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Open AccessEditorial

Prion Pathogenesis Revealed in a Series of the Special Issues “Prions and Prion Diseases”

by Suehiro Sakaguchi

Int. J. Mol. Sci. 2022, 23(12), 6490; https://doi.org/10.3390/ijms23126490 - 10 Jun 2022

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Abstract

Prion diseases are a group of devastating neurodegenerative disorders, which include Creutzfeldt–Jakob disease (CJD) in humans, and scrapie and bovine spongiform encephalopathy (BSE) in animals [...] Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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18 pages, 4672 KiB

Open AccessArticle

Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

by Keiji Uchiyama, Hironori Miyata, Yoshitaka Yamaguchi, Morikazu Imamura, Mariya Okazaki, Agriani Dini Pasiana, Junji Chida, Hideyuki Hara, Ryuichiro Atarashi, Hitomi Watanabe, Gen Kondoh and Suehiro Sakaguchi

Int. J. Mol. Sci. 2020, 21(19), 7260; https://doi.org/10.3390/ijms21197260 - 1 Oct 2020

Cited by 4 | Viewed by 2506

Abstract

Conformational conversion of the cellular prion protein, PrP^C, into the abnormally folded isoform, PrP^Sc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the [...] Read more.

Conformational conversion of the cellular prion protein, PrP^C, into the abnormally folded isoform, PrP^Sc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrP^C, designated Tg(PrP∆91–106)/Prnp^0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp^0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrP^Sc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrP^Sc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrP^Sc∆91–104 after incubation with BSE-PrP^Sc-prions but not with RML- and 22L–PrP^Sc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrP^Sc∆91–104 even after incubation with RML- and 22L-PrP^Sc-prions. These results suggest that residues 91–106 or 91–104 of PrP^C are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrP^C into PrP^Sc. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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23 pages, 6074 KiB

Open AccessArticle

Assessment of Glial Activation Response in the Progress of Natural Scrapie after Chronic Dexamethasone Treatment

by Isabel M. Guijarro, Moisés Garcés, Pol Andrés-Benito, Belén Marín, Alicia Otero, Tomás Barrio, Margarita Carmona, Isidro Ferrer, Juan J. Badiola and Marta Monzón

Int. J. Mol. Sci. 2020, 21(9), 3231; https://doi.org/10.3390/ijms21093231 - 2 May 2020

Cited by 8 | Viewed by 2725

Abstract

Neuroinflammation has been correlated with the progress of neurodegeneration in many neuropathologies. Although glial cells have traditionally been considered to be protective, the concept of them as neurotoxic cells has recently emerged. Thus, a major unsolved question is the exact role of astroglia [...] Read more.

Neuroinflammation has been correlated with the progress of neurodegeneration in many neuropathologies. Although glial cells have traditionally been considered to be protective, the concept of them as neurotoxic cells has recently emerged. Thus, a major unsolved question is the exact role of astroglia and microglia in neurodegenerative disorders. On the other hand, it is well known that glucocorticoids are the first choice to regulate inflammation and, consequently, neuroglial inflammatory activity. The objective of this study was to determine how chronic dexamethasone treatment influences the host immune response and to characterize the beneficial or detrimental role of glial cells. To date, this has not been examined using a natural neurodegenerative model of scrapie. With this aim, immunohistochemical expression of glial markers, prion protein accumulation, histopathological lesions and clinical evolution were compared with those in a control group. The results demonstrated how the complex interaction between glial populations failed to compensate for brain damage in natural conditions, emphasizing the need for using natural models. Additionally, the data showed that modulation of neuroinflammation by anti-inflammatory drugs might become a research focus as a potential therapeutic target for prion diseases, similar to that considered previously for other neurodegenerative disorders classified as prion-like diseases. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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17 pages, 3920 KiB

Open AccessArticle

RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

by Hee-Jun Kim, Mo-Jong Kim, Mohd Najib Mostafa, Jeong-Ho Park, Hong-Seok Choi, Yong-Sun Kim and Eun-Kyoung Choi

Int. J. Mol. Sci. 2020, 21(4), 1255; https://doi.org/10.3390/ijms21041255 - 13 Feb 2020

Cited by 16 | Viewed by 3685

Abstract

Scrapie infection, which converts cellular prion protein (PrP^C) into the pathological and infectious isoform (PrP^Sc), leads to neuronal cell death, glial cell activation and PrP^Sc accumulation. Previous studies reported that PrP^C regulates RhoA/Rho-associated kinase (ROCK) signaling and [...] Read more.

