Viruses that use caveolae-mediated endocytosis
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Since he graduated he has published several peer-reviewed papers at the national and international levels and he has been a guest researcher and lecturer both at Michigan State University (USA) and at the University of Toronto (Canada) where he has developed part of his Ph.D. research with the Financial support from the Portuguese Foundation for Science and Technology (Ph.D. grant).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"108118",title:"Dr.",name:"Luis",middleName:null,surname:"Loures",slug:"luis-loures",fullName:"Luis Loures",profilePictureURL:"https://mts.intechopen.com/storage/users/108118/images/system/108118.png",biography:"Luís Loures is a Landscape Architect and Agronomic Engineer, Vice-President of the Polytechnic Institute of Portalegre, who holds a Ph.D. in Planning and a Post-Doc in Agronomy. Since he graduated, he has published several peer reviewed papers at the national and international levels and he has been a guest researcher and lecturer both at Michigan State University (USA), and at University of Toronto (Canada) where he has developed part of his Ph.D. research with the Financial support from the Portuguese Foundation for Science and Technology (Ph.D. grant).\nDuring his academic career he had taught in several courses in different Universities around the world, mainly regarding the fields of landscape architecture, urban and environmental planning and sustainability. 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Since their discovery sixty years ago [1,2], the functional relevance of caveolae has challenged many scientists, raising numerous debates and controversies. The electron microscopy images of caveolae show a rather cell-type-dependent appearance. In endothelial cells, caveolae opening is more constricted [3], while in epithelial cells they appear open to the extracellular medium and smaller in size [4]. In muscle cells, multiple caveolae units cluster together forming T-like tubules invaginating from sarcolemma [5]. Regardless their shape, caveolae appear as immobile structures, in tight connection with the cortical actin cytoskeleton underlying the plasma membrane. Video microscopy and fluorescence recovery after photobleaching analysis have shown that caveolae detach from the membrane only upon ligand binding and specific signaling [6].
The discovery of caveolins (Cav), the structural proteins enveloping caveolae in a spike-like coat [7] marked a significant breakthrough in understanding the nature and importance of these organelles.
Three members of the Cav family have been described in mammalian cells, to date: Cav-1, -2, -3, which share a significant homology and are conserved throughout evolution [8]. Cav-1 and -2 are relatively ubiquitous, with highest distribution in fibroblasts, adipocytes, endothelial cells, and pneumocytes, being co-expressed in most cells types [9]. Cav-3 is expressed independently of Cav-1 and -2 and is limited to skeletal muscle fibers and cardiac myocytes [10-12]. Over-expression of Cav-1 in caveolae-deficient cells is necessary and apparently sufficient to drive caveolae biogenesis [13]. Moreover, Cav-1 expression is required for the membrane localization and stability of Cav-2. Although unable to drive caveolae biogenesis on its own, Cav-2 may however influence it, at least in several polarized, epithelial cells [14,15]. The capacity to modulate caveolae assembly, shape and size has been shown to depend on Cav-2 phosphorylation status [16]. Similar to Cav-1, Cav-3 protein is sufficient to drive formation of caveolae in muscle cells [17].
Most of the molecular data available on caveolins refer to Cav-1; therefore the following discussion will focus on this protein, as a representative of the caveolin family, which is shown schematically in Fig.1.
Cav-1 is an integral membrane protein of 21kDa with an unusual topology. Both the N- and C-termini are cytoplasmically oriented and connected by a central hydrophobic domain, comprising approximately residues 102-134, inserted into, but not spanning the membrane bilayer, in a hairpin (or U bent, or horseshoe) configuration [18,19]. Interestingly, a peptide corresponding to the last 20 residues of the hydrophilic N-domain, (amino acids 82–101) enriched in aromatic residues, can also bind to membranes independently [20,21]. This so-called caveolin scaffolding domain (CSD) is a highly conserved region responsible for many functions associated with Cav-1.
In silico analysis of the conformation of this hydrophobic domain, showed that mutation of a single residue, Pro (110), changes the stable conformation to a straight hydrophobic helix that would span the membrane. Expression of the Cav-1 P110A mutant in HEK 293 cells followed by confocal immunofluorescence microscopy further confirmed the in silico data and the estimated topology [22].
Schematic presentation of the structural similarities of the caveolin family of proteins.
Very recently, circular dichroism and NMR spectroscopy analysis have shown that the transmembrane domain of Cav-1 is primarily α-helical (57-65%). In addition, the helix–break–helix structure was suggested to be critical for the formation of the intra-membrane horseshoe conformation predicted for the protein. Interestingly, mutations of Ile (109) and Pro (110) to Ala dramatically altered the helix-break-helix structure. Moreover, it was shown that substitution of Pro (110) with any other residue results in disruption of the helix-break-helix structure, confirming the importance of the residue in the stability of the hydrophobic domain [23].
An important structural feature of Cav-1 is represented by its arrangement in high molecular mass oligomers of about 350 kDa, composed of 14-16 individual molecules [24,25]. Oligomerization is initiated in the endoplasmic reticulum (ER), where the Cav-1 monomer is co-translationally inserted into the membrane [19] and is rapidly assembled to form SDS-resistant, 8S complexes considered the building units of caveolae structure [24,25]. Intriguingly, blue native gel analysis evidenced only a few intermediate sized oligomers, suggesting that Cav-1 oligomerization is a highly cooperative process [26]. Oligomerization of the full-length protein requires the presence of the CSD and of the C-terminal domain [27] and appears to be stabilized by the palmitoylation of cysteine residues located at positions 133, 143 and 156 [18,28]. At this stage of their assembly, the complexes appear highly mobile in the ER membrane and rapidly concentrate at the ER exit sites, a process favored by the existence of a di-acidic export sequence located at the N-terminal domain. In the absence of this signal sequence, Cav-1 accumulates in lipid droplets [29,30]. This is an important observation, suggesting that ER exit and lipid droplets localization of caveolin complexes are competing processes, highlighting the role of the di-acidic motif in caveolin trafficking.
Interestingly, co-expression of Cav-1 and -2 results in assembly of mixt 8S complexes, where the Cav-1 to Cav-2 ratio may vary from 2:1 to 4:1 [31]; however, expression of Cav-2 alone does not result in oligomer formation.
The process continues in the trans-Golgi where the oligomers are exported in a COPII-dependent manner and self-associate into a large network of caveolin. However, formation of the 8S complex is not a prerequisite for Golgi transport, as expression of Cav- 2 alone, as well as that of an oligomerization-incompetent variant of Cav-1 does not result in their retention within the ER [32,33].
The Golgi oligomerization step is sensitive to BFA, clearly indicating that formation of large oligomer complexes is dependent on caveolins trafficking to this compartment, probably requiring a specific lipid composition of the membrane. The assembly process continues in a cholesterol-dependent manner, resulting in formation of 70S stable complexes, also evidenced by using a panel of anti-Cav-1 conformational antibodies. These complexes were assumed to correspond to the intact protein scaffold of the caveolae structure [34]. It is interesting that the caveolin assemblies colocalized with medial, rather than trans-Golgi markers, suggesting that, unlike other cargos transported through the secretory pathway, caveolar carrier vesicles are formed in the medial cisternae, being further exported to the plasma membrane in a dynamin-2 independent manner, similar to other raft-associated proteins [34]. This assembly process is schematically shown in Fig.2.
Caveolin oligomerization and assembly
It can be concluded from these observations that the tight regulation of Cav-1 trafficking along the secretory compartments (and the multiple check points) is totally justified by the complexity of the assembly process.
In addition to oligomerization, caveola formation involves association of the complexes with cholesterol-rich lipid-raft domains at plasma membrane. It is estimated that Cav-1 binds to 1–2 cholesterol molecules through the conserved basic and hydrophobic residues of the scaffolding domain [35]; thus, the relative amount of cholesterol concentrated in isolated caveolae can be as high as 20.000 molecules [36]. The relationship between cholesterol and caveolins is very complex. Treatment of cells with cholesterol binding or depleting agents results in caveolae with altered morphology and disrupted protein coat [7]. Moreover, cholesterol regulates Cav-1 expression at both, transcriptional and translational levels, through binding to either two steroid regulatory elements in the Cav-1 promoter, or the protein itself, thus modulating the level of Cav-1 mRNA or the protein stability [37,38].
Caveolae are enriched in glycosphingolipids (like GM1 and GM3) and sphingomyelin, the total lipid density being significantly higher than within the rest of the plasma membrane [36]. This is an important observation implying that certain lipids are recruited in caveolae, possibly to ensure their invagination-competent composition.
