Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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1. Introduction
Globalization is a process that encompasses the accelerated and simultaneous circulation of ideas, goods, and human beings (Appadurai, 1996). In an Amazonian context, this chapter aims at analyzing the impacts of particular land status ownership on the resilience and flexibility of traditional communities facing globalization (Kramer et al, 2009).
The Amazon has been part of the global market since the 16th century: from the drogas do Sertão, through the rubber boom, to Brazil nuts (Bertholletia excelsa) and açaí (Euterpe oleracea), the global demand for Amazonian products has played a crucial role in the phases of human population of this rich basin (Bunker, 1985). Mark Harris (2006), following Moran and Parker, characterizes the “cabocla” populations by their ecological adaptations as well as their economic versatility.
During the 1990s and 2000s, a great number of “traditional” and/or indigenous communities were granted land rights in Brazil. Innovative legal statuses were created, either for the sake of environmental protection or as a function of the peculiar special social status of some social groups, mainly indigenous people and remnants of escaped slave communities (i.e. remnant quilombola communities). At the core of these rights is the recognition of a “special relationship” between these traditional communities and their territories. Due to the acknowledgement of this particular link, almost 30% of the Legal Amazon is officially under the responsibility of traditional communities.
Ludivine Eloy2, François-Michel Le Tourneau3, Claire Couly4, Stéphanie Nasuti3, Dorothée Serges5, Sophie Caillon6, Guillaume Marchand1 and Anna Greissing3.
1 University of Tours, CREDA, France,2 University of Montpellier III, UMR 5281 ART-Dev, France; University of Brasilia, CDS, Brazil,3 CNRS, CREDA, France,4 French Research Institute for the Development and the French National Natural History Museum, France,5 CREDA, France,6 CNRS, CEFE, France.Indigenous Lands cover 20% of the extension of the Legal Amazon, while Extractive Reserves (RESEX) and Sustainable Development Reserves (RDS) cover 4.84%, and Quilombola lands cover 1.6% (Ricardo and Rolla, 2009).
However, traditional communities are now facing contradictory pressures induced by Brazilian public policies and globalization. On the one hand, they were granted land under the assumption that they would maintain their traditional way of life, with low impact on the ecosystems (Diegues, 1996). On the other hand, they are more and more connected to global markets and information technology, and have access to a greater mobility. They face the challenge of improving their living conditions by developing their economic activities. Globalization in this sense should not be understood as a single threat. Isolated forest communities have acquired the chance to access better rural living conditions. But traditional communities are confronted by a “double bind” situation: economic development and the extension of contemporary ecological ideology.
Figure 1.
Localization of the areas considered. Map by F.-M. Le Tourneau
Our work focuses mainly on the status of Quilombola, which we approach on the basis of two case studies in the Brazilian Amazon: one (the village of Cunani) in the Amapá state and the other one (the village of Abuí) in the Pará state. They experience contrasting demographic trends. The Cunani population, still waiting for its legal recognition, is decreasing. The village of Abuí, however, is included within a recognized quilombola land, its leaders are involved in the famous quilombola movement of the Rio Trombetas,and its population is increasing. While unveiling the current land-use situation, we investigate the benefits and consequences of two emerging commercial activities – ranching and açaí extraction. We study how the acquisition of land rights facilitates adaptation to the new economic context of the Amazon region.
2. Globalization and the access to land rights: The ethnic strategy
In “The Production of Locality” (1995: 213), Appadurai points to, among the effects of globalization, “the growing disjuncture between territory, subjectivity, and collective social movements”. At the same time, the author underlines “the steady increase in the efforts of the modern nation-state to define all neighbourhoods under the sign of its forms of allegiance and affiliation”.
In this context, indigenous or traditional populations occupy a special place. They are defined by the International Labour Organization (convention #169, 1989) as having special ties with the territory they occupy, this territory being the guarantee and motor of their social (re)production.
Brazil was innovative in recognizing, in addition to ethnic categories (Amerindians and Quilombolas), another category, that of “traditional populations,” defined not only by their activities and means of existence, but also by the transmission of their knowledge and practices from generation to generation (Barretto Filho, 2006). A number of the inhabitants of Amazonia can lay claim to one or another of these statuses, which differ in their degree of land rights: undivided joint ownership for the Quilombolas, usufruct for the Amerindians, and usage concessions for traditional populations. In order to be recognized as part of one or another of these groups, rural Amazonian communities need to adopt a universal dialectic of ethnicity and tradition.