Scrapie infection, which converts cellular prion protein (PrP^C) into the pathological and infectious isoform (PrP^Sc), leads to neuronal cell death, glial cell activation and PrP^Sc accumulation. Previous studies reported that PrP^C regulates RhoA/Rho-associated kinase (ROCK) signaling and that connexin 43 (Cx43) expression is upregulated in in vitro and in vivo prion-infected models. However, whether there is a link between RhoA/ROCK and Cx43 in prion disease pathogenesis is uncertain. Here, we investigated the role of RhoA/ROCK signaling and Cx43 in prion diseases using in vitro and in vivo models. Scrapie infection induced RhoA activation, accompanied by increased phosphorylation of LIM kinase 1/2 (LIMK1/2) at Thr508/Thr505 and cofilin at Ser3 and reduced phosphorylation of RhoA at Ser188 in hippocampal neuronal cells and brains of mice. Scrapie infection-induced RhoA activation also resulted in PrP^Sc accumulation followed by a reduction in the interaction between RhoA and p190RhoGAP (a GTPase-activating protein). Interestingly, scrapie infection significantly enhanced the interaction between RhoA and Cx43. Moreover, RhoA and Cx43 colocalization was more visible in both the membrane and cytoplasm of scrapie-infected hippocampal neuronal cells than in controls. Finally, RhoA and ROCK inhibition reduced PrP^Sc accumulation and the RhoA/Cx43 interaction, leading to decreased Cx43 hemichannel activity in scrapie-infected hippocampal neuronal cells. These findings suggest that RhoA/ROCK regulates Cx43 activity, which may have an important role in the pathogenesis of prion disease. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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10 pages, 570 KiB

Open AccessArticle

High Diagnostic Accuracy of RT-QuIC Assay in a Prospective Study of Patients with Suspected sCJD

by Michele Fiorini, Giorgia Iselle, Daniela Perra, Matilde Bongianni, Stefano Capaldi, Luca Sacchetto, Sergio Ferrari, Aldo Mombello, Sarah Vascellari, Silvia Testi, Salvatore Monaco and Gianluigi Zanusso

Int. J. Mol. Sci. 2020, 21(3), 880; https://doi.org/10.3390/ijms21030880 - 30 Jan 2020

Cited by 41 | Viewed by 2923

Abstract

The early and accurate in vivo diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) is essential in order to differentiate CJD from treatable rapidly progressive dementias. Diagnostic investigations supportive of clinical CJD diagnosis include magnetic resonance imaging (MRI), electroencephalogram (EEG), 14-3-3 protein detection, and/or real-time [...] Read more.

The early and accurate in vivo diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) is essential in order to differentiate CJD from treatable rapidly progressive dementias. Diagnostic investigations supportive of clinical CJD diagnosis include magnetic resonance imaging (MRI), electroencephalogram (EEG), 14-3-3 protein detection, and/or real-time quaking-induced conversion (RT-QuIC) assay positivity in the cerebrospinal fluid (CSF) or in other tissues. The total CSF tau protein concentration has also been used in a clinical setting for improving the CJD diagnostic sensitivity and specificity. We analyzed 182 CSF samples and 42 olfactory mucosa (OM) brushings from patients suspected of having sCJD with rapidly progressive dementia (RPD), in order to determine the diagnostic accuracy of 14-3-3, the total tau protein, and the RT-QuIC assay. A probable and definite sCJD diagnosis was assessed in 102 patients. The RT-QuIC assay on the CSF samples showed a 100% specificity and a 96% sensitivity, significantly higher compared with 14-3-3 (84% sensitivity and 46% specificity) and tau (85% sensitivity and 70% specificity); however, the combination of RT-QuIC testing of the CSF and OM samples resulted in 100% sensitivity and specificity, proving a significantly higher accuracy of RT-QuIC compared with the surrogate biomarkers in the diagnostic setting of patients with RPD. Moreover, we showed that CSF blood contamination or high protein levels might interfere with RT-QuIC seeding. In conclusion, we provided further evidence that the inclusion of an RT-QuIC assay of the CSF and OM in the diagnostic criteria for sCJD has radically changed the clinical approach towards the diagnosis. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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Review

