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Article ; Online: Cutaneous manifestations associated with SARS-CoV-2: an emerging topic in a pandemic era.

Luís, Helena / Barros, Carolina / André, Diogo / Malheiro, Alexandra

BMJ case reports

2021 Volume 14, Issue 9

Abstract: A 70-year-old man was admitted to our COVID-19 ward with thoracalgia, productive mucus cough, fatigue and erythematous-violaceous macules on the inner side of feet and interdigital regions. The patient was started on oxygen and dexamethasone. On the day ... ...

Abstract	A 70-year-old man was admitted to our COVID-19 ward with thoracalgia, productive mucus cough, fatigue and erythematous-violaceous macules on the inner side of feet and interdigital regions. The patient was started on oxygen and dexamethasone. On the day of discharge, he maintained the skin changes despite the resolution of COVID-19 symptoms. A 57-year-old woman initially presented with diffuse urticarial rash on the cervical and chest region. Oral cetirizine was started, and pruritus improved. Thirty days after the discharge, the patient maintained the rash, but without pruritus. A 49-year-old man was admitted with thoracalgia, shortness of breath, dry cough and urticarial rash on the cervical and chest region. The patient was treated with cetirizine. The pruritus improved, and 5 days after discharge, the urticarial areas completely disappeared.
MeSH term(s)	Aged ; COVID-19/complications ; Exanthema/virology ; Female ; Humans ; Male ; Middle Aged ; Pandemics ; Urticaria/virology
Language	English
Publishing date	2021-09-03
Publishing country	England
Document type	Case Reports ; Journal Article
ISSN	1757-790X
ISSN (online)	1757-790X
DOI	10.1136/bcr-2021-244763
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Article: Correction to: Animal Models to Study Cancer and Its Microenvironment.

Mendes, N / Dias Carvalho, P / Martins, F / Mendonça, S / Malheiro, A R / Ribeiro, A / Carvalho, J / Velho, S

Advances in experimental medicine and biology

2024 Volume 1219, Page(s) C1

Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Published Erratum
ZDB-ID	410187-X
ISSN	0065-2598
ISSN	0065-2598
DOI	10.1007/978-3-030-34025-4_24
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Zs.A 3192: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Identification of proofs via syzygies.

Malheiro, António / Reis, José Francisco

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences

2019 Volume 377, Issue 2140, Page(s) 20180275

Abstract: In 1900, Hilbert gave a lecture at the International Congress of Mathematicians in Paris, for which he prepared 23 problems that mathematicians should solve during the twentieth century. It was found that there was a note on a 24th problem focusing on ... ...

Abstract	In 1900, Hilbert gave a lecture at the International Congress of Mathematicians in Paris, for which he prepared 23 problems that mathematicians should solve during the twentieth century. It was found that there was a note on a 24th problem focusing on the problem of simplicity of proofs. One of the lines of research that was generated from this problem was the identification of proofs. In this article, we present a possible method for exploring the identification of proofs based on the membership problem original from the theory of polynomial rings. To show this, we start by giving a complete worked-out example of a membership problem, that is the problem of checking if a given polynomial belongs to an ideal generated by finitely many polynomials. This problem can be solved by considering Gröbner bases and the corresponding reductions. Each reduction is a simplification of the polynomial and it corresponds to a rewriting step. In proving that a polynomial is a member of an ideal, a rewriting process is used, and many different such processes can be considered. To better illustrate this, we consider a graph where each rewriting step corresponds to an edge, and thus a path corresponds to a rewriting process. In this paper, we consider the identification of paths, within the context of the membership problem, to propose a criterion of identification of proofs. This article is part of the theme issue 'The notion of 'simple proof' - Hilbert's 24th problem'.
Language	English
Publishing date	2019-04-09
Publishing country	England
Document type	Journal Article
ZDB-ID	208381-4
ISSN	1471-2962 ; 0080-4614 ; 0264-3820 ; 0264-3952 ; 1364-503X
ISSN (online)	1471-2962
ISSN	0080-4614 ; 0264-3820 ; 0264-3952 ; 1364-503X
DOI	10.1098/rsta.2018.0275
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Article ; Online: Peripheral neurovascular link: an overview of interactions and in vitro models.

Malheiro, Afonso / Wieringa, Paul / Moroni, Lorenzo

Trends in endocrinology and metabolism: TEM

2021 Volume 32, Issue 8, Page(s) 623–638

Abstract: Nerves and blood vessels (BVs) establish extensive arborized networks to innervate tissues and deliver oxygen/metabolic support. Developmental cues direct the formation of these intricate and often overlapping patterns, which reflect close interactions ... ...