The creation of quilombola territories is a response to a convergence between the global movement recognizing cultural diversity as being linked to biological diversity (UNESCO 2003), and the local movement of access to land. These two movements are mediated by the intervention of the Brazilian state, which imposes its structures and hierarchies in the creation of differentiated territories, for either nature conservation or cultural patrimonialization (Véran, 2002).
2.1. The splendor and misery of Cunani
The community of Cunani was formed over two periods. The first, that of the Franco-Brazilian Dispute (1770 – 1900), created an area frequented by French and Brazilian traders, while the main part of the population was composed of fugitive slaves. The latter, initially settling upriver, went on to colonize downstream as well. This period culminated with the proclamation of the short-lived “Republic of Cunani” (1882 – 1885), supported by the French, and ended in 1900 with the resolution of the Dispute in favor of Brazil. Then began a neo-Brazilian migration of people originally from the “islands” (south from Amapá and north-east from Pará). The two populations continued to intermingle, with the colonists returning upstream along the Cunani River.
Up until 1970, the inhabitants of Cunani benefited from a relative prosperity, though suffering the economic risks tied to the exploitation of Amazonian products: fur trade, fish, manatee oil, non-wood forest products, and logistical support for the garimpos of the region. Governor Janari, in the 1950s, began a politics of education that bore fruit.
But the opening of BR156 linking Macapá to Oiapoque at the beginning of the 1970s changed all this: Calçoene, 50 km from Cunani, became the new economic centre of the region, leaving the enclaved communities to the side. A process of migration followed, due to the presence in town of commodities (health, education). The creation of the National Park of Cape Orange, in 1980, aggravated the situation, by restricting access to the Cunani River. With the increasing enforcement of environmental laws, the inhabitants of Cunani saw a continuously receding future. Finally, the route between Calçoene and Cunani, finished in 1987, is passable only part of the year, and at high transportation costs. The Amazonian “black gold” açaí, came too late for the possible creation of an Extractive Reserve (RESEX) bordering the Park. The projects of the Park management team concerning the community were quickly oriented toward equitable tourism, but the project never amounted to anything.
It was then that INCRA (National Institute for Colonization and Agrarian Reform, a branch of the Ministry of Agrarian Development charged with putting in place the process of surveying, demarcation, and land registry) intervened in the conflict between the community in outright decline and IBAMA (Brazilian Institute for the Environment and Renewable Resources). This intervention is part of a longstanding tradition of rivalry between the two federal organizations. In the struggle the community was waging for its survival and its remaining in place, the quilombola statute offered the advantage of a definitive land title. But the conversion of the inhabitants of Cunani into Quilombolas was not an easy thing: the local history was marked more by the Franco-Brazilian Dispute and by immigration from Pará than by the Quilombolas. As the oral traditions do not go back more than three generations, the identifying elements relative to belonging to Quilombolas are relatively recent contributions, contemporary with the community mobilization around this question.
It is thus that in the same phrase an informant could state that to be Quilombola “is to have black skin, like me,” and then add “My grandfather wasn’t black, he was like me.” This paradoxical affirmation recurs in the context of quilombola claims (see also Boyer, 2002: 169).
Through the intervention of the INCRA, the identification and demarcation of the quilombola territory of Cunani was pushed through in 2004, though without passing the step of ratification because the anthropological study was – and still is – missing. The ICMBio (Chico Mendes Institute for Biodiversity, now in charge of National Parks and Protected Areas) also requested a study, not on the real character or the quilombola ascendance, but questioning the 36,000 ha (22,000 of which are in the Park) attributed to this community in decline.
These risks split the movement, some of whom (residing in Calçoene) wanted to invest in tourism by promoting the quilombola identity, while others, more pragmatic, wanted to start a cooperative with the aim of commercializing açaí. Faced with an uncertain future, migration to Calçoene went on, to the point that the school at Cunani went from 12 students in 2007 to only 5 three years later.
2.2. Abuí, a quilombola community in the Trombetas valley
During the pre-Columbian period, the valley of the Trombetas river was occupied by various Amerindian groups (Porró, 2008). At the beginning of the 17th century, Europeans occupied the Amazon valley, establishing cacao plantations and cattle ranches in the region of Óbidos, Santarém, and Belém. Following this period, African slaves were imported from the Gulf of Guinea. But the number of slaves escaping rapidly multiplied, and the fugitives organized themselves into communities along the branches of the Amazon. As punitive expeditions increased, the groups of fugitives spread out, going back up the main branch of the Trombetas river, seeking a sure refuge upstream from main rapids where navigation was particularly difficult.
