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Comparative Biochemistry and Physiology, Part A 155 (2010) 134138

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Comparative Biochemistry and Physiology, Part A

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c b p a


Life is a huge compromise: Is the complexity of the vertebrate immune-neuroendocrine

system an advantage or the price to pay?
Davide Malagoli, Enzo Ottaviani
Department of Animal Biology, University of Modena and Reggio Emilia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Recent advances in comparative immunology have established that invertebrates produce hypervariable
Received 10 September 2009 molecules probably related to immunity, suggesting the possibility of raising a specic immune response.
Received in revised form 19 October 2009 Priming and tailoring are terms now often associated with the invertebrate innate immunity.
Accepted 19 October 2009
Comparative immunologists contributed to eliminate the idea of a static immune system in invertebrates,
Available online 30 October 2009
making necessary to re-consider the evolutive meaning of immunological memory of vertebrates. If the
anticipatory immune system represents a maximally efcient immune system, why can it be observed only
Immune-neuroendocrine system
in vertebrates, especially in consideration that molecular hypervariability exists also in invertebrates? Using
Evolution well-established theories concerning the evolution of the vertebrate immunity as theoretical basis we
Immunological memory analyze from an Eco-immunology-based perspective why a memory-based immune system may have
represented an evolutive advantage for jawed vertebrates. We hypothesize that for cold-blooded vertebrates
memory represents a complimentary component that anks the robust and fundamental innate immunity.
Conversely, immunological memory has become indispensable and fully exploited in warm-blooded
vertebrates, due to their stable inner environment and high metabolic rate, respectively.
2009 Elsevier Inc. All rights reserved.


1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2. Three questions regarding the evolution of immune-neuroendocrine complexity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
3. What is the advantage that vertebrates derive from the increased complexity of the immune-neuroendocrine system? . . . . . . . . . . . . 135
4. Are costs minimized in increasingly complex organisms? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
5. Is there an evolutive alternative to the complexity of the immune-neuroendocrine system?. . . . . . . . . . . . . . . . . . . . . . . . . 136
6. One last question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

1. Introduction trend towards a broader conceptualization of immune responses, one of

the main holistic perspectives is represented by Eco-immunology,
It is well documented that in mammals the functions of the immune which considers how the activity of the immune system of an organism
and neuroendocrine systems are based on a common pool of molecules is linked and negotiated with the environment and occurs within
that are functionally deeply interconnected (Weigent and Blalock, 1987, environmental constraints (Lochmiller and Deerenberg, 2000). Since to
1989). We have hypothesized that this interplay between the major the complexity of immune responses corresponds a high energetic cost
systems devoted to body maintenance has a long evolutionary basis (Derting and Compton, 2003), a basic assumption of Eco-immunology
(Ottaviani and Franceschi, 1996) and functional and molecular evidence hypothesizes that immunological defenses have to be minimized for
collected in different invertebrate species have been corroborating this what energy expenditure is concerned (Lochmiller and Deerenberg,
perspective in the last decade (Ottaviani et al., 2007). In the present 2000). Applying the Eco-immunological approach to a macro-evolution
perspective, the great complexity and energetic cost of vertebrate
Corresponding author. Department of Animal Biology, via Campi 213/D, 41100
immune systems (Shanley et al., 2009) must have been counter-
Modena, Italy. Tel.: +39 059 205 5536; fax: +39 059 205 5548. balanced by a correspondent advantage in natural selection. Since we
E-mail address: (E. Ottaviani). consider immune and neuroendocrine systems sharing a common