Recently, a crucial role in the last steps of caveolae biogenesis has been attributed to PTRF (Polymerase I and transcript release factor), originally described as an RNA Pol I transcription factor (also called Cav-P60 or cavin-1) [39,40]. Interestingly, cavin-1 is able to associate with plasma membrane caveolae but not with caveolins with other intracellular distribution (such as Golgi caveolins) [34]. Cavin-1 is recruited by Cav-1 to plasma membrane caveolar domains, where the two proteins are found to be in close proximity and an approximate ration of 1:1 [39]; however, whether or not they directly interact with each other is still a matter of debate. It was clearly demonstrated that cavins bind to phosphatidylserine and are phosphorylated at multiple sites, suggesting they may act as regulatory proteins of caveolae functions [41].
Based on sequence homology with cavin-1, three other proteins named cavin-2 to 4, sharing similar molecular organization, have been identified as part of the cavin family [42-44]. While cavin-1 expression is strictly associated to that of Cav-1 [39] contributing to the stability of the caveolae unit like a scaffolding protein, cavin-2 promotes recruitment of cavin-1 in caveolae and appears to have a role in the membrane-curvature [45].
The role of cavin-3 and -4 in caveolae biogenesis is less well understood. Cavin-3 was shown to regulate caveolae budding and Cav-1 trafficking, suggesting a function in coupling caveolae to the intracellular transport network [44]. Cavin-4 is co-expressed with Cav-3 in cardiac and muscle tissues where their function appears to be tightly correlated [42].
All members of the cavin family interact in a multimeric complex of about 60-80 cavins, in a Cav-1 independent manner. These complexes were detected both in the cytosol and plasma membrane fractions, suggesting they are the result of a succession of events, starting with cavin association into the cytosol and ending with the recruitment of the multimeric complexes to caveolae, during the final step of their biogenesis [42].
In contrast to caveolins, cavins are peripheral membrane proteins, and bind molecular components of the caveolar domain facing the cytosol. Given the high affinity of cavins for phosphatidylserine and the rapid dissociation from caveolae in the presence of nonionic detergents, it was suggested that binding to the lipid membrane, rather than to the protein scaffold, was highly probable.
The identification of cavins in caveolae opened new perspectives in understanding the complexity of caveolar structure. Although our knowledge on caveolae architecture and molecular composition has improved since their discovery, the main structural pillars defined at the time have not dramatically changed. Thus, today, caveolae are referred to as invaginations of the plasma membrane lipid bilayer, enriched in cholesterol and sphingolipids, embedding an integral membrane scaffold formed by caveolin oligomers assembled in a stable network, peripherally covered by a protein layer of cavin complexes. Once formed, this structure appears to remain stable also during endocytosis [46].
The protein composition of caveolae has been addressed in a more systematic manner within the last years, using proteomic approaches [47-49]. A variety of signal transduction proteins were found to localize in caveolae, in tight connection with either the CSD or the lipid domains.
According to the caveolin signaling hypothesis, the role of caveolae is to trigger specific signal transduction by concentrating downstream effectors close to plasma membrane receptors, through direct interaction with the CSD [50,51]. Palmitoylation appears to play an important function in this process by facilitating the caveolar localization of proteins [52]. Of the signaling molecules identified, several have been more thoroughly investigated:
G proteins were abundant in caveolae; their binding to caveolin has a role in maintaining the Gα subunits in an inactive GDP-bound state [53]. Small GTP-binding proteins of the Ras superfamily also localized in caveolae, a process enhanced by palmitoylation of the C-terminal hypervariable region [54,55]. Binding of the H-Ras to the CSD results in inactivation of the protein, which is relevant in certain human cancers were H-Ras -caveolin interaction is prevented and the protein is maintained in an active state [56].
Src family kinases, such as c-Src, Fyn, Lyn [57] are nonreceptor tyrosine kinases, also enriched in caveolae. Their localization depends on the N-terminal myristoylation and subsequent interaction with the caveolins. Interestingly, Cav-1 palmitoylation is equally important for caveolae/c-Src interaction [52], which results in c-Src and Fyn inactivation [58]. In turn, the tyrosine phosphorylation of Cav-1 and -2 facilitates the recruitment of matrix metalloproteinases [58,59], and promotes caveolins localization to focal adhesions [60,61].
Several steroid hormone receptors were localized in caveolae, a process depending on both, palmitoylation and association with Cav-1 [62] and facilitating their activation [63].
Endothelial nitric oxide synthase (eNOS) is one of the most extensively studied Cav-1 interacting protein [64]. eNOS binds to the CSD of both Cav-1 and -3, which inhibit its enzymatic activity [65,66]. This observation lead to a novel concept of eNOS regulation, whereby, the interaction with caveolins is necessary to keep the enzyme inactive under basal conditions, while its concentration in caveolae will allow a quick response upon stimulation [67].
Many ion channels and pumps are targeted to caveolae and interact with caveolins, such as the calcium signaling molecules calmodulin, Ca2+-ATPase, L-type Ca2+ channels [68,69]. Transient receptor potential (TRP) channels, and large-conductance Ca2+-activated K+ channels also localize in cholesterol-rich membrane areas, suggesting an important role of these domains in Ca2+ homeostasis [70,71]. Other transporters, like the Na/K-ATPase, involved in maintaining the Na+ membrane gradient, are also found in caveolae, owing this localization to the existence of two caveolin-binding motifs in their amino acid sequence [72].
Protein kinases of different families were found in caveolae, due to their direct interaction with the Cav-1 CSD. For PKA, this interaction results in inhibition of the enzymatic activity [73], with consequences on regulation of other proteins, such as ATP-dependent K+ channels or eNOS in muscle and endothelial cells, respectively [74,75]. Different isoforms of the PKC family of enzymes are also caveolae resident and appear to participate in regulation of caveolar proteins [76]. Caveolae interaction with PKC is more complex, leading to either activation (via ceramide interaction) [77], or inactivation, following endosomal delivery [78]. Caveolae also recruit the phosphatidylinositol-3-kinase (PI3K) through direct binding to Cav-1 [79] and the protein kinase B (PKB). Integration of this signaling pathway by caveolae plays a significant role in managing the cellular physiological stress, and regulating cell survival and death [80].
Phosphodiesterases (PDEs), involved in cyclic nucleotides (cAMP and cGMP) hydrolysis, have a preference for lipid rafts association (Abrahamsen H, 2004). For some isoformes, such as PDE3B, a direct interaction with Cav-1, with a stabilizing effect on PDE3B, has been clearly confirmed by co-immunoprecipitation [81]. Other PDEs (PDE5, PDE4A4) appear to be recruited by caveoale through indirect mechanisms, possibly involving adapter proteins; [82]. Nevertheless, this association influences the establishment of cAMP/cGMP gradients and the downstream events [83].
Electron microscopy data show that caveolae are tightly connected to submembranous actin filaments [84,85], suggesting a function of the cytoskeleton in caveolae-mediated endocytosis. However, the exact role of the actin cytoskeleton is not clearly defined, as its disruption inhibits uptake of the caveolae ligand, alkaline phosphatase, on one hand [86] and promotes clustering of caveolae and internalization of Cav-1-labeled vesicles, on the other hand [6,87]. These observations fit into a model whereby actin would play a dual role in caveolae internalization: one is to keep the organization of caveolae and maintain their immobility at the plasma membrane, and the other to promote vesicle budding and release from the membrane.
Caveolae endocytosis relies heavily on dynamin, a multi-domain GTPase [88,89], which was shown to interact directly with Cav-1 [90]. Ligand binding initially disrupts the local actin cytoskeleton and promotes dynamin II recruitment to the site of internalization [91,92]. Dynamin oligomerization and the GTP-dependent conformational changes result in a structural collar around the neck of caveolae, directly mediating formation of free transport vesicles, following vesicular fission from the plasma membrane. It was shown that the protein regulates the actin tail formation [93,94], possibly through binding to cortactin [95-97] or intersectin, which promotes actin polymerization [98].
Another player in this complex molecular game was recently suggested, following the initial observation that Cav-1 binds to actin cross-linking proteins, filamin A and B, both in vitro and in vivo [99]. The main intracellular function of these proteins is to organize the actin cytoskeleton. The Cav-1 filamin A interaction was further confirmed in different cell types [100,101] and it was implicated in activation of the actin-folding and chaperone protein T-complex protein-1, [100] and inhibition of calpain-mediated cleavage of filamin A [102]. Thus, by providing the missing link between Cav-1 and the actin cytoskeleton, filamin is an important regulator of caveolae-mediated endocytosis and trafficking [103].