Abstract	Nerves and blood vessels (BVs) establish extensive arborized networks to innervate tissues and deliver oxygen/metabolic support. Developmental cues direct the formation of these intricate and often overlapping patterns, which reflect close interactions within the peripheral neurovascular system. Besides the mutual dependence to survive and function, nerves and BVs share several receptors and ligands, as well as principles of differentiation, growth and pathfinding. Neurovascular (NV) interactions are maintained in adult life and are essential for certain regenerative mechanisms, such as wound healing. In pathological situations (e.g., type 2 diabetes mellitus), the NV system can be severely perturbed and become dysfunctional. Unwanted neural growth and vascularization are also associated with the progression of some pathologies, such as cancer and endometriosis. In this review, we describe the fundamental NV interactions in development, highlighting the similarities between both networks and wiring mechanisms. We also describe the NV contribution to regenerative processes and potential pathological dysfunctions. Finally, we provide an overview of current in vitro models used to replicate and investigate the NV ecosystem, addressing present limitations and future perspectives.
MeSH term(s)	Blood Vessels/physiology ; Cell Differentiation ; Diabetes Mellitus, Type 2 ; Endometriosis ; Female ; Humans ; Neoplasms ; Peripheral Nerves/physiology ; Wound Healing
Language	English
Publishing date	2021-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2021.05.004
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Article: Development of an In Vitro Biomimetic Peripheral Neurovascular Platform

Malheiro, Afonso / Seijas-Gamardo, Adrián / Harichandan, Abhishek / Mota, Carlos / Wieringa, Paul / Moroni, Lorenzo

ACS applied materials & interfaces. 2022 July 11, v. 14, no. 28

2022

Abstract: Nerves and blood vessels are present in most organs and are indispensable for their function and homeostasis. Within these organs, neurovascular (NV) tissue forms congruent patterns and establishes vital interactions. Several human pathologies, including ...

Abstract	Nerves and blood vessels are present in most organs and are indispensable for their function and homeostasis. Within these organs, neurovascular (NV) tissue forms congruent patterns and establishes vital interactions. Several human pathologies, including diabetes type II, produce NV disruptions with serious consequences that are complicated to study using animal models. Complex in vitro organ platforms, with neural and vascular supply, allow the investigation of such interactions, whether in a normal or pathological context, in an affordable, simple, and direct manner. To date, a few in vitro models contain NV tissue, and most strategies report models with nonbiomimetic representations of the native environment. To this end, we have established here an NV platform that contains mature vasculature and neural tissue, composed of human microvascular endothelial cells (HMVECs), induced pluripotent stem cell (iPSCs)-derived sensory neurons, and primary rat Schwann cells (SCs) within a fibrin-embedded polymeric scaffold. First, we show that SCs can induce the formation of and stabilize vascular networks to the same degree as the traditional and more thoroughly studied human dermal fibroblasts (HDFs). We also show that through SC prepatterning, we are able to control vessel orientation. Using our NV platform, we demonstrate the concomitant formation of three-dimensional neural and vascular tissue, and the influence of different medium formulations and cell types on the NV tissue outcome. Finally, we propose a protocol to form mature NV tissue, via the integration of independent neural and vascular constituents. The platform described here provides a versatile and advanced model for in vitro research of the NV axis.
Keywords	biomimetics ; blood ; diabetes ; fibroblasts ; homeostasis ; humans ; polymers ; rats ; stem cells
Language	English
Dates of publication	2022-0711
Size	p. 31567-31585.
Publishing place	American Chemical Society
Document type	Article
ISSN	1944-8252
DOI	10.1021/acsami.2c03861
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Editorial: The Role of Gene Polymorphisms in Modulating the Immune Responses Against Tropical Infectious Diseases.

Malheiro, Adriana / Ramasawmy, Rajendranath / Courtin, David / Donadi, Eduardo Antonio

Frontiers in immunology

2021 Volume 12, Page(s) 714237

MeSH term(s)	Animals ; Communicable Diseases/etiology ; Disease Susceptibility/immunology ; Genetic Predisposition to Disease ; Humans ; Immunity/genetics ; Polymorphism, Genetic ; Tropical Medicine
Language	English
Publishing date	2021-07-22
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.714237
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Article ; Online: Development of an In Vitro Biomimetic Peripheral Neurovascular Platform.