1095-6433/$ see front matter 2009 Elsevier Inc. All rights reserved.
D. Malagoli, E. Ottaviani / Comparative Biochemistry and Physiology, Part A 155 (2010) 134138 135

evolutionary origin, we have proposed that the immune-neuroendo- Before answering these questions, it is useful to remember some
crine system could be seen as an integrated whole, also in an Eco- concepts well-described by Ayala (2007). Natural selection takes place
immunology-based perspective (Ottaviani et al., 2008). Accordingly, in in the evolution of biological complexity in response to local
the present essay we will focus mainly on the evolution of the immune environmental conditions, i.e., ecological niches. Indeed, the relative
component, but we will always refer to the immune-neuroendocrine adaptations of natural selection together with evolution (which occurs
system when drawing general conclusions. by casual mutations) have produced the great biological diversity of
living beings. Natural selection produces combinations of genes over
long periods of time, acts without a predetermined work plan, and it is
2. Three questions regarding the evolution of the consequence of the differential survival and reproduction of living
immune-neuroendocrine complexity beings (Ayala, 2007). However, natural selection does not have the
capacity for foresight and does not anticipate the future. It could be said
Even if we assume that immune-neuroendocrine responses have that organisms present a design, but not a designer (Ayala, 2007).
been well-conserved during diversication of metazoans, this conser-
vation has to be restricted only to its molecular basis. The comparison 3. What is the advantage that vertebrates derive from the
between the response to stressful conditions in invertebrate and increased complexity of the immune-neuroendocrine system?
vertebrate models may help in clarifying the concept. In protostomian
invertebrate models such as molluscs (e.g., snails and mussels), we have A useful example to answer this question is the so-called jaw
observed that the stress response principally involves circulating cells hypothesis (Matsunaga and Rahman, 1998). Primitive jawed sh
endowed with phagocytic capability that we refer to as immunocytes evolved from the jawless vertebrates usually dubbed with the
(Ottaviani and Franceschi, 1996). In vertebrates, stress response paraphyletic term of ostracoderms. The appearance of the jaws in
typically involves different organs, e.g., the hypothalamus, pituitary vertebrates not only led to a profound anatomical transformation of
and adrenal glands. However, in both invertebrates and vertebrates, the the cranium, but also caused an increased frequency of physical
key mediator molecules are conserved and the cascade of molecular injuries in the wall of the digestive tract due to the greater capacity to
events follows the same order, i.e., corticotrophin-releasing hormo- capture, bite and swallow other animals for food, while also increasing
ne N adrenocorticotropic hormone N biogenic amines (Ottaviani and the risk of bacterial and viral infections. It is well-known that various
Franceschi, 1996). Unfortunately, several details of stress response bacteria constitute a commensal ora in the gut lumen of most
and neuroendocrine system in invertebrate taxa have not been metazoans, vertebrates or not, and they are considered to be
disclosed, yet, even if molecular evidence about the conservation of benecial for the host so long as they are maintained within their
stress-related molecules have been reported (Malagoli et al., 2002). boundaries. This situation needs an efcient gut-associated host
As observed for the neuroendocrine system, also the immune defense system, which was reasonably present also in ostracoderms.
system of vertebrates is usually considered to be more complex than The jaw hypothesis assumes that the early memory-based immune
those of invertebrate models studied so far (Lemaitre and Hoffmann, system may have evolved in gnatostomes from the gut-associated
2007). However, while the major complexity of the neuroendocrine lymphoid tissue (GALT) of the primitive jawed sh (Matsunaga and
system of recent vertebrates is generally accepted as a self-evident Andersson, 1994; Andersson and Matsunaga, 1996). In support to this
