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Article ; Online: Inverse Reinforcement Learning Intra-Operative Path Planning for Steerable Needle.

Segato, Alice / Marzo, Marco Di / Zucchelli, Sara / Galvan, Stefano / Secoli, Riccardo / De Momi, Elena

IEEE transactions on bio-medical engineering

2022 Volume 69, Issue 6, Page(s) 1995–2005

Abstract: Objective: This paper presentsa safe and effective keyhole neurosurgery intra-operative planning framework for flexible neurosurgical robots. The framework is intended to support neurosurgeons during the intra-operative procedure to react to a dynamic ... ...

Abstract	Objective: This paper presentsa safe and effective keyhole neurosurgery intra-operative planning framework for flexible neurosurgical robots. The framework is intended to support neurosurgeons during the intra-operative procedure to react to a dynamic environment. Methods: The proposed system integrates inverse reinforcement learning path planning algorithm combined with 1) a pre-operative path planning framework for fast and intuitive user interaction, 2) a realistic, time-bounded simulator based on Position-based Dynamics (PBD) simulation that mocks brain deformations due to catheter insertion and 3) a simulated robotic system. Results: Simulation results performed on a human brain dataset show that the inverse reinforcement learning intra-operative planning method can guide a steerable needle with bounded curvature to a predefined target pose with an average targeting error of 1.34 ± 0.52 (25 Conclusion: With this work, we demonstrate that the presented intra-operative steerable needle path planner is able to avoid anatomical obstacles while optimising surgical criteria. Significance: The results demonstrate that the proposed method is fast and can securely steer flexible needles with high accuracy and robustness.
MeSH term(s)	Algorithms ; Brain/surgery ; Computer Simulation ; Humans ; Needles
Language	English
Publishing date	2022-05-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	160429-6
ISSN	1558-2531 ; 0018-9294
ISSN (online)	1558-2531
ISSN	0018-9294
DOI	10.1109/TBME.2021.3133075
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Article ; Online: The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures.

Masperone, Lara / Codrich, Marta / Persichetti, Francesca / Gustincich, Stefano / Zucchelli, Silvia / Legname, Giuseppe

Molecular neurobiology

2022 Volume 59, Issue 3, Page(s) 1577–1588

Abstract: The cellular prion protein ( ... ...

Abstract	The cellular prion protein (PrP
MeSH term(s)	Animals ; Mice ; Prion Proteins/metabolism ; Protein Binding ; Sequestosome-1 Protein/metabolism ; Solubility ; TNF Receptor-Associated Factor 6/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Prion Proteins ; Sequestosome-1 Protein ; Sqstm1 protein, mouse ; TNF Receptor-Associated Factor 6 ; TRAF6 protein, mouse ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2022-01-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-021-02666-6
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Article ; Online: In the Chalcogenoxide Elimination Panorama: Systematic Insight into a Key Reaction.

Madabeni, Andrea / Zucchelli, Simone / Nogara, Pablo A / Rocha, João B T / Orian, Laura

The Journal of organic chemistry

2022 Volume 87, Issue 17, Page(s) 11766–11775

Abstract: The selenoxide elimination is a well-known reaction in organochalcogen chemistry, with wide synthetic, biological, and toxicological implications. In this work, we apply benchmarked density functional theory (DFT) calculations to investigate different ... ...

Abstract	The selenoxide elimination is a well-known reaction in organochalcogen chemistry, with wide synthetic, biological, and toxicological implications. In this work, we apply benchmarked density functional theory (DFT) calculations to investigate different aspects of the title reaction in three (bio)chemically relevant models, spanning minimal systems of theoretical interests as well as biological or synthetic organochalcogenides. The activation strain analysis (ASA) methodology is employed along a suitable reaction coordinate to obtain insight into the role of the chalcogen and of the oxidation state, to pinpoint the factors that tune the elimination reactivity of the investigated systems. Lastly, we computationally validate the hypothesis that telluroxides eliminate more slowly than selenoxides because of a detrimental hydration process that leads to unreactive hydrates.
MeSH term(s)	Oxidation-Reduction
Language	English
Publishing date	2022-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	123490-0
ISSN	1520-6904 ; 0022-3263
ISSN (online)	1520-6904
ISSN	0022-3263
DOI	10.1021/acs.joc.2c01454
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Article ; Online: Conformational ensembles of an RNA hairpin using molecular dynamics and sparse NMR data.