Increasingly, the interdiction of slave trafficking (1850) and the various laws improving the condition of the slaves, and finally the abolition of slavery (1888), led to the displacement of the fugitive slave communities, which nonetheless traded freely with the towns of the region. The Quilombolas abandoned the territories upstream from the Amerindian populations and increasingly resettled the middle course of the Trombetas (Coudreau, 1900).
The peace between the Quilombolas and Brazilian society did not, however, bring them land security. Starting in 1920, the families of merchants increasingly appropriated the lands along the middle of the Trombetas to control the areas of Brazil nuts trees (Castanhais) and practice cattle ranching on the river banks. The merchants used the widespread system of aviamento, wherein the collectors who gathered Brazil nuts on a merchant’s land were obligated to deliver all of their production to him, and to get their provisions from his storehouse (Geffray, 1995). This system of patronage disappeared little by little during the 1960s and 70s, when the trade in Brazil nuts slowed.
The population of Abuí grew from the 1960s on, but settlement continued to be relatively isolated until the 1980s. After this period, the land situation in the Trombetas region was redefined many times. The first changes were linked to the installation in 1976 of a mining complex to extract bauxite from the right bank of the river. Shortly thereafter, as an ecological counterbalance to the mine, the federal government set up two protected areas, in 1979 and 1989, on either side of the river, which led to the expropriation of the land of the local communities. It was the merchants, however, being the official owners of the land, who were compensated, while the numerous inhabitants were evicted, sometimes quite violently (Nasuti, 2005). The inhabitants were thus forced to relocate to other villages in the valley, such as Abuí, which saw a major increase in its population.
The environmental measures of this period were even less in harmony with the presence of local populations (Barretto Filho, 2006), which led to the emergence of social movements fighting for the rights of local populations. Thus, in reaction to the evictions, after 1982 the inhabitants of Abuí were strongly mobilized under the guidance of a priest, Father Patrício, who came with the Rural Workers Union to inform the inhabitants of their rights and incite them to organize as an independent community. Thanks to their participation in the gatherings of the “black roots” (raizes negras), the inhabitants of the Trombetas valley found their identity and created an association in 1989 (Associação das Comunidades Remanescentes de Quilombos do Município de Oriximiná - ARQMO). Their territorial demands were expressed in ever more clear terms at the beginning of the 1990s.
In 1995, the community of Boa Vista, the first in the continuum of black communities in the Trombetas valley, was the first quilombola land to be recognized under this statute in Brazil, opening the way for other communities in the region. Thus, among the interstices of protected areas, Indigenous Lands, and the mining complex, five quilombola territories have since been demarcated, comprising 22 communities over an area of approximately 362,000 ha. It was in this way that the land statute of the Abuí community, and its four neighbours
The communities of Paraná do Abuí, Tapagem, Sagrado Coração, and Mãe Cué.
, was stabilized in 2003, thanks to the granting of a land title for the quilombola territory “Mãe Domingas” (61 211,96 ha).
3. Globalization and market access: Economic strategies and their impact on forms of development
Populations that depend on extractive activities adapt continuously to the conditions of the market. They reconfigure themselves very quickly in the face of a changing socio-economic environment. Diversification of revenues is thus vital, when the object of public politics is to support the empowerment of local populations through aid to development. Public authorities, unfortunately, is discontinuous (Greissing et al., 2008), and depends largely on global orientations targeting sometimes environmental conservation, sometimes the fight against poverty. The object of this second section is to describe the relationship between economic choices and forms of development, this relationship having an indirect impact on environmental conservation (Kramer et al., 2009). For access to joint ownership of land does not mean an end to problems of subsistence. Even in extractive reserves, demarcated as a function of economic projects, the inhabitants often have to turn to unforeseen alternatives (as, for instance, cattle in the PAE Chico Mendes – Pantoja et al, 2009). And while the quilombola statute allows people to benefit from certain advantages in terms of cultural funding and access to education, it does not offer, in itself, a means of subsistence, at least for those who live far from tourist itineraries. The Quilombolas thus need to strengthen institutional alliances and commercial partnerships in order to stabilize their access to commodities and services.
3.1. Açaí, an expanding global market in Cunani
Among the plant species exploited by the villagers of Cunani, açaí is without doubt that which has gained most in economic value over the last few years. Açaí in effect is the perfect example of a local product that has become the target of a globalized market, avid for new and “ecological” products (Brondizio, 2002, 2008).