truth, more attention should be paid for the immune system. Indeed, hypothesis, it has been demonstrated that GALT is a primary immune
in several taxa of protostomian and deuterostomian invertebrates it site for local T cells that act in a thymus-independent manner (Rocha
has been suggested the possibility of tailoring an immune response et al., 1994; Kanamori et al., 1996). In the gut epithelia of
specically directed against a pathogen (Zhang and Loker, 2003; elasmobranches (e.g., sharks and rays, cartilaginous sh considered
Watson et al., 2005; Dheilly et al., 2009; Okado et al., 2009). still similar to their progenitors), simple aggregations of lymphoid
Accordingly, the somatic recombination of receptorial and possibly elements appear. In modern bony sh, such as teleosts, that are much
immune-related molecules has been ascertained (Watson et al., more diversied with respect to their progenitors, a well-organized
2005). However, denite evidence of an immunological memory structure of GALT is observable (Zapata et al., 1995). However, even if
based on specic immunoglobulins that are massively produced by all jawed vertebrates have GALT, Peyer's patches are present only in
lymphocytes after a second exposure to the same stimulus has not birds and mammals, i.e., the two more diffused and recent classes of
been provided in invertebrates, so far (Brehlin and Roch, 2008). Only terrestrial vertebrates (Whitesides et al., 1991; Turner, 1994). In other
in this sense the invertebrates may be considered as having a simpler words and not surprisingly, the jaw was positively selected because it
immune system than that of the vertebrates, in which a complex represented an efcient means to introduce more and previously
network of lymphoid tissue and lymphocytes has been positively unreachable food, but this has been possible only because structures
selected (Cooper and Alder, 2006; Geenen, 2006). already existing were able to face and adapt to the conditions imposed
Another important point to consider is that within the paraphyletic by the new component. To come at the question whether complexity
term of invertebrates is included the most represented and widespread is an advantage, it is possible to hypothesize that the increased
phylum of metazoans, i.e., arthropods, which has been prospering for complexity of the immune system in jawed vertebrates has
hundred millions of years and has colonized countless niches, with a represented an advantageous change (or better a sustainable cost,
highly efcient immune system apparently devoid of the anticipatory in an Eco-immunolgical perspective), paid by the augmented food
component (Lemaitre and Hoffmann, 2007). This denitely indicates resources obtained through the jaw. However, it has to be underlined
that the immunological memory as described in vertebrates is not to be here, that equally recent taxa such as teleosts, birds and mammals
considered as fundamental for evolutive success in general, whereas it present different levels of complexity in their GALT, as well as the
appears to be crucial for modern vertebrates. If we consider the efciency of the secondary and memory-based response presents a
relatively high success of vertebrates from an Eco-immunological quite different degree of intensity between teleosts, by one side, and
perspective over the last 500 million years, three questions arise: birds and mammals on the other (Matsunaga and Rahman, 1998;
Watts et al., 2001). This indicates that even if the jaw may have
1) What is the advantage that vertebrates derive from the increased represented an event that gave a determinant contribution for the
complexity of the immune-neuroendocrine system? positive selection of the memory-based immune system of verte-
2) Are costs minimized in increasingly complex organisms? brates, probably other events, for instance the passage from water to
3) Is there an evolutive alternative to the complexity of the immune- dry land, promoted its increase in complexity during evolution.
neuroendocrine system? Accordingly, the fundamental basis for an anticipatory immune
136 D. Malagoli, E. Ottaviani / Comparative Biochemistry and Physiology, Part A 155 (2010) 134138