It was proposed that following budding, caveolae can fuse with either preformed vesicles, called “caveosome” at the time of their discovery, or early endosome, the latter process being dependent on Rab5 expression [46].
The caveosome was initially described as an immobile structure which did not co-localize with fluid phase markers or ligands of the clathrin-dependent pathway [104]. Moreover, the compartment was characterized by neutral pH and was unable to accumulate a lysosomal dye (lysotracker), reinforcing the notion of an independent organelle, clearly distinct from other endocytic compartments, which delivers its cargo to other cellular locations, such as the ER [104,105]. However, in a recent investigation of Cav-1 trafficking using pH-sensitive fluorophores, the existence of a neutral pH compartment was seriously doubted [106]. Rather, it was suggested that the caveosomes would correspond to modified late endosomes, where Cav-1 accumulates when over-expressed, undergoing ubiquitination and being further targeted to degradation [106]. Conversely, under physiological conditions, caveolae would bud from the plasma membrane transporting their viral cargo to early endosomes and eventually to the ER, in a microtubule-dependent manner [107], following a series of maturation events, which will be detailed below.
Clearly, more work is necessary to have the correct picture of the highly atypical caveolar trafficking, which appears to allow access of its ligands to intracellular destinations that are not reachable from other endocytic pathways. Despite the remaining uncertainties, the continuous development of the field has considerable advanced our knowledge of virus infection of host cells using caveolae endocytosis.
The current view of caveolae internalization and trafficking is depicted in Fig. 3.
Ligand internalization and intracellular trafficking following caveolae-mediated endocytosis
Owing to the vast amount of experimental data characterizing cell infection by the simian virus 40 (SV40), the pathogen has become the “star” of the caveolae-mediated entry pathway, being now extensively used in other studies as a marker of it [104,108]. Other well-characterized viruses using this entry pathway belong to the polyoma virus family, which has gained more interest recently, with the increasing number of human viruses identified. These include the KI polyoma virus, the WU polyoma virus and the Merkel cell polyoma virus [109-111], the latter being associated with an aggressive form of neuroendocrine skin cancer, the Merkel cell carcinoma. These are all non enveloped DNA viruses that replicate in the nucleus.
Viruses that use the same pathway to initiate a productive infection in target cells are listed in Table 1. Amongst them, Echovirus 1 (EV1), Human Hepatitis B virus (HBV) [112], Murine Leukemia Virus (MLV) [113], enteroviruses [114], have been more intensely investigated.
Virus | Reference |
Simian virus 40 | Stang, E., J. Kartenbeck, and R.G. Parton. 1997. Major histocompatibility complex class I molecules mediate association of SV40 with caveolae. Mol Biol Cell. 8:47-57. Pelkmans, L., J. Kartenbeck, and A. Helenius. 2001. Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the ER. Nat Cell Biol. 3:473-83. |
KI polyoma virus | Allander, T., K. Andreasson, S. Gupta, A. Bjerkner, G. Bogdanovic, M.A. Persson, T. Dalianis, T. Ramqvist, and B. Andersson. 2007. Identification of a third human polyomavirus. J Virol. 81:4130-6 |
WU polyoma virus | Gaynor, A.M., M.D. Nissen, D.M. Whiley, I.M. Mackay, S.B. Lambert, G. Wu, D.C. Brennan, G.A. Storch, T.P. Sloots, and D. Wang. 2007. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog. 3:e64 |
Merkel cell polyoma virus | Feng, H., M. Shuda, Y. Chang, and P.S. Moore. 2008. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 319:1096-100 |
Echovirus 1 | Marjomaki, V., V. Pietiainen, H. Matilainen, P. Upla, J. Ivaska, L. Nissinen, H. Reunanen, P. Huttunen, T. Hyypia, and J. Heino. 2002. Internalization of echovirus 1 in caveolae. J Virol. 76:1856-65. Stuart, A.D., H.E. Eustace, T.A. McKee, and T.D. Brown. 2002. A novel cell entry pathway for a DAF-using human enterovirus is dependent on lipid rafts. J Virol. 76:9307-22 |
Human Hepatitis B virus | Macovei, A., C. Radulescu, C. Lazar, S. Petrescu, D. Durantel, R.A. Dwek, N. Zitzmann, and N.B. Nichita. 2010. Hepatitis B virus requires intact caveolin-1 function for productive infection in HepaRG cells. J Virol. 84:243-53. |
Murine Leukemia Virus | Beer, C., D.S. Andersen, A. Rojek, and L. Pedersen. 2005. Caveola-dependent endocytic entry of amphotropic murine leukemia virus. J Virol. 79:10776-87 |
Tiger Frog Virus | Guo, C.J., D. Liu, Y.Y. Wu, X.B. Yang, L.S. Yang, S. Mi, Y.X. Huang, Y.W. Luo, K.T. Jia, Z.Y. Liu, W.J. Chen, S.P. Weng, X.Q. Yu, and J.G. He. 2011. Entry of tiger frog virus (an Iridovirus) into HepG2 cells via a pH-dependent, atypical, caveola-mediated endocytosis pathway. J Virol. 85:6416-26 |
Infectious spleen and kidney necrosis virus | Guo, C.J., Y.Y. Wu, L.S. Yang, X.B. Yang, J. He, S. Mi, K.T. Jia, S.P. Weng, X.Q. Yu, and J.G. He. 2011. Infectious spleen and kidney necrosis virus (a fish iridovirus) enters Mandarin fish fry cells via caveola-dependent endocytosis. J Virol. 86:2621-31. |
Influenza viruses | Nunes-Correia, I., A. Eulalio, S. Nir, and M.C. Pedroso de Lima. 2004. Caveolae as an additional route for influenza virus endocytosis in MDCK cells. Cell Mol Biol Lett. 9:47-60. |
Coronavirus 229E | Nomura, R., A. Kiyota, E. Suzaki, K. Kataoka, Y. Ohe, K. Miyamoto, T. Senda, and T. Fujimoto. 2004. Human coronavirus 229E binds to CD13 in rafts and enters the cell through caveolae. J Virol. 78:8701-8 |
Papillomavirus 31 | Bousarghin, L., A. Touze, P.Y. Sizaret, and P. Coursaget. 2003. Human papillomavirus types 16, 31, and 58 use different endocytosis pathways to enter cells. J Virol. 77:3846-50 |
Respiratory syncytial virus | Brown G, Jeffree CE, McDonald T, Rixon HW, Aitken JD, et al. Analysis of the interaction between respiratory syncytial virus and lipid-rafts in Hep2 cells during infection. Virology 2004;327(2) 175-185. Werling D, Hope JC, Chaplin P, Collins RA, Taylor G, et al. Involvement of caveolae in the uptake of respiratory syncytial virus antigen by dendritic cells. J Leukoc Biol 1999;66(1) 50-58. |
Newcastle disease virus | Cantin, C., J. Holguera, L. Ferreira, E. Villar, and I. Munoz-Barroso. 2007. Newcastle disease virus may enter cells by caveolae-mediated endocytosis. J Gen Virol. 88:559-69 |
Ebola virus | Empig, C.J., and M.A. Goldsmith. 2002. Association of the caveola vesicular system with cellular entry by filoviruses. J Virol. 76:5266-70. |
BK polyoma virus | Eash, S., W. Querbes, and W.J. Atwood. 2004. Infection of vero cells by BK virus is dependent on caveolae. J Virol. 78:11583-90. |
Marburg virus | Empig, C.J., and M.A. Goldsmith. 2002. Association of the caveola vesicular system with cellular entry by filoviruses. J Virol. 76:5266-70. |
Viruses that use caveolae-mediated endocytosis
After binding to the host cell, the virus particles are able to cluster the receptor molecules such as certain integrins (a2h1 in the case of EV1) [118] or glycosphingolipids (GM1 or GD1a in the case of SV40 or polyoma viruses), within the lipid rafts [119]. Accumulation of viral particles in caveolae induces a cascade of tyrosine phosphorylation reactions followed by rearrangements of the cortical actin cytoskeleton, as described above [91].
Several models addressing virus capturing into the plasma membrane invaginations have been proposed, the most recent relying on the observation that Cav-1 polymer remains intact once formed in the Golgi complex, during transport to the plasma membrane. According to this model, caveolae result from the fusion of a pre-existing caveolar vesicle with the plasma membrane [46]. As a consequence of virus binding to an increasing number of sphingolipids and/or integrins, the affinity of the pathogen for caveolar domains increases, facilitating entrapment in these areas. Another possibility is that virus particles bind and release the plasma membrane gangliosides in a transient manner, thus screening the whole cell surface. When reaching a caveolar region where multiple gangliosides interactions can occur simultaneously, binding becomes permanent and the virus particles are sequestered [104].
