClinicalTrials.gov NCT04615234. Registered on November 4, 2020.
MeSH term(s)	Antidepressive Agents/adverse effects ; Depressive Disorder, Major/diagnosis ; Depressive Disorder, Major/drug therapy ; Depressive Disorder, Major/genetics ; Humans ; Pharmacogenetics ; Prospective Studies ; Quality of Life
Chemical Substances	Antidepressive Agents
Language	English
Publishing date	2021-12-11
Publishing country	England
Document type	Journal Article ; Observational Study ; Randomized Controlled Trial
ZDB-ID	2040523-6
ISSN	1745-6215 ; 1468-6694 ; 1468-6708
ISSN (online)	1745-6215 ; 1468-6694
ISSN	1468-6708
DOI	10.1186/s13063-021-05775-8
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Article: Effect of Delayed Refrigeration on the Microbial Carcass Contamination of Wild Boars (

Cenci-Goga, Beniamino / Amicabile, Alberto / Karama, Musafiri / El-Ashram, Saeed / Saraiva, Cristina / García-Díez, Juan / Finotti, Simone / Genna, Viviana / Moretti, Giampaolo / Murari, Riccardo / Muliari, Riccardo / Bonizzato, Sabrina / Lugoboni, Erica / Cassini, Sabina / Dal-Ben, Caterina / Grispoldi, Luca

Animals : an open access journal from MDPI

2021 Volume 11, Issue 5

Abstract: The immediate refrigeration of meat after slaughter is a key issue for the proper storage and aging of meat. The industry standard cold chain relies on low temperatures and ventilation to lower the internal carcass temperature to 0-4 °C within the first ... ...

Abstract	The immediate refrigeration of meat after slaughter is a key issue for the proper storage and aging of meat. The industry standard cold chain relies on low temperatures and ventilation to lower the internal carcass temperature to 0-4 °C within the first 48 h, i.e., within four times the so-called semi-cooling time. On the other hand, for games, once bled and eviscerated, the carcass must be sent to a point where it can be sectioned or kept on air for maturation at refrigeration temperature. The precautions to observe are few and simple but essential: protect the meat and start the cooling process quickly. After preparing the animal (bleeding and evisceration), it may be necessary to face a period of transport that is sometimes long and not very easy; while small animals can be easily transported in a backpack, larger ones must necessarily be carried by several people or sometimes dragged to the vehicle capable of transporting them. It is obvious that a wild boar opened from the jaws to the pelvis and dragged for hundreds of meters will tend to be contaminated, although these contaminations are to be considered secondary for the preservation of the meat, compared to contamination by the intestinal contents. In an attempt to investigate the effect of delayed refrigeration on wild boar carcass contamination, the aim of this work was to determine a correlation between several hunting and logistic parameters (age, sex, animal weight, shooting distance, number of shots, weather and temperature and time from shot to refrigeration and to analysis) and bacterial contamination of the carcass. The correlation coefficient, r, was found to be 0.038 for the eviscerated body weight (
Language	English
Publishing date	2021-05-17
Publishing country	Switzerland
Document type	Journal Article
ISSN	2076-2615
ISSN	2076-2615
DOI	10.3390/ani11051434
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Article ; Online: Circular RNA differential expression in blood cell populations and exploration of circRNA deregulation in pediatric acute lymphoblastic leukemia.

Gaffo, Enrico / Boldrin, Elena / Dal Molin, Anna / Bresolin, Silvia / Bonizzato, Annagiulia / Trentin, Luca / Frasson, Chiara / Debatin, Klaus-Michael / Meyer, Lueder H / Te Kronnie, Geertruij / Bortoluzzi, Stefania

Scientific reports

2019 Volume 9, Issue 1, Page(s) 14670

Abstract: Circular RNAs (circRNAs) are abundantly expressed in the haematopoietic compartment, but knowledge on their diversity among blood cell types is still limited. Nevertheless, emerging data indicate an array of circRNA functions exerted through interactions ...

Abstract	Circular RNAs (circRNAs) are abundantly expressed in the haematopoietic compartment, but knowledge on their diversity among blood cell types is still limited. Nevertheless, emerging data indicate an array of circRNA functions exerted through interactions with other RNAs and proteins, by translation into peptides, and circRNA involvement as regulatory molecules in many biological processes and cancer mechanisms. Interestingly, the role of specific circRNAs in leukemogenesis has been disclosed by a few studies, mostly in acute myeloid leukemia. In this study, circRNA expression in B-cells, T-cells and monocytes of healthy subjects is described, including putative new circRNA genes. Expression comparison considered 6,228 circRNAs and highlighted cell population-specific expression and exon usage patterns. Differential expression has been confirmed by qRT-PCR for circRNAs specific of B-cells (circPAX5, circAFF3, circIL4R, and circSETBP1) or T-cells (circIKZF1, circTNIK, circTXK, and circFBXW7), and for circRNAs from intronic (circBCL2) and intergenic regions that were overexpressed in lymphocytes. Starting from this resource of circRNA expression in mature blood cell populations, targeted examination identified striking and generalized upregulated expression of circPAX5, circPVT1 and circHIPK3 in pediatric B-precursor acute lymphoblastic leukemia, and disclosed circRNAs with variable expression across cytogenetic subtypes.
MeSH term(s)	Blood Cells/pathology ; Cell Line, Tumor ; Cell Lineage/genetics ; Child ; Female ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Male ; Pediatrics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; RNA, Circular/classification ; RNA, Circular/genetics
Chemical Substances	RNA, Circular
Language	English
Publishing date	2019-10-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-50864-z
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