system has been very recently retrieved in the sea lamprey Petromy- existing structures and molecules is a well-established concept in
zon marinus (Guo et al., 2009). The memory-endowed immune comparative anatomy (e.g., feathers were initially not related to the
system of jawless vertebrates appears to be the fruit of convergent ight) as well as in all evolutionary biology-related disciplines (Jacob,
evolution and it should not be considered as the ancestor of the 1977). As previously mentioned, in several invertebrate taxa, also of
anticipatory immunity of vertebrates (Guo et al., 2009). deuterostomian lineage, it is now becoming evident the capability of
producing molecules probably related to immunity and presenting
4. Are costs minimized in increasingly complex organisms? hypervariability (Dheilly et al., 2009), and there is no reason to
exclude a similar situation also in the vertebrate progenitors. The
As indicated above, the jaw hypothesis may be analyzed in an possible existence of an anticipatory immunity that evolved inde-
enlarged Eco-immunological perspective indicating in the jaw a key pendently in agnathan vertebrates, is a further indication that along
component that revealed to be particularly procuous in the presence vertebrate lineages were present all the genetic requirements for the
of a memory-based immune system, while providing in the meantime evolution of acquired immunity (Guo et al., 2009).
the energy necessary to sustain and nally to x such a system.
One point that needs to be claried here, is whether to consider the 5. Is there an evolutive alternative to the complexity of
memory-based immune system of vertebrates more energy costly than the immune-neuroendocrine system?
the invertebrate innate immune response. Some experiments have
indicated that basal metabolic rate of adult lymphocyte-decient mice is In tackling this third question, the answer may probably be
higher than that of wild type mice (Rberg et al., 2002). This could hypothesized to be negative for vertebrates, while our knowledge of
indicate that the combination of innateacquired immunity has immune-neuroendocrine system of invertebrates is still too prelim-
represented and advantage because it resulted in energy savings inary to jump at a conclusion.
(Rberg et al., 2002). The result ts well with the consideration that Even if increased biological complexity is not a necessary conse-
Eco-immunology foresees a minimization in the energy expenditure of quence of natural selection, complexity emerges when mutations that
immune responses (Lochmiller and Deerenberg, 2000). However, in tend to increase complexity are more favoured (Geenen, 2006) and
these respects, it could be noticed that lymphocyte-decient mice, even nally xed in the next generations. Complexity is an advantage as long
though an undoubtedly intriguing model, can hardly be considered as a as it is related to better adaptation. However, when complexity is
good representation of primitive jawed vertebrates, because the co- favoured because it leads to better adaptation, then natural selection
evolution of innate and adaptive immunity (Falconer and Mackay, will prompt more complex, and so more adapted, organisms. From this
1997) had the possibility to realize for hundred millions of years before point of view, the complexity of vertebrates could seem to be bound to
mammalian appearance. Conversely, other authors report that the grow indenitely towards the progressive specialization for a given
energetic demand of an immune system include also the costs of its niche. However, this race towards complexity has one of its most
development, maintenance and the cost of ghting the infection probable brakes in the energy expenditure required to maintain a
(Klaising, 2004). In terms of development, the acquired immunity of complex organism (Shanley et al., 2009). Ultimately, in an Eco-
jawed vertebrates is characterized by the costs related to the production immunological perspective ((Lochmiller and Deerenberg, 2000), in
of a large number of cells early in life. An important fraction of these cells given conditions the most adapted organism will be the one that would
is discarded as a consequence of the negative selection occurring in the have reached the highest degree of adaptation with respect to its proper
lymphoid organs (Shanley et al., 2009). In these respects, while during energetic demand.
adulthood the costs of maintaining the innate and acquired immunity After their upsurge, the rst jawed vertebrates were able to
may not be high (Rberg et al., 2002; Klaising, 2004), this does not seem colonize various unoccupied niches, but their competitors started to
to be the case during the rst stages of life (Shanley et al., 2009). be also jawed vertebrates themselves. This competition selected the
Even if we assume that the increased costs of the more articulated more adapted vertebrates. As can be deduced from fossils they
immune system (Shanley et al., 2009) of jawed vertebrates were displayed a more complex nervous system, which can reasonably be
sustained by the jaws themselves, it seems plausible that the associated with better energetic efciency, i.e., to achieve the best
components necessary to the development of an anticipatory immune result with the minor effort. Similarly, when jawed vertebrates started
component were already present in the progenitors of jawed verte- to occupy the dry land, they also found various unoccupied niches.
brates. Indeed, it sounds contradictory that animals that certainly Again vertebrate diversication pushed towards more adapted
already possessed an efcient immune system set up a new immune animals that presented an increasingly complex nervous system
component, adding immunoglobulins to the already present immune- (Rogers, 1999; Shimeld and Holland, 2000). Even if we have no idea of
related molecules. the components of the immune system in the extinct taxa of
In these respects, Stewart's theory (1992) relating to the terrestrial vertebrates, the analysis of the immune functions of the
appearance of primordial variable region molecules (VRMs) has most widespread and diversied terrestrial vertebrates today, i.e.,
already analyzed the possible origin of immunoglobulins. According birds and mammals, clearly indicates the success of a memory-based
to Stewart (1992), the VRM system was initially mainly linked to the immune system among tetrapods (Cooper and Alder, 2006). Along the
integration of the internal molecular milieu. This assumption is other major branch of the vertebrate evolutionary tree, i.e., teleosts
supported by the presence of cell adhesion molecules that are known (bony sh such as carp, catsh and swordsh), a high degree of
to play an important role in cell differentiation and tissue organization specialization in immune functions is again evident (Yada and
(Edelman, 1987). Only subsequently was the VRM system re- Nakanishi, 2002; Bowden et al., 2005), although secondary response
deployed for others functions, e.g., the anticipatory immune system. seems less intense than in birds or mammals (Watts et al., 2001). In
In particular, the immunoglobulins enhance the vertebrates' recogni- vertebrate evolution, therefore, the progressive increase in the
tion system, allowing them to face new events, such as the passage of complexity of the immune-neuroendocrine system would appear to
the animals from water to dry land (new ecological niches), but also be the result of natural selection, probably because it is associated
increasing the probability of encountering potentially damaging with a greater efciency in utilizing available resources.
pathogens. Enlarging the vision of Stewart, we can consider that
immunoglobulins have represented a proper and already available 6. One last question
resources (we might use the term exaptation), that were used as an
additional component grafted to the already present and functioning As usual in biology, one answer generates more than one question.
innate component. The possibility of a different utilization of pre- One of the questions that arises from our previous answers is whether
D. Malagoli, E. Ottaviani / Comparative Biochemistry and Physiology, Part A 155 (2010) 134138 137