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16 pages, 1548 KiB

Open AccessReview

Microglia in Prion Diseases: Angels or Demons?

by Caterina Peggion, Roberto Stella, Paolo Lorenzon, Enzo Spisni, Alessandro Bertoli and Maria Lina Massimino

Int. J. Mol. Sci. 2020, 21(20), 7765; https://doi.org/10.3390/ijms21207765 - 20 Oct 2020

Cited by 10 | Viewed by 4174

Abstract

Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrP^Sc) of the cellular prion protein (PrP^C) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced [...] Read more.

Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrP^Sc) of the cellular prion protein (PrP^C) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced microglial proliferation and activation. As immune cells of the CNS, microglia participate both in the maintenance of the normal brain physiology and in driving the neuroinflammatory response to acute or chronic (e.g., neurodegenerative disorders) insults. Microglia involvement in prion diseases, however, is far from being clearly understood. During this review, we summarize and discuss controversial findings, both in patient and animal models, suggesting a neuroprotective role of microglia in prion disease pathogenesis and progression, or—conversely—a microglia-mediated exacerbation of neurotoxicity in later stages of disease. We also will consider the active participation of PrP^C in microglial functions, by discussing previous reports, but also by presenting unpublished results that support a role for PrP^C in cytokine secretion by activated primary microglia. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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19 pages, 915 KiB

Open AccessReview

A New Take on Prion Protein Dynamics in Cellular Trafficking

by Rodrigo Nunes Alves, Rebeca Piatniczka Iglesia, Mariana Brandão Prado, Maria Isabel Melo Escobar, Jacqueline Marcia Boccacino, Camila Felix de Lima Fernandes, Bárbara Paranhos Coelho, Ailine Cibele Fortes and Marilene Hohmuth Lopes

Int. J. Mol. Sci. 2020, 21(20), 7763; https://doi.org/10.3390/ijms21207763 - 20 Oct 2020

Cited by 8 | Viewed by 4627

Abstract

The mobility of cellular prion protein (PrP^C) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrP^C works in concert with several partners to organize signaling platforms implicated in various [...] Read more.

The mobility of cellular prion protein (PrP^C) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrP^C works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrP^C is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrP^C through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrP^C traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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39 pages, 7555 KiB

Open AccessReview

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

by Neil A. Mabbott, Barry M. Bradford, Reiss Pal, Rachel Young and David S. Donaldson

Int. J. Mol. Sci. 2020, 21(19), 7299; https://doi.org/10.3390/ijms21197299 - 2 Oct 2020

Cited by 9 | Viewed by 4836

Abstract

Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease [...] Read more.

Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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38 pages, 1544 KiB

Open AccessReview

Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction

by Hajar Miranzadeh Mahabadi and Changiz Taghibiglou

Int. J. Mol. Sci. 2020, 21(19), 7058; https://doi.org/10.3390/ijms21197058 - 25 Sep 2020

Cited by 20 | Viewed by 10496

Abstract

Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide [...] Read more.

Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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19 pages, 2234 KiB

Open AccessReview

The Role of Vesicle Trafficking Defects in the Pathogenesis of Prion and Prion-Like Disorders

by Pearl Cherry and Sabine Gilch

Int. J. Mol. Sci. 2020, 21(19), 7016; https://doi.org/10.3390/ijms21197016 - 23 Sep 2020

Cited by 6 | Viewed by 3268

Abstract

Prion diseases are fatal and transmissible neurodegenerative diseases in which the cellular form of the prion protein ‘PrP^c’, misfolds into an infectious and aggregation prone isoform termed PrP^Sc, which is the primary component of prions. Many neurodegenerative diseases, like [...] Read more.