Malheiro, Afonso / Seijas-Gamardo, Adrián / Harichandan, Abhishek / Mota, Carlos / Wieringa, Paul / Moroni, Lorenzo

ACS applied materials & interfaces

2022 Volume 14, Issue 28, Page(s) 31567–31585

Abstract	Nerves and blood vessels are present in most organs and are indispensable for their function and homeostasis. Within these organs, neurovascular (NV) tissue forms congruent patterns and establishes vital interactions. Several human pathologies, including diabetes type II, produce NV disruptions with serious consequences that are complicated to study using animal models. Complex in vitro organ platforms, with neural and vascular supply, allow the investigation of such interactions, whether in a normal or pathological context, in an affordable, simple, and direct manner. To date, a few in vitro models contain NV tissue, and most strategies report models with nonbiomimetic representations of the native environment. To this end, we have established here an NV platform that contains mature vasculature and neural tissue, composed of human microvascular endothelial cells (HMVECs), induced pluripotent stem cell (iPSCs)-derived sensory neurons, and primary rat Schwann cells (SCs) within a fibrin-embedded polymeric scaffold. First, we show that SCs can induce the formation of and stabilize vascular networks to the same degree as the traditional and more thoroughly studied human dermal fibroblasts (HDFs). We also show that through SC prepatterning, we are able to control vessel orientation. Using our NV platform, we demonstrate the concomitant formation of three-dimensional neural and vascular tissue, and the influence of different medium formulations and cell types on the NV tissue outcome. Finally, we propose a protocol to form mature NV tissue, via the integration of independent neural and vascular constituents. The platform described here provides a versatile and advanced model for in vitro research of the NV axis.
MeSH term(s)	Animals ; Biomimetics ; Endothelial Cells/metabolism ; Humans ; Induced Pluripotent Stem Cells ; Nerve Tissue ; Rats ; Schwann Cells/metabolism
Language	English
Publishing date	2022-07-10
Publishing country	United States
Document type	Journal Article
ISSN	1944-8252
ISSN (online)	1944-8252
DOI	10.1021/acsami.2c03861
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Article ; Online: Cross Contamination of 2,4,6-Trichloroanisole in Cork Stoppers.

Monteiro, Susana / Bundaleski, Nenad / Malheiro, Ana / Cabral, Miguel / Teodoro, Orlando M N D

Journal of agricultural and food chemistry

2022 Volume 70, Issue 22, Page(s) 6747–6754

Abstract: Cork stoppers are the preferred choice for sealing bottled wines around the world. However, the quality of cork stoppers is also defined by the presence of 2,4,6-trichloroanisole (TCA), which gives the wine an unpleasant moldy/musty taste. It is a matter ...

Abstract	Cork stoppers are the preferred choice for sealing bottled wines around the world. However, the quality of cork stoppers is also defined by the presence of 2,4,6-trichloroanisole (TCA), which gives the wine an unpleasant moldy/musty taste. It is a matter of concern for both cork stopper manufacturers and wine producers whether TCA can be transported between stoppers. As little is known about cross contamination between stoppers, this work provides enough experimental data to discuss the extent of TCA transfer in naturally contaminated stoppers in the liquid and gas phase that can be useful to the cork industry and the wine industry. We found that when a clean stopper is soaked together with a contaminated one in hydro-alcoholic solution, 12% of the TCA can be transferred. In gas-phase contamination, only stoppers with 12 ng/L, or more, contaminate clean stoppers when enclosed together for several days. In a second experiment, where clean corks were exposed to a controlled contaminated environment, it was found that TCA contamination was not confined to the outermost layer of the stoppers. Based on these findings, some recommendations are given to prevent TCA cross contamination between stoppers during the cork stopper manufacturing, storage, wine making, and bottling.
MeSH term(s)	Anisoles ; Food Contamination/analysis ; Taste ; Wine/analysis
Chemical Substances	Anisoles ; 2,4,6-trichloroanisole (31O3X41254)
Language	English
Publishing date	2022-05-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	241619-0
ISSN	1520-5118 ; 0021-8561
ISSN (online)	1520-5118
ISSN	0021-8561
DOI	10.1021/acs.jafc.2c02493
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Article ; Online: Phosphodiesterase (PDE) 4 inhibition boosts Schwann cell myelination in a 3D regeneration model.

Schepers, Melissa / Malheiro, Afonso / Gamardo, Adrián Seijas / Hellings, Niels / Prickaerts, Jos / Moroni, Lorenzo / Vanmierlo, Tim / Wieringa, Paul

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2023 Volume 185, Page(s) 106441

Abstract: Phosphodiesterase 4 (PDE4) inhibitors have been extensively researched for their anti-inflammatory and neuroregenerative properties. Despite the known neuroplastic and myelin regenerative properties of nonselective PDE4 inhibitors on the central nervous ... ...