vertebrates can be considered as paradigmatic in the evolution of especially steady in warm-blooded vertebrates. In this respects, a highly
metazoans, especially in terms of immune-neuroendocrine system. efcient memory-based immune system becomes fundamental, be-
While the increase in the complexity of the immune-neuroendocrine cause a secondary and specic response able to counteract the pathogen
system has been rewarded in vertebrates, such a trend in invertebrate in a brief time may represent the difference between survival and death.
taxa is less evident (Geenen, 2006), despite recent ndings of In accordance with Eco-immunology perspectives, the highly costly
comparative immunologists that undoubtedly contributed to the memory-based immune system (Lochmiller and Deerenberg, 2000;
elimination of the vision of a static immune system in invertebrates Derting and Compton, 2003; Shanley et al., 2009) is therefore fully
(Sadd and Schmid-Hempel, 2006; Lemaitre and Hoffmann, 2007; Dheilly exploited only in those animals that have high level of energy
et al., 2009; Okado et al., 2009). In the immune system of numerous immediately available, even if obviously the energy expenditure must
invertebrates there are several indications of elevated specicity be negotiated with the requirements of all the body systems
(Lemaitre and Hoffmann, 2007), highly variable molecules possibly (Lochmiller and Deerenberg, 2000; French et al., 2007). For instance,
involved in immunity (Watson et al., 2005; Bowden et al., 2007; Dheilly immunological memory is compromised by food restriction in deer
et al., 2009) and perhaps clues of memory (Sadd and Schmid-Hempel, mice (Martin et al., 2008). So what is immunological memory for cold-
2006; Brehlin and Roch, 2008; Okado et al., 2009), but nothing that blooded jawed vertebrates? Probably an advantageous but comple-
could be compared to the lymphocyte-based solutions observed in mentary component that is functionally linked to the more robust,
vertebrates (Cooper and Alder, 2006). fundamental and ancient innate immune system (Matsunaga and
However, if the anticipatory and memory-based immune system Rahman, 1998; el Ridi et al., 1981; Arkoosh and Kaattari, 1991), which in
that we observe today in mammals is really the expression of a any case still remains a pillar of the immune system also in warm-
maximally efcient immune system, it is somehow unexpected that it blooded vertebrates as well as in all metazoans (Kimbrell and Beutler,
cannot be observed outside vertebrates, also in consideration that 2001; Beutler, 2004). On this purpose, it could be of some interest to
molecular hypervariability does exist in several invertebrate taxa that report a question made by Boman in 1996, even if in a different
share ecological niches with mammals. A most obvious answer could context:Why do sharks and Xenopus have immunolgobulins (func-
be that diversied immune responses may reect the specic habitat, tions?) when they make marvellous peptides and steroids, both potent
potential pathogens, physiology and, not last, lifespan of a taxon. But low molecular weight antibiotics? (Boman, 1996).
at the end, this is not really an answer. Several invertebrates share
ecological niches with vertebrates, but their survival is granted by the 7. Concluding remarks
innate immunity alone (Lemaitre and Hoffmann, 2007). Although the
invertebrate innate immunity seems to present traits of specicity A glance at the evolutionary tree of celomatic metazoans from an
that were unsuspected ten years ago (Zhang and Loker, 2003; Watson Eco-immunological perspective isolates vertebrates as an exception
et al., 2005; Dheilly et al., 2009), and even if in invertebrates the (Fig. 1). They seem the only group in which the increase in the
existence of immunological memory cannot be excluded a priori complexity of the immune-neuroendocrine system has constituted an