The intracellular trafficking of caveolae cargos has been recently re-evaluated using SV40 as a model and a series of complementary, state-of-the art techniques, including live-cells and electron microscopy, video recordings, pharmacological inhibitors and inhibition of expression of trafficking regulators [120]. It was shown that productive SV40 infection depends on the virus transport through a series of classical endocytic vesicles. Initially, the virus is found in Rab5-, EEA1-positive early endosomes and subsequently becomes associated with Rab7-positive domains, during endosome maturation. As this process proceeds, SV40 co-localizes with LAMP1-, Rab9-, and Rab7-positive late endosomes resembling multivesicular bodies and possibly endolysosomes. Endosome maturation also involves acidification of the compartments, as a consequence of vacuolar ATPase (v-ATPase) recruitment and activity. At this stage, acidification is required for SV40 subsequent transport steps and the initiation of productive infection. Interestingly, BK and JC viruses were also shown to enter the endosomes and depend on acidification for infection [121-123]. In the case of the mouse polyoma virus, the recycling, as well as late endosomes have been involved in infection [124,125].
From the late compartments of the endocytic pathway, SV40 appears to be directly transported to the ER, although an indirect ER targeting, via the Golgi complex, has not been completely excluded. Similarly, other polyoma viruses are transported to the ER lumen, before reaching the nucleus [121,125].
However, there are some notable exceptions of virus trafficking diverting from this pathway, despite being internalized through caveolae. Thus, cellular penetration of the EV1, a positive-stranded RNA human pathogen, depends on caveolins, dynamin II, and signaling events but does not require actin filaments or microtubules. The virus uptake was much faster than that of SV40 and was followed by rapid co-localization with Cav-1. Beyond this step, the virus failed to enter the Golgi complex, the ER, or the lysosomes, as none of the markers used to label these organelles co-localized with viral proteins. This observation raised the hypothesis that the virus particles remain sequestered in the Cav-1 positive endocytic vesicles until replication is initiated, further using them for cytoplasmic penetration and uncoating.
The lack of transport to the ER or Golgi was also confirmed by the absence of any inhibition of infection in the presence of nocodazole. Although more experimental data is needed to substantiate it, it is tempting to speculate that the different sorting pathway of the two viruses is related to their replication mechanism; thus, a DNA virus such as SV40 needs the nucleus for replication, which might be more accessible through the ER, whereas for a positive-stranded RNA virus the release of the genome into the cytoplasm is sufficient to initiate replication.
Either way, the precise molecular details characterizing this segment of the trafficking pathway are still to be defined, but understanding the factors involved in these unusual trafficking pathways is crucially important as other, yet uninvestigated viruses, may well use them when accessing the host cell via caveolae.
Importantly, there is accumulating evidence suggesting that several viruses take advantage of cross talk between endocytosis routes. For instance, JCV, bovine papillomavirus type 1 and human papillomavirus type 16 have been shown to access cells using the clathrin-dependent endocytosis, but intriguingly, they require Cav-1-mediated trafficking to initiate productive infection [123,126,127]. The internalized virions were trafficked to early endosomes before being transported to the caveolar pathway. From the Cav-1-positive vesicles, the viral cargo is further moved to the ER in a COPI-mediated, BFA-sensitive manner [127].
The newly described trafficking routes taken by these viruses may have an explanation in their absolute requirement to reach the ER compartment, a target that is not on the clathrin-mediated route.
The intriguing question as to why these viruses travel to the lumen of the ER, instead of using the endosomes for genome release, have received several interesting answers lately. One possibility is that the pathogens take advantage of the ER machinery of folding enzymes and chaperones, for uncoating and membrane penetration, being activated by lumenal thiol oxidoreductases before release into the cytosol/nucleoplasm [128].
Very recently, BiP and the ER-membrane protein BAP31 (both involved in ERAD) were shown to be essential factors for SV40 infection; thus incoming SV40 particles are structurally remodeled leading to exposure of the amino-terminal sequence of the minor viral protein VP2. These hydrophobic sequences anchor the virus to the ER membranes helping the particles release into the cytosol [129].
The molecular details of virus entry have been investigated through a variety of techniques, by perturbing endocytotic internalization with various inhibitors or interfering with the expression or function of key regulator proteins, using siRNA or dominant-negative mutants of the proteins, or by using transgenic animals. Because no single method to assess caveolae is perfect, the use of complementary techniques is crucial for such a task. These can employ cell fractionation, immunoprecipitation, protein and organelle labeling, immunofluorescence microscopy. Since caveolae are best characterized by their microscopic appearance, studies employing alteration of the intracellular level of caveolins, cholesterol, or different molecules enriched, but not exclusively present in caveolae, should ideally follow the impact of such changes to other internalization and trafficking pathways, by electron microscopy
A pharmacologic approach involves the treatment of cells with agents that deplete membranes of cholesterol, or inhibit various structural or signaling molecules involved in controlling the pathway. Having the advantage of being readily available and convenient to use, chemical inhibitors have been extensively employed to characterize different endocytic pathway; however, stringent controls must be included and results should be interpreted with care, because of the pleiotropic effects these drugs may have within the treated cell.
The usefulness as well as the pitfalls associated with the use of these agents will be detailed below.
Methyl-β-cyclodextrin (MβCD) – Cyclodextrins are cyclic oligomers of glucose that have the property to bind and extract lipophiles, including cholesterol, from their hydrophobic core [130]. Based on the tight dependency of caveolae stability and function on the amount of cholesterol present in the lipid rafts, the compound has been widely used to define the caveolar-mediated entry of many pathogens [6,117,131-135].
A major issue of MβCD treatment is its cellular toxicity, which was initially associated with longer incubation times (for example, the cell viability decreases form 90% during a 30 minutes incubation, to as low as 64%, if the drug is used for 12 h) [117]. A thorough study performed on multiple cell lines showed, however, that MβCD significantly decreased cellular viability, even after short treatment and at concentrations routinely used to inhibit endocytosis, a phenomenon which was cell line dependent [136]. Moreover, a low level of plasma membrane cholesterol was shown to interfere with other endocytic pathways, such as the clathrin-mediated endocytosis [137,138], or even with cholesterol independent endocytosis [139], demonstrating a rather poor specificity of the drug in inhibiting a distinct pathway.
Statins – are a group of drugs that lower the intracellular cholesterol level by competitively inhibiting the 3 hydroxy 3 methylglutaryl coenzyme A reductase involved in its biosynthesis. As a consequence, efficient depletion of membrane cholesterol and decreased formation of caveolae are observed [140]. Despite showing good toxicity profiles, statins also exert pleiotropic effects through a variety of mechanisms, which appear to be unrelated to their cholesterol-lowering activity. Thus, several immunosuppressive effects have been involved; amongst them well-documented are the prevention of activation of the transcription factor NF-kappaB or up-regulation of the pro-inflammatory cytokine production [141,142].
Filipin - is a macrolide pentene polyene with antibiotic properties relying on sterol binding with high affinity [143]. Filipin III has been employed to block caveolae entry since it complexes with membrane cholesterol, thus interfering with cholesterol-sensitive processes [144]. Treatment with filipin dispersed the receptors found in caveolae and promoted disassembly of these structures [145]. Similar to MβCD, filipin treatment is toxic and at least for certain cell lines, its inhibitory effect on endocytosis was exclusively due to cytotoxicity [146]. However, a narrow window of specific inhibitory function can be identified in most cell lines.
Genistein – inhibits several tyrosine kinases in mammalian cells and thus, caveolae internalization [86,147]. Genistein has been however shown to suppress the entry of several types of viruses that use different endocytic ways to gain access to the replication sites: SV40 [91], adenoviruses [148], human herpesvirus 8 (HHV-8) [149], HBV [112]. However, the general need of tyrosine kinases-mediated signaling of diverse families of viruses, both at early entry steps, or later in infection, makes it difficult to clearly ascertain the endocytic route used, only by using genistein.
U18666A - is an amphiphilic amine that arrests cholesterol transport and suppresses sterol biosynthesis. Treatment of cells with this inhibitor was shown to induce cholesterol accumulation in late endosomes/lysosomes and deplete cholesterol from the Golgi complex [150]. Interestingly, the mobility of Cav-1 significantly increased in the Golgi complex of U18666A-treated cells.
Phorbol 12-myristate 13-acetate (PMA) – is an activator of classical 2,3-diacylglycerol (DAG)-dependent protein kinase isoforms, owing this property to their high affinity for the DAG binding site. Interestingly, PMA treatment results in constitutive phosphorylation of caveolin [151] with significant inhibitory effects on caveola invagination from the intracellular face of the plasma membrane [86,152,153].