Reißer, Sabine / Zucchelli, Silvia / Gustincich, Stefano / Bussi, Giovanni

Nucleic acids research

2019 Volume 48, Issue 3, Page(s) 1164–1174

Abstract: Solution nuclear magnetic resonance (NMR) experiments allow RNA dynamics to be determined in an aqueous environment. However, when a limited number of peaks are assigned, it is difficult to obtain structural information. We here show a protocol based on ... ...

Abstract	Solution nuclear magnetic resonance (NMR) experiments allow RNA dynamics to be determined in an aqueous environment. However, when a limited number of peaks are assigned, it is difficult to obtain structural information. We here show a protocol based on the combination of experimental data (Nuclear Overhauser Effect, NOE) and molecular dynamics simulations with enhanced sampling methods. This protocol allows to (a) obtain a maximum entropy ensemble compatible with NMR restraints and (b) obtain a minimal set of metastable conformations compatible with the experimental data (maximum parsimony). The method is applied to a hairpin of 29 nt from an inverted SINEB2, which is part of the SINEUP family and has been shown to enhance protein translation. A clustering procedure is introduced where the annotation of base-base interactions and glycosidic bond angles is used as a metric. By reweighting the contributions of the clusters, minimal sets of four conformations could be found which are compatible with the experimental data. A motif search on the structural database showed that some identified low-population states are present in experimental structures of other RNA transcripts. The introduced method can be applied to characterize RNA dynamics in systems where a limited amount of NMR information is available.
MeSH term(s)	Cluster Analysis ; Molecular Dynamics Simulation ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Nucleotide Motifs ; RNA/chemistry
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2019-12-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkz1184
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Article ; Online: Synthetic in vitro transcribed lncRNAs (SINEUPs) with chemical modifications enhance target mRNA translation.

Toki, Naoko / Takahashi, Hazuki / Zucchelli, Silvia / Gustincich, Stefano / Carninci, Piero

FEBS letters

2020 Volume 594, Issue 24, Page(s) 4357–4369

Abstract: Chemically modified mRNAs are extensively studied with a view toward their clinical application. In particular, long noncoding RNAs (lncRNAs) containing SINE elements, which enhance the translation of their target mRNAs (i.e., SINEUPs), have potential as ...

Abstract	Chemically modified mRNAs are extensively studied with a view toward their clinical application. In particular, long noncoding RNAs (lncRNAs) containing SINE elements, which enhance the translation of their target mRNAs (i.e., SINEUPs), have potential as RNA therapies for various diseases, such as haploinsufficiencies. To establish a SINEUP-based system for efficient protein expression, we directly transfected chemically modified in vitro transcribed (mIVT) SINEUP RNAs to examine their effects on target mRNA translation. mIVT SINEUP RNAs enhanced translation of EGFP mRNA and endogenous target Sox9 mRNA in both cultured cells and a cell-free translation system. Our findings reveal the functional role of RNA modifications in SINEUPs and suggest several broad clinical applications of such an RNA regulatory system.
MeSH term(s)	Green Fluorescent Proteins/biosynthesis ; Green Fluorescent Proteins/genetics ; HEK293 Cells ; Hep G2 Cells ; Humans ; In Vitro Techniques ; Protein Biosynthesis ; RNA Stability ; RNA, Long Noncoding/chemical synthesis ; RNA, Long Noncoding/chemistry ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/metabolism ; SOX9 Transcription Factor/biosynthesis ; SOX9 Transcription Factor/genetics ; Up-Regulation
Chemical Substances	RNA, Long Noncoding ; RNA, Messenger ; RNA-Binding Proteins ; SOX9 Transcription Factor ; SOX9 protein, human ; enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2020-10-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13928
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Article ; Online: The Yin and Yang of nucleic acid-based therapy in the brain.