Prion diseases are fatal and transmissible neurodegenerative diseases in which the cellular form of the prion protein ‘PrP^c’, misfolds into an infectious and aggregation prone isoform termed PrP^Sc, which is the primary component of prions. Many neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases, such as Huntington’s disease, are considered prion-like disorders because of the common characteristics in the propagation and spreading of misfolded proteins that they share with the prion diseases. Unlike prion diseases, these are non-infectious outside experimental settings. Many vesicular trafficking impairments, which are observed in prion and prion-like disorders, favor the accumulation of the pathogenic amyloid aggregates. In addition, many of the vesicular trafficking impairments that arise in these diseases, turn out to be further aggravating factors. This review offers an insight into the currently known vesicular trafficking defects in these neurodegenerative diseases and their implications on disease progression. These findings suggest that these impaired trafficking pathways may represent similar therapeutic targets in these classes of neurodegenerative disorders. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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18 pages, 2031 KiB

Open AccessReview

Prion Protein at the Leading Edge: Its Role in Cell Motility

by Mariana Brandão Prado, Maria Isabel Melo Escobar, Rodrigo Nunes Alves, Bárbara Paranhos Coelho, Camila Felix de Lima Fernandes, Jacqueline Marcia Boccacino, Rebeca Piatniczka Iglesia and Marilene Hohmuth Lopes

Int. J. Mol. Sci. 2020, 21(18), 6677; https://doi.org/10.3390/ijms21186677 - 12 Sep 2020

Cited by 8 | Viewed by 4079

Abstract

Cell motility is a central process involved in fundamental biological phenomena during embryonic development, wound healing, immune surveillance, and cancer spreading. Cell movement is complex and dynamic and requires the coordinated activity of cytoskeletal, membrane, adhesion and extracellular proteins. Cellular prion protein (PrP [...] Read more.

Cell motility is a central process involved in fundamental biological phenomena during embryonic development, wound healing, immune surveillance, and cancer spreading. Cell movement is complex and dynamic and requires the coordinated activity of cytoskeletal, membrane, adhesion and extracellular proteins. Cellular prion protein (PrP^C) has been implicated in distinct aspects of cell motility, including axonal growth, transendothelial migration, epithelial–mesenchymal transition, formation of lamellipodia, and tumor migration and invasion. The preferential location of PrP^C on cell membrane favors its function as a pivotal molecule in cell motile phenotype, being able to serve as a scaffold protein for extracellular matrix proteins, cell surface receptors, and cytoskeletal multiprotein complexes to modulate their activities in cellular movement. Evidence points to PrP^C mediating interactions of multiple key elements of cell motility at the intra- and extracellular levels, such as integrins and matrix proteins, also regulating cell adhesion molecule stability and cell adhesion cytoskeleton dynamics. Understanding the molecular mechanisms that govern cell motility is critical for tissue homeostasis, since uncontrolled cell movement results in pathological conditions such as developmental diseases and tumor dissemination. In this review, we discuss the relevant contribution of PrP^C in several aspects of cell motility, unveiling new insights into both PrP^C function and mechanism in a multifaceted manner either in physiological or pathological contexts. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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14 pages, 594 KiB

Open AccessReview

N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases

by Hideyuki Hara and Suehiro Sakaguchi

Int. J. Mol. Sci. 2020, 21(17), 6233; https://doi.org/10.3390/ijms21176233 - 28 Aug 2020

Cited by 14 | Viewed by 3448

Abstract

The normal cellular isoform of prion protein, designated PrP^C, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP^Sc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP^C is [...] Read more.

The normal cellular isoform of prion protein, designated PrP^C, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP^Sc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP^C is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrP^C to PrP^Sc, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrP^Sc. Reverse genetic studies using reconstituted PrP^C-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP^C and the conversion of PrP^C to PrP^Sc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP^C, the conversion of PrP^C to PrP^Sc, and the neurotoxicity of PrP^Sc by focusing on the roles of the N-terminal regions in these topics. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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12 pages, 475 KiB

Open AccessReview

Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process

by Stefano Martellucci, Costantino Santacroce, Francesca Santilli, Valeria Manganelli, Maurizio Sorice and Vincenzo Mattei

Int. J. Mol. Sci. 2020, 21(11), 4168; https://doi.org/10.3390/ijms21114168 - 11 Jun 2020

Cited by 15 | Viewed by 3414

Abstract

The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its [...] Read more.

The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrP^C) in physiological processes, including cellular differentiation. Indeed, the PrP^C, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrP^C and stem cells. Full article

(This article belongs to the Special Issue Prions and Prion Diseases)

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