PMA has been shown to specifically inhibit the caveolae-mediated entry of Ebola and Marburg viruses, two negative-stranded RNA pathogens, members of the Filoviridae family [154]. PMA has a low citotoxicity even when used for longer incubation times (82% of the cell are still viable following incubation for 24 h, at concentrations required to inhibit caveolae endocytosis [117].
It is important to note that PMA can stimulate endocytosis of other ligands and interferes with the endocytic trafficking by stimulating a factor required for endosome fusion after Rab5 activation [155]. PMA treatment may have opposite effects on internalization of certain ligands (such as FITC-dextran) in polarized cells, increasing for instance, its basolateral, but not apical uptake.
Okadaic acid – is an inhibitor of phosphatases 1 and 2A, which are important in caveolae function [156]. Treatment with okadaic acid has been shown to promote removal of caveolar structures from the cell surface and stimulate endocytosis via these structures [6,86]. Importantly, the drug also inhibits the clathrin-mediated endocytosis [86] making the time of addition to the cells an important experimental factor in drawing the right conclusions on viral entry. Thus, pretreatment of cells with okadaic acid interferes with both, caveolae and clathrin pathways, while addition after virus binding to the target cells enhances infection, as it was shown for MLV [113].
Cytoskeleton inhibitors - the actin cytoskeleton localized near the plasma membrane appear to be a critical regulator of caveolae endocytosis [157].
Depolymerization of microtubules with colchicine or disruption of actin microfilaments with cytochalasin D resulted in a significant reduction of the amount of Cav-3 in plasma membrane fractions isolated from cardiac myocytes. Treatment with either drug also led to the exclusion of Cav-1 and -2 from similar fractions and the decrease of tyrosine-phosphorylated Cav-1 [101].
Other drugs interfering with actin polymerization are latrunculin A (actin monomer-sequestering drug) and jasplakinolide (an actin polymer-stabilizing compound), both were shown to reduced SV40 internalization by more than 60% [91]. Since function of many cellular processes such as trafficking and organelle movement are regulated by microtubules and the actin cytoskeleton, the biochemical assays should be combined with microscopy analysis to clearly define the role of the cytoskeleton in viral infection mediated by caveolae. Also, it is important to keep in mind that viruses induce cytoskeletal reorganization and reconfiguration to initiate, maintain and spread the infection. Therefore, the impact of the cytoskeleton perturbation on the outcome of infection highly depends on the stage of the viral life cycle the drug is acting upon [158].
As threshold levels of Cav-1 regulate caveolae formation [155,159,160], modulating the expression and/or function of this protein is one the most reliable approach to investigate caveolae entry. Cav-1 down-regulation using anti-sense, small interfering (si) or short hairpin (sh) RNA results in a significant decrease in the number of caveolae. For instance, the siRNA-mediated knockdown of Cav-1 expression was sufficient to inhibit albumin uptake in endothelial cells; however, intriguingly enough, the caveolae localization of signaling proteins, including eNOS, Rac, tyrosine kinase Src and insulin receptor was not altered. Using this technique, several viruses were shown to depend on caveolae for productive infection such as the Avian Reovirus [161], BK polyomavirus [133].
Cavin proteins are also important targets to study caveolae-mediated entry, since absence of cavin-1 results in lower expression level of caveolins and eventually, the loss of caveole. Down-regulation of cavin-1, using specific shRNA, increases mobility of caveolin-1, which is released from the cell surface and rapidly internalized and degraded [39]. Interfering with cavin-2 expression is also a valuable tool when assessing the role of caveolae in viral infection, since its down-regulation induces loss of cavin-1 and caveolin expression and therefore, it limits caveolae formation [43]. Similarly, suppression of cavin-3 biosynthesis uncouples caveolae from the intracellular transport machinery [44].
Caveolae budding from the plasma membrane and subsequent internalization strictly depends on dynamin II [89], thus silencing its expression is also often used in combination with caveolin inhibition.
An elegant alternative to silencing the expression of the proteins involved in caveolae architecture and function is over-expression of their mutant counterparts, which compete with the wild-type proteins for the same function. An important advantage of this technique is that, at any time during the experiment, the wild-type protein is still expressed ensuring the functioning of the pathway at a basal level and reducing toxicity. This approach was used to show the dependence of HBV internalization on functional Cav-1 and dynamin II (Fig. 4) [112].
Hepatitis B Virus (HBV) infection of permissive HepaRG cells stably expressing dynamin II (A and B) and caveolin-1 (C and D) proteins with either wild-type (A and C) or dominant-negative (B and D) functions. HBV infection is evidenced by immunofluorescence microscopy using antibodies against the envelope proteins (in red). The dominant-negative dynamin II contains the K44A mutation which abolishes the GTP-ase activity (B). The dominant negative caveolin-1 contains a deletion of the 1-81 amino acid domain, at the N-terminal end (D). Expression of the wild-type and dominant-negative variants is evidenced through the Green Fluorescent Protein (GFP), which is either co-expressed from bicistronic GFP-caveolin DNA constructs (C and D) or expressed in fusion with dynamin II (A and B).
Cav -1 dominant negative proteins – disturb the formation of Cav-1-positive lipid rafts and cause the redistribution of endogenous caveolin to detergent soluble membrane fractions [162]. These are N-terminally truncated or N-terminally GFP-tagged caveolin constructs, which strongly inhibit SV40 entry [104,163] and were used to characterize the internalization pathway of many other viruses [134,164,165].
Other caveolin constructs containing the point mutations, Y14F and P132L were recently demonstrated to have dominant-negative activity [166]. Expression of the Cav-1 variant containing the P110A mutation was shown to determine a profound inhibition of caveolae endocytosis, cellular lipid accumulation and lipid droplet biogenesis. Moreover, this is a potent mutant to take into account when investigating the caveolae pathway, as it significantly reduces the Cav-1 localization into detergent-resistant domains of the plasma membrane and caveolae formation [22].
An interesting caveolin mutant is cavDGV, a deleted Cav-3 form, which lacks the first 53 residues of the protein, but contains an intact scaffolding domain. The truncated protein acts as a dominant negative inhibitory mutant, causing the intracellular accumulation of free cholesterol in late endosomes, a reduction of surface cholesterol, efflux and synthesis [30].
Dynamin -II dominant negative proteins - as important regulators of clathrin, caveolae and other endocytic pathaways [88,167], dynamin II inhibition is often used in combination with modulation of other, more specific proteins involved in caveolae function (listed above). By far, the most used mutant dynamin is the K44A variant, defective in GTP hydrolysis, which was clearly shown to inhibit release of caveolae from plasma membranes in an in vitro assay [89].
A long term expression of a dominant negative protein may be toxic for the cells, determining changes of morphology. Also it is important to keep in mind that down-regulation of a certain pathway may promote up-regulation of other, compensatory entry mechanisms, if cells express dominant negative proteins for a long time. A solution to overcome these potential problems is the use controlled/inducible expression systems (such as the TetOn/Tet Off switch).
Generation of knockout (KO) mice – is a powerful approach for the study of caveolae in vivo. Caveolin-KO mice (Cav-1, -2, -3 and Cav-1/-3 double KO mice have already been generated and characterized. They displayed different phenotypes, but interestingly, were viable and fertile [168]. While Cav-2 KO mice retain normal expression of caveolae, Cav-1 KO mice are devoid of Cav-2 expression and caveolae in certain cell lines, and develop many cardiac and pulmonary diseases. More work is needed to understand whether or not these pathologies are directly correlated with the loss of expression of caveolins and caveolae and a good approach toward this aim would be to investigate each individual caveolins and the development of the corresponding phenotypes over a longer period of time.
The new experimental evidence emerged with the advance of the techniques used to investigate ligand internalization and intracellular trafficking, have consolidated the notion that endocytosis through caveolae is a true alternative to the clathrin-mediated pathway. By employing this route for entry into the target cell, viruses could benefit from the enormous advantage of being targeted directly to specific organelles that are essential for their replication; moreover, degradative compartments can be bypassed, which could enhance the efficiency of productive infection. Nevertheless, despite the tremendous development of the field in the last decade, many conceptual and mechanistic aspects are still to be clarified or reevaluated. Certainly, important issues regarding: a) the regulation of the crosstalk between different internalization pathways; b) the similarities between caveolae and other clathrin-independent entry routes; c) the exact mechanism of ligand sorting; d) the properties of the compartment(s) where it occurs; d) the preferential targeting of caveolae ligands to other intracellular compartments than the ER; are already under the scrutiny of many cell biologists and will find an answer in the near future.