Gustincich, Stefano / Zucchelli, Silvia / Mallamaci, Antonello

Progress in neurobiology

2017 Volume 155, Page(s) 194–211

Abstract: The post-genomic era has unveiled the existence of a large repertory of non-coding RNAs and repetitive elements that play a fundamental role in cellular homeostasis and dysfunction. These may represent unprecedented opportunities to modify gene ... ...

Abstract	The post-genomic era has unveiled the existence of a large repertory of non-coding RNAs and repetitive elements that play a fundamental role in cellular homeostasis and dysfunction. These may represent unprecedented opportunities to modify gene expression at the right time in the correct space in vivo, providing an almost unlimited reservoir of new potential pharmacological agents. Hijacking their mode of actions, the druggable genome can be extended to regulatory RNAs and DNA elements in a scalable fashion. Here, we discuss the state-of-the-art of nucleic acid-based drugs to treat neurodegenerative diseases. Beneficial effects can be obtained by inhibiting (Yin) and increasing (Yang) gene expression, depending on the disease and the drug target. Together with the description of the current use of inhibitory RNAs (small inhibitory RNAs and antisense oligonucleotides) in animal models and clinical trials, we discuss the molecular basis and applications of new classes of activatory RNAs at transcriptional (RNAa) and translational (SINEUP) levels.
Language	English
Publishing date	2017-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2016.11.001
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Article ; Online: FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice.

Merlin, Simone / Famà, Rosella / Borroni, Ester / Zanolini, Diego / Bruscaggin, Valentina / Zucchelli, Silvia / Follenzi, Antonia

Blood advances

2019 Volume 3, Issue 5, Page(s) 825–838

Abstract: Here we describe a successful gene therapy approach for hemophilia A (HA), using the natural F8 promoter (pF8) to direct gene replacement to factor VIII (FVIII)-secreting cells. The promoter sequence and the regulatory elements involved in the modulation ...

Abstract	Here we describe a successful gene therapy approach for hemophilia A (HA), using the natural F8 promoter (pF8) to direct gene replacement to factor VIII (FVIII)-secreting cells. The promoter sequence and the regulatory elements involved in the modulation of F8 expression are still poorly characterized and biased by the historical assumption that FVIII expression is mainly in hepatocytes. Bioinformatic analyses have highlighted an underestimated complexity in gene expression at this locus, suggesting an activation of pF8 in more cell types than those previously expected. C57Bl/6 mice injected with a lentiviral vector expressing green fluorescent protein (GFP) under the pF8 (lentiviral vector [LV].pF8.GFP) confirm the predominant GFP expression in liver sinusoidal endothelial cells, with a few positive cells detectable also in hematopoietic organs. Therapeutic gene delivery (LV.pF8.FVIII) in hemophilic C57/Bl6 and 129-Bl6 mice successfully corrected the bleeding phenotype, rescuing up to 25% FVIII activity, using a codon-optimized FVIII, with sustained activity for the duration of the experiment (1 year) without inhibitor formation. Of note, LV.pF8.FVIII delivery in FVIII-immunized HA mice resulted in the complete reversion of the inhibitor titer with the recovery of therapeutic FVIII activity. Depletion of regulatory T cells (Tregs) in LV-treated mice allowed the formation of anti-FVIII antibodies, indicating a role for Tregs in immune tolerance induction. The significant blood loss reduction observed in all LV.pF8.FVIII-treated mice 1 year after injection confirmed the achievement of a long-term phenotypic correction. Altogether, our results highlight the potency of pF8-driven transgene expression to correct the bleeding phenotype in HA, as well as potentially in other diseases in which an endothelial-specific expression is required.
MeSH term(s)	Animals ; Disease Models, Animal ; Factor VIII/administration & dosage ; Factor VIII/genetics ; Factor VIII/therapeutic use ; Genetic Therapy/methods ; Green Fluorescent Proteins ; Hemophilia A/therapy ; Immune Tolerance ; Lentivirus ; Mice ; Promoter Regions, Genetic ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Green Fluorescent Proteins (147336-22-9) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2019-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2876449-3
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2018027979
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Article ; Online: A Metabologenomic approach reveals alterations in the gut microbiota of a mouse model of Alzheimer's disease.