Although it has always been the object of local and seasonal consumption, this resource is now exploited for commercial ends by almost all families. Harvesting of açaí takes place from February to May/June. The harvest is often done with the help of brothers and sisters, children or nephews gone to live in Calçoene. The quantity gathered varies greatly according to the family: from 200 to 1500 kg /day on average according to the workforce, density, and distance to the açaí palms. The revenues tied to açaí corresponds to a large part of their annual household income (this revenue may complement the salaries of teachers, nurse aids, or watchmen, or even retirees and welfare recipients). However, the harvest is very irregular because of the heavy rains that fall during this time of year (the rainy season runs from January to June).
As opposed to other local produce, and in particular to manioc flour whose sale is strictly limited by the high cost of transport to take it to town, the problem of transporting sacks of açaí poses no problem. The buyers, coming from Calçoene or Macapá, go to the entrance of the village to load the produce. This in large part explains the importance of the commercialization of the fruit of this species in relation to other product. The açaí is then resold in Calçoene for up to 3.5 R$/kg, and even more in Macapá. Paradoxically, the number of trucks loaded with açaí between February and May make the route impracticable for the rest of the year, contributing to the rise in the cost of transporting people as well as other product.
There is no management, properly speaking, of “wild” açaís, also called “natives”: the villagers can use the wild stocks without really appropriating them for themselves, whence the fact that the gathering areas vary yearly (“Não tem açaízal fixo”). They are considered to be open access to all the members of the village, as well as people originally from Cunani living in town. These wild açaís are found in family fields, on the banks of the river, or in the igapós situated in Terra firme forests, without there being any quotas for gathering imposed. On the other hand, the occasional but repeated harvesting of the wild açaís by people outside the community is denounced by the locals. Certain among them know how to take advantage of this fad for the “black gold” by renting their açaís or demanding a tax on each 50 kg sack taken (a practice called matança).
Apart from the “wild” açaís, there are also “cultivated” açaís (according to local terminology): these include açaís not planted but the object of special management (manejado) as well as planted açaís: the palms that are too big or old are cut down to give more space to the productive açaís. But there are also açaís directly planted in swidden fields. This cultural practice aimed at the plantation of açaí on a large scale – more than 5000 açaí trees planted around the vila – is very recent (five years) and its appearance coincides with the strong economic value of this species in the region. In both cases, the açaí plantations are no longer considered to be of open access: the other inhabitants can only gather fruit there on the condition that they are authorized by the owners of the plants.
But the inhabitants who remain in Cunani, held by family loyalty towards their family in Calçoene, cannot pretend to have exclusive rights to the collection of açaí. What is more, the dependence of the inhabitants vis-à-vis the intermediaries and buyers engenders a loss of control over the açaís in the future perimeter of the quilombola territory. These “buyers” purchase the sacks sold by the inhabitants, and profit from illegal exploitation of the palms in the region by importing cheap labor from town. Thus, because of lack of regulation, certain inhabitants of Calçoene with access to means of transport, whether or not they have family ties with the local population, can with little expense obtain a large part of the production.
The practice of one of the principal families of the village, which consists of recruiting outsiders to harvest its açaís, illustrates the difficulty the community is faced with to unify in order to create a cooperative. With no collective organization, the greater value given to a particular hierarchy results in an individual appropriation of resources (the populations of açaís) and a certain concentration of wealth, even without the existence of private property, just as in Abuí with the introduction of cattle ranching. In this case, the recognition of collective quilombola land does not seem to be sufficient to avoid this socio-economic differentiation.
3.2. Brazil nuts and introduction of cattle ranching in Abuí
The principal economic activity of Abuí is the collection of Brazil nuts. This is an important activity for not only is it the principal source of income for the community (or at least it was until very recently), but it is also a source of local identity since the Quilombolas of the Trombetas River have been used as the labour source for the collection of Brazil nuts since the end of the 19th century.
This activity, which requires long stays in the forest, as well as a familiarity with the territory and the forest itself, carries a strong element of identity (the sharing of knowledge, a feeling of belonging). Collection is a seasonal activity, done after the nuts have fallen until all the areas of collection have been exhausted. Commercialization can occur in the field, with itinerant traders criss-crossing the area during the collecting season, or in town. The second solution is more interesting from a financial perspective, but it presupposes the ability to command transport to Oriximiná (250 km), something not everyone can do. Since 1998, a cooperative begun by the ARQMO has tried to play the role of intermediary by gathering the production of its associates and then transporting the nuts to be sold in town, but its somewhat chaotic management and the ties that continue to unite certain merchants and families of Quilombolas have led to this initiative remaining somewhat marginal. However, the production of the Brazil nuts from Abuí has not yet found its place in alternative circuits (fair trade, green, sustainable) because the cooperative has not succeeded in renewing its commercial partners. Thus, the Quilombolas of Trombetas have not found the means to convince their buyers of the value of the ethical/sustainable mode of their collection in order to obtain a higher sales price.