This work was supported by the Romanian Academy project 3 of the Institute of Biochemistry, the IDEI grant ID-84 and the POSDRU/89/1.5/S/60746 grant.
\nSunday:\n
\n\n“Well, this is a disaster” said Jojo, the 19 year old apprentice to his mentor, Raj. They were pulling in the fishing nets near the usually beautiful seaside village of Tucci, now dull and grey and partly under water. The nets were heavy with debris from the churning sea. Raj grunted a mirthless laugh. “No. This is just a hard day of work. Tomorrow will be the disaster.”\n
\n\nThen the old man added, “unless it stops raining, the bridge stays above water, the power line’s fixed, and we have enough sandbags for everyone to keep their houses from washing away.”\n
\n\nIt wasn’t totally exaggerated. The rain had been the worst in decades. Many homes in the low-lying village were already flooded. Those that were a little higher than the rest were already overcrowded with friends and relatives who’s houses were in a foot or two of water. And the bridge, the only land access to the village, was visible only as rail posts marking a dotted line through the sea between the village and the green foothills.\n
\nDisasters require both a potentially harmful event and a component of vulnerability [1]. If an event overwhelms local response capacity, whether by insufficient material resources or by inadequate social systems or structure, outside help is needed. This is a disaster. Thus the magnitude of an event that causes a disaster will vary by organizational capacity. Many of the natural events described elsewhere in this textbook (earthquakes, tsunamis, etc.) create disasters. An earthquake in a remote, uninhabited area might be called a natural disaster, but it is not truly a disaster if people are not severely impacted. Disasters occur at the interface of nature and civilization [2].
\nEmergency management is usually described in terms of planning, mitigation, response, and recovery. As we move along the spectrum of severity, from emergency to disaster, the same principles apply, with an emphasis on adaptability and collaboration. Specific to hospital disaster management, contextual issues such as triage, decontamination, and patient care are built upon a general and pervasive approach to disaster readiness. In resource-poor environments, the challenge is magnified as the impacts of natural disasters are greater, and the ability to respond and recover less. Education and training will be most effective if methods match the objectives. With all the uncertainty therein, training for disaster must include establishing relationships between organizations and allowing for flexibility in the face of events that can be predicted but never fully anticipated.
\n\nNot every windstorm, earth-tremor, or rush of water is a catastrophe…So long as the ship rides out the storm, so long as the city resists the earth-shocks, so long as the levees hold, there is no disaster. It is the collapse of the cultural protections that constitutes the disaster proper. ([3], p. 211)
\nFrom crisis to catastrophe, emergency to disaster, there is a spectrum of events that may threaten people and organizations. Not just the event, but the characteristics of the affected population define disaster. Risk and resilience are opposing forces that must be considered with disaster management.
\nDisasters and emergencies differ in quality and magnitude but are often and inaccurately used synonymously. “Disasters are not just ‘big emergencies’” ([4], p. 293). Emergencies are time-sensitive, potentially harmful events that put life and well-being at risk. Resources are available at the local level to prevent, mitigate, or minimize the harm, and a single responding organization is responsible [5, 6]. Local resources, as a variable in the equation, can affect what constitutes an emergency, and what goes beyond. An event of the same magnitude, in locations or situations with different capabilities and resources, may be managed within the organization (emergency) or need outside help (disaster). An example in a health care context might be a car crash involving one or two seriously injured people requiring prompt medical investigations and treatment, assuming the facility is equipped to deal with such an event.
\nDisasters are sometimes considered “hypercomplex emergencies” or “major emergencies” involving multiple people at risk of harm, multiple jurisdictions responding, and resources that are not immediately available locally ([5], p. 8; [7]). Coordination between agencies, many of whom have no prior relationships, becomes a challenge [5]. Plans for resource utilization must change when those resources are overwhelmed [8]. Preparations, planning, and training at the local level, within the abilities and available resources of a single agency, do little to prepare for disaster.
\nCrisis is a more generic description. A crisis is a “critical event or point of decision which, if not handled in an appropriate and timely manner (or if not handled at all), may turn into a disaster or catastrophe” [9]. We use the word crisis, then, nonspecifically, as an emergency event that has potential to evolve; emergency as time-sensitive event with potential harm; and disaster as an event larger and more harmful than an emergency, with many people at risk, and where management requires resources outside of the responding organization or department.
\nThe word catastrophe, more severe than a disaster, completes the spectrum [5]. Many variations of the definition exist, but all suggest a magnitude of harm and inadequacy of response capabilities beyond what would be considered disaster [1] (Figure 1).
\nSpectrum of crises.
\nMonday:\n
\n\nThe school gymnasium was packed with wet bodies. A kind of bored panic filled the air. After all, what more could they do but wait for the worst the storm threw at them and then pick up the pieces when it blew itself out?\n
\n\n“Thanks for being here, I know it’s been hard for everyone. And there’s still lots of work to do to clean up after yesterday’s catastrophe” said Ros, the town’s mayor, referring to the wind that had blown off parts of a few roofs, and torn off a main limb of the biggest cedar in town, crushing a corner of J. Z.’s corner store.\n
\n\nIan spoke up, “we can’t worry about yesterday’s fiasco. We gotta think about the crisis we’re gonna be in tomorrow if the power’s not back. Then it will be a real emergency!”\n
\nOur first thought when we think of a hazard will often be an event—earthquake, flood, or fire. But only thinking in terms of characteristics of the event — windspeed, the size of tsunami wave, the magnitude of an earthquake, etc. — is to neglect a critical component. To become relevant to disaster management, nature must collide with human activity [10]. Hazards can be quantified simplistically as the probability of an event occurring, causing harm [11]. And there is no separating hazard from risk and resilience [12]. So the hazard is the oncoming storm and the potential for harm to the village it approaches (Figure 2).
\nHazard, risk, and vulnerability illustrated.
Risk is connected choice and probability [11]. Choice by the decisions we make. We build in flood zones, we develop seaside resorts, and we ignore all but the most active fault lines when looking at real estate. We buy fire insurance or not. We upgrade the old building to comply with seismic billing codes or not. We run disaster drills or not.
\nProbability is the other face of risk. Risk is an abstract concept, forever in the future, always uncertain.
\n\nRisk is a complex and, at the same time, curious concept. It represents something unreal, related to random chance and possibility, with something that still has not happened. It is imaginary, difficult to grasp and can never exist in the present, only in the future. ([11], p. 47).
\nVulnerability will create harm from the hazard. A predisposition to be harmed, intrinsic to the organization or organism is its vulnerability [11]. Poverty, age, gender, racial identification, geography, and many social, economic, and political factors are all parts. The vulnerability can accumulate until recovery is complete [12].
\nThe ability to adapt is central to an organization’s ability to resist and rebound from disaster [13]. Resilience is woven through all aspects of disaster management—from preparation through mitigation, response, and recovery [12, 14]. Resilience alters the disaster threshold. The more resilient a system, the more harm can be absorbed before the system is overcome [13]. More resilience means less susceptibility to disaster.
\nPreparation and planning, mitigation, response, and recovery are the basic principles of emergency management. [15]. It is called emergency management, but should really be called disaster management. Necessarily limited to first responders, the title emergency management gives an illusion of control that makes it both “a misnomer and an oxymoron” ([16], p. 5). Regardless of the size of the event’s magnitude, management includes all those efforts before, during, and after to minimize physical, social, and economic damages. Both planned and improvised actions should be included [16].
\nPreparation occurs before the disaster and includes preventative measures [17]. Disaster preparation, then, can also raise the disaster threshold if the disaster is thus avoided. At least, effects are minimized through planned measures. In our example settlement, prevention of a storm may not have been possible, but prevention of harm was through city planning, weather warning systems, and flood-resistant housing and infrastructure. Food and fuel stores could only be built up before the flooding.
\nMitigation also includes a component of prevention but is closer to the event than planning. Anything to minimize harms that are not prevented could be considered mitigation. This can be through the reduction of the effects of the hazard, vulnerability of those affected in harm’s way. In Tucci, they could build up walls of sandbags to protect their homes. They could moor their boats securely. They could evacuate, or they may have been able to if they had made adequate plans and preparations. Clearly, all these components are intricately connected.
\nThe response may be what we typically think of when we envision a disaster. This is the responders—firefighters, paramedics, police, military, municipal forces, and volunteers—dousing the flames, treating the wounded, rescuing the stranded, and searching for victims.