Favero, Francesco / Barberis, Elettra / Gagliardi, Mara / Espinoza, Stefano / Contu, Liliana / Gustincich, Stefano / Boccafoschi, Francesca / Borsotti, Chiara / Lim, Dmitry / Rubino, Vito / Mignone, Flavio / Pasolli, Edoardo / Manfredi, Marcello / Zucchelli, Silvia / Corà, Davide / Corazzari, Marco

PloS one

2022 Volume 17, Issue 8, Page(s) e0273036

Abstract: The key role played by host-microbiota interactions on human health, disease onset and progression, and on host response to treatments has increasingly emerged in the latest decades. Indeed, dysbiosis has been associated to several human diseases such as ...

Abstract	The key role played by host-microbiota interactions on human health, disease onset and progression, and on host response to treatments has increasingly emerged in the latest decades. Indeed, dysbiosis has been associated to several human diseases such as obesity, diabetes, cancer and also neurodegenerative disease, such as Parkinson, Huntington and Alzheimer's disease (AD), although whether causative, consequence or merely an epiphenomenon is still under investigation. In the present study, we performed a metabologenomic analysis of stool samples from a mouse model of AD, the 3xTgAD. We found a significant change in the microbiota of AD mice compared to WT, with a longitudinal divergence of the F/B ratio, a parameter suggesting a gut dysbiosis. Moreover, AD mice showed a significant decrease of some amino acids, while data integration revealed a dysregulated production of desaminotyrosine (DAT) and dihydro-3-coumaric acid. Collectively, our data show a dysregulated gut microbiota associated to the onset and progression of AD, also indicating that a dysbiosis can occur prior to significant clinical signs, evidenced by early SCFA alterations, compatible with gut inflammation.
MeSH term(s)	Alzheimer Disease ; Animals ; Disease Models, Animal ; Dysbiosis ; Gastrointestinal Microbiome/physiology ; Humans ; Mice ; Neurodegenerative Diseases
Language	English
Publishing date	2022-08-24
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.0273036
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Article ; Online: Specific transcriptional programs differentiate ICOS from CD28 costimulatory signaling in human Naïve CD4

Gigliotti, Casimiro Luca / Boggio, Elena / Favero, Francesco / Incarnato, Danny / Santoro, Claudio / Oliviero, Salvatore / Rojo, Josè Maria / Zucchelli, Silvia / Persichetti, Francesca / Baldanzi, Gianluca / Dianzani, Umberto / Corà, Davide

Frontiers in immunology

2022 Volume 13, Page(s) 915963

Abstract: Costimulatory molecules of the CD28 family play a crucial role in the activation of immune responses in T lymphocytes, complementing and modulating signals originating from the T-cell receptor (TCR) complex. Although distinct functional roles have been ... ...

Abstract	Costimulatory molecules of the CD28 family play a crucial role in the activation of immune responses in T lymphocytes, complementing and modulating signals originating from the T-cell receptor (TCR) complex. Although distinct functional roles have been demonstrated for each family member, the specific signaling pathways differentiating ICOS- from CD28-mediated costimulation during early T-cell activation are poorly characterized. In the present study, we have performed RNA-Seq-based global transcriptome profiling of anti-CD3-treated naïve CD4
MeSH term(s)	CD28 Antigens ; CD4-Positive T-Lymphocytes ; Cholesterol/metabolism ; Glycosaminoglycans/metabolism ; Humans ; Inducible T-Cell Co-Stimulator Protein/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Transcription, Genetic ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	CD28 Antigens ; Glycosaminoglycans ; ICOS protein, human ; Inducible T-Cell Co-Stimulator Protein ; Receptors, Antigen, T-Cell ; Cholesterol (97C5T2UQ7J) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2022-09-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.915963
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Article: HMGA2 Antisense Long Non-coding RNAs as New Players in the Regulation of HMGA2 Expression and Pancreatic Cancer Promotion.

Ros, Gloria / Pegoraro, Silvia / De Angelis, Paolo / Sgarra, Riccardo / Zucchelli, Silvia / Gustincich, Stefano / Manfioletti, Guidalberto

Frontiers in oncology

2020 Volume 9, Page(s) 1526

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2020-01-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.01526
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