Abstract	Phosphodiesterase 4 (PDE4) inhibitors have been extensively researched for their anti-inflammatory and neuroregenerative properties. Despite the known neuroplastic and myelin regenerative properties of nonselective PDE4 inhibitors on the central nervous system, the direct impact on peripheral remyelination and subsequent neuroregeneration has not yet been investigated. Therefore, to examine the possible therapeutic effect of PDE4 inhibition on peripheral glia, we assessed the differentiation of primary rat Schwann cells exposed in vitro to the PDE4 inhibitor roflumilast. To further investigate the differentiation promoting effects of roflumilast, we developed a 3D model of rat Schwann cell myelination that closely resembles the in vivo situation. Using these in vitro models, we demonstrated that pan-PDE4 inhibition using roflumilast significantly promoted differentiation of Schwann cells towards a myelinating phenotype, as indicated by the upregulation of myelin proteins, including MBP and MAG. Additionally, we created a unique regenerative model comprised of a 3D co-culture of rat Schwann cells and human iPSC-derived neurons. Schwann cells treated with roflumilast enhanced axonal outgrowth of iPSC-derived nociceptive neurons, which was accompanied by an accelerated myelination speed, thereby showing not only phenotypic but also functional changes of roflumilast-treated Schwann cells. Taken together, the PDE4 inhibitor roflumilast possesses a therapeutic benefit to stimulate Schwann cell differentiation and, subsequently myelination, as demonstrated in the biologically relevant in vitro platform used in this study. These results can aid in the development of novel PDE4 inhibition-based therapies in the advancement of peripheral regenerative medicine.
MeSH term(s)	Rats ; Animals ; Humans ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Phosphodiesterase 4 Inhibitors/pharmacology ; Phosphodiesterase 4 Inhibitors/metabolism ; Schwann Cells/metabolism ; Myelin Sheath/genetics
Chemical Substances	Roflumilast (0P6C6ZOP5U) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; Phosphodiesterase 4 Inhibitors
Language	English
Publishing date	2023-03-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2023.106441
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Article ; Online: A three-dimensional biomimetic peripheral nerve model for drug testing and disease modelling.

Malheiro, Afonso / Morgan, Francis / Baker, Matthew / Moroni, Lorenzo / Wieringa, Paul

Biomaterials

2020 Volume 257, Page(s) 120230

Abstract: In vitro peripheral nerve models provide valuable tools to study neurobiology questions and assess drug performance, in a regenerative or pathology context. To this end, we have developed a representative model of the peripheral nerve that displays three- ...

Abstract	In vitro peripheral nerve models provide valuable tools to study neurobiology questions and assess drug performance, in a regenerative or pathology context. To this end, we have developed a representative model of the peripheral nerve that displays three-dimensional (3D) neural anisotropy and myelination, which we showcase here as a simple and low-cost platform for drug screening. The model is composed of three main parts, including rat primary Schwann cells (SCs) seeded onto an electrospun scaffold to create bands of Büngner (BoB), primed PC12 cells as neuronal cell population, and a fibrin hydrogel to provide three-dimensionality. We also validated the use of primed PC12 as a neuron population by comparing it to rat dorsal root ganglions (DRGs) neurons. In both models we could obtain well aligned neurites and mature myelin segments. In short term cultures (7 days), we found that the addition of exogenous SCs enhanced neurite length and neurite growth area, compared to scaffolds with a laminin coating only. Addition of fibrin also lead to increased outgrowth of DRG and primed PC12 neurites, compared to 2D cultures. Moreover, neurite outgrowth in fibrin cultures was simultaneously multiplanar and anisotropic, suggesting that the SC-seeded scaffold can direct not only the growth of adjacent neurites, but also those growing above it. These results highlight the feasibility of the combination of a SC pre-seeded scaffold with a fibrin hydrogel, to direct and improve neurite growth in 3D. To demonstrate the model potential, we tested our platform at an immature (7 days in vitro) and mature state (28 days in vitro) of development. At the immature stage we could inhibit neurite growth through protein blocking (via antibody binding) and show suramin (200 μM) neurotoxicity on cells. At the mature stage, when myelin is compact, we exposed cells to hyperglycemic conditions (45 mM glucose) to mimic diabetic conditions and showed that myelin deforms consequently. Moreover, we demonstrated that by supplementing cultures with epalrestat (1 μM), myelin deformation can be partly prevented. In sum, we developed a biomimetic nerve platform using an affordable and accessible cell line as neuronal population, which displays similar results to primary neurons, but does not require recurrent animal sacrifice. This platform holds great promise as it can be used to conveniently and inexpensively perform drug screenings on peripheral nerve-like tissue, in a normal or pathological state.
MeSH term(s)	Animals ; Biomimetics ; Cells, Cultured ; Ganglia, Spinal ; Myelin Sheath ; Neurites ; Rats ; Schwann Cells
Language	English
Publishing date	2020-07-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2020.120230
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