The Brazil nut groves are “communal”, which means that there is not a right of pre-emption of an “owner” over such or such an area. The first comer can thus collect wherever he sees fit. In Amazonia, such a system is less frequent than the system of colocação, which holds for the collection of latex from rubber trees (Hevea brasiliensis), and in which a family is entitled to the collection of a demarcated area. But this system is not as open as it appears since there are secret collection zones known to a single family that one avoids showing to others.
A better organization of production, or the possibility of adding to the value by an initial processing in the field, would probably be an important factor to intensify exploitation, which is currently in decline. Cattle ranching is now the fastest growing alternative. Even there are not more than 100 head of cattle in Abuí, the phenomenon is particularly recent and rapid, the village having passed from one to thirteen ranchers since 1995. The introduction of monetary revenue, tied to the rise in salaried functions (teachers, health agents, school boat drivers, etc.) with external economic activities (salaried work around the Trombetas mine) or with social benefits (rural retirees, etc.), gives to some the possibility of investing small amounts of capital. Instead of risking it in Brazil nuts, a seasonal activity of uncertain return because of the oscillations in price, families prefer to invest in raising animals, where the return is guaranteed and which allows for savings until they have enough head of cattle to finance a large purchase (boat, motor, etc.). In addition, the practice of share breeding
Arrangement in which a big rancher, having productive capital and generally living in town, places his cattle in several small ranchers’ fields, who, in exchange for half of the production, plant and maintain the pasture (Cochet et al., 2010).
by the two principal ranchers of Abuí shows that the chain of production is controlled by the political and commercial elite located in Oriximiná. The outlets for ranching are thus guaranteed through these political connections, which grant access to the municipal slaughterhouse.
But another phenomenon should be underscored here. The recognition of the quilombola territory Mãe Domingas was made in the context of an alliance between the people of the forest and the environmental movements. In this context, collection activities such as that of Brazil nuts were favoured, and ranching, which is considered as a vector of deforestation, was very marginal and little practiced. Once their territory was recognized, the Quilombolas of Abuí found themselves in a situation of land security, and it is possible that this new context favoured the increase in ranching. In effect, the alliance with the environmental movements became less indispensable to them, since the territory was now guaranteed, which may have led them to give in to a certain economic realism, encouraging a more profitable activity to the detriment of that which offered less financial security. One might thus put in parallel the marked weakening of the cooperative of the ARQMO, which barely functions, and the increase in the number of ranchers.
4. Migration routes and urbanization
The profound integration of the urban and rural worlds in Amazonia, which leads one to talk of “rural cities and urban forests” (Padoch et al, 2008), corresponds to a very old tradition of multi-sited households. Previously arising from socialization needs (feasts of the saints) and the commercialization of extractive and agricultural products, these multiple residences today are motivated, among other things, by access to care, education for children, and paid employment.
Thus, with globalization, the traditional populations of Amazonia make up increasingly diverse and extended socio-spatial networks (Granchamp, 2001; Padoch et al., 2008). This mobility is accompanied by the transformation in types of residency, the dispersion and fragmentation of social groups, and the hybridization of knowledge and identity, but also the reconfiguration of use and rights to resources (Alexiades, 2009; McSweeney and Jokisch, 2007; Eloy and Le Tourneau, 2009). The impact of this rural-urban mobility on resource management and the socio-demographic behaviour of the Quilombolas depends on land tenure issues but also on the nature of social and commercial networks established with the town, which are nested in a particular economic and political context. In addition, means of transport play a key role in these recompositions, the high cost of which can only be deemed worthwhile if individuals maintain strong ties with the community from whence they come. In this light, the two villages studied present strongly contrasting profiles.
4.1. The decline of Cunani, an irreversible phenomenon?
In the 1930s, a large landowner from Belém brought employees from Marajó and Vigia to work in his agricultural lands located at the mouth of the Cunani River. The population naturally increased, with a mixture of inhabitants from upstream and downstream, until it reached approximately 300 people. At that time, the settlement pattern was dispersed (retiros), with main houses located near swidden fields.