\nRecovery entails returning, rebuilding, restoring. It is regaining a sense of normalcy, if not returning exactly to the pre-disaster state. Tucci will never be the same. The coastline will be altered. Attitudes may change forever. Lives may be lost. Houses will have to be repaired or rebuilt. Few residents will rebuild their houses exactly as they were before the storm. Recovery should focus on learning from the disaster and improving those liabilities made apparent by the wind and waves. This applies not only to the repairs to physical structures but to emotional health and economic stability.
\nPreparation, planning, mitigation, and recovery are all important management principles for crises of any magnitude. As complexity increases towards disasters, we focus on the response at the front lines. This is because this phase sees the most variation and inconsistency [18]. On the front and back ends, in planning and recovery, the skies are clear. There is time to think. Not so in response. The response is the result of planning and facilitates recovery. To be prepared for an emergency should be routine. Preparedness for a disaster does not automatically follow.
\nBy definition, local resources are sufficient to respond to an emergency. When these resources are overwhelmed, either by supply (nature of the event) or demand (response capabilities), the situation is a disaster ([19], Ch1). Outside help is needed. Intra-agency communication and coordination are required, usually without the benefit of established relationships and protocols. As complexity increases, more emphasis must be placed on flexibility and coordination between teams.
\nWhen the crisis moves from emergency to disaster, flexibility becomes increasingly important in planning, preparation, and response. In disaster planning, people should be prepared not to respond to specific circumstances, but to be able to adapt to the unanticipated. Training for disaster, then, ideally trains flexibility, communication, and the ability to work across organizational boundaries [20, 21]. Some structure is necessary to create the ability to adapt the structure to the situation. Brandrud’s [22] description of their successful system is excellent: “…[the] written preparedness and response plan was structured just enough to remind the health professional of their role and task, yet flexible enough to enable them to release their creativity to improvise solutions” (p. 811).
\n\nTuesday:\n
\n\n“Anyone got a charger?” The question was becoming a little repetitive. At first, the people that asked this were given sympathetic smiles and apologies. Now, if anyone dared ask, it was only met with grunts and grumbles. Part of ‘the plan’ involved keeping in touch with people by cell phone. There were only a handful of people who still had any battery life left on their phones, and no one had reception.\n
\n\nAll but a few of the townspeople were crammed into the school for the night. It was loud. Fifty quiet conversations, a few crying babies, the howling wind, and the incessant rain added up. And the air was thick with sweat and sewer (the toilets had all overflowed). A dozen people were standing in a circle in the middle of the gym, sorting through a pile of walky-talkies.\n
\n\nThe side door flew open with the outside coming inside, and a group of bodies in rain gear, dripping from head to toe. It was a crew from Uah, an even smaller town down the coast. They had got their whole village out last week and came here on a few all-terrain vehicles to lend a hand. Apparently, there was a team coming from the city to take everyone out. If the rain ever stopped…\n
\nCrisis standards of care are a reflection of the flexibility needed to respond when resources are lacking for the situation’s need [23]. The same standards employed in day to day operations, or even in an emergency (when an organization has the capability to manage it), will consume valuable assets (time, supplies, personnel, cognition) when the system is asked to perform beyond capacity. Awareness of the difference between disaster standards and the standards applied to usual operations will facilitate effective disaster planning and response (Figure 3).
\nPrinciples in management when emergency becomes disaster.
Natural hazards alone do not result in disaster, but rather the vulnerability of the populations of countries impacted [24]. The complexity and chaos of disasters make management challenging in many ways. Even the best plans will be unable to address each difficulty encountered in a disaster [25].
\nResources are defined as the organization’s fundamental financial, physical, individual and organizational capital attributes [26, 27]. In resource-poor environments, the challenge is greatly magnified. The environments most often impacted by a lack of resources are those of a lower socioeconomic status. Poverty and disasters are strongly associated [19]. Developing countries are repeatedly subject to disasters resulting in reduced or negative development [19].
\n\nWednesday:\n
\n\nThere was a lot of talk about fixing houses, repairing roads, upgrading the bridge. People didn’t want to talk about the deeper issues. Most would never be able to afford anything more than patching the holes. Someone brought up the idea of building up on the hillside where the waves couldn’t reach. But that was so utterly inconceivable. How would they build a new town if they couldn’t even build new houses? Some would have to leave. Hard to live in a fishing village if your boat got washed away and you got no other way to make a living.\n
\nMore impoverished communities are more vulnerable to natural disasters due to a mixture of social, political, cultural and economic factors [28]. Residents within these poorer communities tend to live in environments more prone to hazards such as rural areas with limited access to resources. The reduction in resources results in a more extended reconstruction period and can further delay developmental lag [19]. For example, in 2001, both El Salvador and the United States were hit by earthquakes, resulting in $2 billion in damages [19]. Although the same monetary value, the impact on each country’s economy varied drastically. This $2 billion in damages had minimal impact on the U. S. economy, whereas, in El Salvador it resulted in 15% of the countries GDP [19]. These financial setbacks to developing countries can create a cyclical impact of further delayed development lag and economic growth.
\nBeyond the economic impacts, developing countries also face higher casualty rates. Over 96% of disaster-related deaths in recent years have taken place in developing countries [29]. Disasters may bring about harm to poor, developing countries in many ways beyond death, injury and destruction [19]. Some of the numerous examples include an increase in crime due to poverty and desperation, damage to schools leading to longterm impacts on education and further employment, destruction to hospitals which increase the vulnerability of disease, and the impact to vital infrastructure such as roads, bridges and airports, which may take years to rebuild and further impact resource access [19].
\nFor meaningful disaster preparedness, the focus must be on improving availability and access to resources. This improvement should be a continual improvement effort to implement these resources to the area permanently. This implementation will help to support improvement to the quality of life to those impacted and decrease the inequity of resources and support when faced by disasters. Improved governance, combined approaches on all government levels, empowering communities, assessing vulnerability, ensuring access to quality information, and increasing the resilience of livelihood and infrastructure within these environments will reduce poverty and increase the quality of life [29].
\nClimate change and sustainable development both also influence the frequency and severity of disasters, particularly in resource-poor countries. Climate change, and irresponsible use of natural resources such as deforestation, make the environment more susceptible to hazards and disaster [30]. Disasters related to natural hazards, such as floods, storms and earthquakes, have significantly risen over recent years [30]. Such an increase in disasters is likely to further the frequency and severity of the impacts on the resource poor countries. Sustainable development is crucial to help reduce this burden.
\nDisasters are easily forgotten. The unfortunate truth is that the longer the distance in time and space from disasters, the less influence they have on preparedness and planning [31]. This is especially relevant to hospitals because of a number of other interactions. Perception of disaster preparedness is often quite different between planners and frontline workers, the latter decidedly less optimistic about the facility’s state of readiness [31]. And the pressures and problems of everyday operations can easily push aside concerns for an unforeseeable event. The attitude of disaster preparedness needs to pervade all aspects of the organization in the face of so many unseen but real hazards [32].
\nSpecific hospital management principles include, but are definitely not limited to, vulnerability analysis, communications, triage, surge capacity, psychosocial effects, and medicolegal issues [31]. Hospitals must consider the disaster and its effects not only on a massive influx of patients but on existing patients, as well as health care workers in and out of hospital [33]. Patient care may be complicated and compromised by issues of security, chemical or biological exposure, and capacity for definitive care [29, 34].
\nTypically, an ‘all-hazards’ approach is employed as a basis of preparation for crises of any nature. More advanced preparedness will be tailored to specific hazards [30, 35]. We cannot plan for every possibility, especially not every extreme and infrequent event covered in this textbook. Plans must be broad enough to allow adaptation as needed [22]. If plans are too narrowly focused the preparation may be ineffective. Flexibility is key.
\n\nThursday:\n
\n\nGood thing we made it out when we did, although, an hour earlier would have been ideal. The leak that had been dripping constantly in the west corner of the gym turned into a stream, then a river, then the storm outside as the tiles gave way. The sick and the injured were evacuated first, down to Mayor Ros. Raj and me came on the last load. The hospital at Alec wasn’t used to a hundred people at all, much less all within a couple hours. It was hard to tell who was who - doctors, nurses, housekeepers — might have been the president of the hospital — who were finding blankets, mopping up the incessant streams of muddy water, handing out bottles of clean water, looking at cuts and bruises and sore throats.\n
\nHospital disaster planning has important ramifications for capacity-building. That is, the threshold for disaster, an event that overwhelms local abilities, is intricately connected to capacity. “If a disaster is defined as an event that outstrips the organization’s ability to deliver healthcare, preparedness is a method of “vaccination,” raising the threshold not only in disaster periods but also in normal day-to-day function” ([31], p. xi). Disaster preparation is capacity-building.