(Brehlin and Roch, 2008), a highly efcient anticipatory immune advantage, even if the price to pay has been the consumption of
system does not appear to be a key component for the survival of resources that a vertebrate has had to sustain in order to win the
invertebrate metazoans. Looking at the whole animal kingdom, or at competition for life and reproduction. The process is more evident in
least among metazoans, it seems rather that memory is a comple- the warm-blooded vertebrates, where a high rate of energy
mentary component that in jawed vertebrates revealed to be consumption is fundamental to sustain a highly efcient and now
particularly procuous. indispensable memory-based immune system. It seems a paradox, but
More precisely, it is nowadays commonly accepted that in several it could be that comparative immunology has in one of its main terms
modern vertebrates such as teleosts, the memory is present, but the of comparison, the immune system of mammals, one of the most
secondary response is sluggish compared with that of mammals notable exceptions.
(Matsunaga and Rahman, 1998; Watts et al., 2001). The same relative
inefciency of adaptive immunity has been reported for almost all cold-
blooded vertebrates (el Ridi et al., 1981; Arkoosh and Kaattari, 1991;
Matsunaga and Rahman, 1998). A possible explanation could be that
cold-blooded vertebrates can be considered more primitive, or more
similar to their progenitors, than warm-blooded vertebrates, but this
old-fashioned perspective has been overcome by modern interpreta-
tions on vertebrate phylogeny (Telford and Budd, 2003). For instance,
teleosts are a quite divergent branch of ray-nned bony sh, they
present a highly complex central nervous system (Northcutt, 2008) and
have colonized several aquatic niches (Ravi and Venkatesh, 2008). They
cannot be considered primitive at all, even if their immunological
memory seems less reactive than that of equally modern vertebrates
such as birds and mammals (Watts et al., 2001). Birds and mammals, on
their turn, present a completely different evolutive history along the
amniotes lineages (dipasid and synapsid, respectively) but at the same
time display an immune system that is equally based on a highly Fig. 1. A schematic representation of the major bilaterian groups highlighting their
efcient anticipatory component (Matsunaga and Andersson, 1994; main immunological characteristics. The fundamental innate immunity, as well as
highly variable molecules probably connected to immunity can be retrieved in all the
Andersson and Matsunaga, 1996; Matsunaga and Rahman, 1998). In
three groups of bilaterian metazoans, i.e., Ecdysozoa, Lophotrocozoa and Deuterosto-
terms of comparative anatomy, the main characteristic shared exclu- mata (white backround). At present, the presence of memory has been ascertained only
sively by birds and mammals is that they are warm-blooded, that's to in vertebrates (agnathans and gnatostomes) even though it usually displays the
say they have a high rate basic metabolism and that they maintain their features of an advantageous but complementary component (light grey background).
temperature within a controlled interval. In such a highly energized Only in birds and mammals, two taxa derived from different branches of the amniote
lineage, the potentialities of immunological memory appears to have been fully
environment, several microorganisms can grow very quickly and exploited (dark grey background), probably as a consequence of high level of energy
rapidly modify the composition of extracellular uids, dangerously immediately available. In all cases, innate immunity remains the basic and fundamental
unbalancing the delicate homeostatic equilibrium, that has to be component of the immune system of all metazoans.
138 D. Malagoli, E. Ottaviani / Comparative Biochemistry and Physiology, Part A 155 (2010) 134138

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