\nDisaster preparedness is also about building networks. Again it comes back to the definition of disaster that requires help outside the immediately-affected organization. Coordination and communication between agencies are important in the success or deficiency of disaster response [23, 31, 36]. Establishing and enhancing relationships between organizations cannot be done in the moment of need. This should be a high priority for any organization in this time of global connectedness. Whether for a hospital, a nation, or a single-family, Alexander’s [32] words for current and future emergency managers applies here: “Nothing can substitute for personal relationships” ([32, 37], p. 10).
\nThe worst possible outcome of preparedness activities is to engender complacency. A “paper plan syndrome” refers to passively placing confidence in a document detailing a facility’s readiness ([35], p. 3). Written plans do not obviate problems [33, 38]. To be effective, training needs to be continuous, team-centred, and at least as far as disasters go, focused on the non-technical aspects of working in teams [22]. They have to use existing resources and include the possibility of the loss of these resources. The loss of electrical power is particularly important to consider. Our increasing reliance on technology is a modern blessing in times of peace and a serious susceptibility when things are bad [12].
\nPlans are only ‘fantasy documents’ if they have no real implementation through training ([39], p. 2). Exercises also may only be preparation in fantasy if not implemented conscientiously. When planning disaster training exercises, we should consider our purposes. Is the intent to expose participants to the disaster response plan or their roles in the organizational structure? Is it to test the implantation of the response plan, to expose its weaknesses and oversights? This is often the objective, intended or not ([40], p. 277). Evaluation and improvement of disaster plans may be a useful objective if that is the need [31]. But simply observing shortcomings does not itself remedy them. Lessons “identified” does not mean lessons “learned” ([40], p. 280) Is the intent to learn from or improve collaboration with other agencies? Is the intent to improve decision-making and specific skills? These are all valid objectives and need to be determined to meet the organization’s needs, lest any coincidental success be wrongly attributed to ineffective plans [41]. Disaster training should focus on adaptability. “Exercises and training on how to be creative and imaginative under such circumstances would be more useful than detailed disaster plans” ([25], p. 376).
\n\nA month later…\n
\n\n“We just need to stick to the plan next time,” Jan said, the last part sounding like a question. The storm was a memory like a bad dream. The town meeting, those who were left, was about getting ready for the next one.\n
\n\nThe plan was new to almost everyone. Ros dug up some dusty old binder a few days ago. Too bad it made it, untouched, through the storm. It was full of detailed instructions about houses reporting to block leaders, block leaders reporting to councillors, councillors to the mayor, the mayor to the assistance team that was supposed to come from Alec, the capital city. Only thing was, households were all rearranged, trying to find somewhere dry to sleep. The block leaders didn’t even know who they were, the mayor didn’t have any councillors, and the team, well, not sure there ever was one.\n
\nDisaster exercises may not accomplish what is intended during their design [20]. Excessive complexity, targeting the wrong audience, and unforeseen social psychological effects are some of the problems that can impair the efficacy of disaster education.
\nComplexity. More complex does not mean better when it comes to training exercises [21]. Thinking that testing more skills will improve more skills, stressing more processes will improve more processes, and designing more complex scenarios will enhance a greater repertoire of individual and systemic responses is flawed. The opposite can occur. Complexity can obscure the purpose of the exercise, lead to passivity among participants, and decrease collaboration [42]. Complexity can also interfere with learning [20]. Complex responses may be better trained by simple exercises. The goal is internal complexity with external simplicity (Loveluck cited in [21], p. 423).
\nLeaders versus participants. Many exercises benefit the designers and facilitators more than the participants [20, 21]. This may be effective when that is the goal. Some exercises explicitly target leaders and not participants [43]. But often, the intent is to train participants. Even when that is the stated objective, participants may not see it that way [44]. Facilities and educators may not be training who they hope to train. It is important to consider who the exercise is for, and who is actually benefitting.
\nSocial psychological. Recognizing that crisis simulations are meant to evoke some stress in individuals and organizations, some researchers have examined the adverse social and psychological effects of exercises [20, 43]. Sometimes “unintended consequences” of these effects can appear as a failure to participate when trainees fear evaluation from superiors ([20], p. 422). Supervisors giving feedback can reinforce incorrect behaviors if hierarchical relationships are ignored [20].
\nThere is no doubt that planning and training is key to disaster preparedness [41]. Disaster exercises are beneficial when objectives are clear, and debriefing is effective. When objectives are appropriate and align with needs, response capacities improve. Debriefing helps with this and with all aspects of learning and growth. The debrief is one of the most important parts of effective exercise.
\nClearly defined objectives. Objectives should identify whether the purpose of the exercise is evaluation or training, individual skills or collaboration, crisis or emergency response. Experts commonly identify the need for objectives to guide disaster exercises [20, 45]. Yet hospital exercises often do not include specific objectives [46] or have not clearly defined them [47]. Objectives help operationalize disaster training. That means we can identify what we wish to improve, measure to see if we have improved, and actually improve in the desired area [20, 21, 43, 46]. In many cases, the method of training and objectives of an exercise is not complementary and do not create the conditions for improvement in operational capacities [46, 48].
\nDisaster vs emergency, stability vs flexibility, training vs drills. Disasters and emergencies are different events and require different responses [21]. Training for emergencies requires drills, practicing being able to perform planned responses to anticipated events [20, 42, 51]. In a disaster, responses outside an organization’s policies and protocols are required [20, 44]. Training for disaster ideally trains flexibility, communication, and the ability to work across organizational boundaries [20, 21].
\nCollaboration. Disasters require interactions across and within organizations that is outside of usual lines of communication [20]. Collaboration, then, is key. Collaborative communication can help organizations recognize crises in the first place [49] and throughout the event. If there are barriers to effective communication across organizational boundaries, the response will be less timely, flexible, and effective [51]. We should prepare for the need to collaborate through practice working within new relationships and organizational structures [25].
\nDebriefing. “… the only reason for running a simulation is so that an exercise can be debriefed” (Thiagarjan cited in [20], p. 421). Debriefing is essential in order for learning to occur [20, 49]. Debriefing helps accomplish objectives, be they developing plans, training existing skills, or learning new things [50]. Learning from an exercise increases with reflection individually and collectively [21, 44, 51]. The utility of an effective and adequate debrief cannot be underemphasized (Table 1).
\n\n
| \n
Questions to ask to make disaster training effective.
\nSeems like a dream. A dream I’d like to forget. I said as much to Raj, adding “won’t see another one like that for a hundred years.”\n
\n\nHe was just shaking his head. “Forget this dream and it might as well be three days till the next one. Be the same dream all over again unless you keep this one in mind.”\n
\nDisaster management is challenged by the difficulty we have as people and organizations to think about future, uncertain events. The complexity and chaos of disasters further complicate the tasks of planning, preparing, and responding. The more complex the event, the more an organization must adapt and collaborate with other organizations. This frameworks of resource management in disasters will guide organizations in their disaster preparedness activities. We have touched on some applications of these principles to hospitals and resource-poor environments. From an accurate understanding of what constitutes a disaster, education and training will more likely be effective — directed to the right people, developing the right skills in the right places.
\nThe Internet has irrevocably changed the dynamics of scholarly communication and publishing. Consequently, we find it necessary to indicate, unambiguously, our definition of what we consider to be a published scientific work.
",metaTitle:"Prior Publication Policy",metaDescription:"Prior Publication Policy",metaKeywords:null,canonicalURL:"/page/prior-publication-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\\n\\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\\n\\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\\n\\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\\n\\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\\n\\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
\\n\\n1. CONFERENCE PAPERS & PRESENTATIONS
\\n\\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\\n\\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\\n\\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\\n\\n2. NEWSPAPER & MAGAZINE ARTICLES
\\n\\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\\n\\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\\n\\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\\n\\n3. GREY LITERATURE
\\n\\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\\n\\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\\n\\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\\n\\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\\n\\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\\n\\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\\n\\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\\n\\nFor more information on this policy please contact permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-03-20
\\n"}]'},components:[{type:"htmlEditorComponent",content:'A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\n\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
\n\n1. CONFERENCE PAPERS & PRESENTATIONS
\n\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\n\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\n\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\n\n2. NEWSPAPER & MAGAZINE ARTICLES
\n\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\n\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\n\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\n\n3. GREY LITERATURE
\n\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\n\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\n\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\n\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\n\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\n\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\n\nFor more information on this policy please contact permissions@intechopen.com.
\n\nPolicy last updated: 2017-03-20
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