The construction of a public school led to families relocating to Vila Cunani around 1940/45. The village began to become more lively, notably during the religious festivals of Santa Maria in August, and São Benedito in December. However, the school stopped at the primary level, and the children could not pursue their education past the fourth year. Some of them were taken in by a godfather or godmother (compadre or comadre) in the main towns of the State of Pará (Belém, Vigia). A first generation of migrants was thus formed outside of Cunani but came back to marry, set up house, and raised on average eight children. These movements were periodic – most often for several months – and were organized around economic opportunities: an initial migrant calling others to the towns of Calçoene, Macapa, Belém, Oiapoque, and Cayenne, in order to work there in carpentry, gold mining, agriculture, and warehouse work. Then, during the 1980s, in order to be able to educate their children, the families moved definitively to Calçoene, which had become a regional economic centre since the opening of BR156.
As a consequence, families started to sell their “retiros” to buy land and have a house built in Calçoene, while keeping a house in Vila Cunani in case of an eventual return. Cunani has seen its population fall, going from 250 in 1970 to 26 in 2010, 16 of whom are more than 40 years old. The majority of children are raised in Calçoene (nearly 9000 inhabitants), then in Macapa and/or Belém for now, as they say, “Cunani is outdated”. Except for the period of gathering açaí, when the inhabitants of Calçoene come to help their families, and fishing or hunting during the vacations, the younger generations (15 – 25 years old) refuse to stay in this town in decline, with neither running water, electricity, or internet access.
According to our interviews, four inhabitants of Cunani also frequent two other villages, Lourenço and Vila União. These are not quilombola communities, but rather places of leisure and religious festivals. But most displacements focus on Calçoene, followed by Macapa and then Oiapoque.
Calçoene fulfills a number of possible functions (economic, social, services) and brings together visits of relatives (the equivalent of Oriximiná for Abuí). Macapá (the capital of Amapá) is essentially visited for family and not for economic reasons, similar to how Manaus is visited by people from Abuí (see below). Trips to Oiapoque, exclusively tied to IBAMA/ICMBIO, are made by men and concern community interests.
Figure 2 shows the dispersion of the kinship network of people from Cunani, living in Cunani, or having migrated to Calçoene fewer than 30 years ago. It shows that the families are dispersed exclusively among the towns, since no village appears in the network, which confirms the process of a rural exodus on a regional scale. The network confirms the preponderance of Calçoene in the social organization of Cunani. The residents of Cunani have most of their relatives in this town and in Macapa. Individuals having their families the most dispersed (3A, 5A, and 8C, at the centre of the network) are inhabitants of Cunani. These are among the oldest families of Cunani, who are looking to diversify their activities (trainings at IBAMA, plantations of açaí), which explains their dispersion. On the other hand, it seems that the inhabitants of Calçoene, living on commerce, social benefits, and agriculture, have no need to disperse in this way to develop their activities. The area of dispersion for women is smaller than that for men, though more qualitative, both as to length and frequency.
Figure 2.
Spatial dispersion of the kinship network of the inhabitants of Cunani and migrants from Cunani recently moved to Calçoene (29 surveys)
Considered as relatives in this graphic: father, mother, brothers and sisters, children, step-brothers and adopted children included, as well as current spouses.
\n\t\t\t\t\t\t
Thus, following the analysis of Domenach and Picouet (1987), thinking about the reversibility of migrations – and its corollary, irreversibility – allows us to highlight the importance of networks. The myth of return remains present in many discourses, as much for the affective ties as for the quality of life in the village. Once they have left, however, no family has returned to Cunani – with the exception of one person who had a serious accident – and the pensions of the retirees does not allow the migrants as frequent return visits as they might wish for. The oldest inhabitants would rather finish their days close to their children, in the hospital at Calçoene. Such a choice shows the increasing rootedness of the inhabitants of Cunani in the neighboring town of Calçoene. The analysis by network shows that the geographic mobility towards Calçoene may also constitute a step before that towards Macapa, where the university is a strategic asset for the younger generations.
Is the quilombola statute, on its way to recognition, a possible means of reversing this tendency? The funds released by the Secretary for Minorities, and given to the Quilombolas in the State of Amapá, can no longer be invested in local education, due to the lack of students. The teacher, who is also the president of the village association, has therefore proposed the building of a new community center, in the shape of an indigenous long house, or Maloca, thus hoping to give some prestige to the village; such an option, which shows the difficulty of characterizing culturally the Quilombolas of Brazil, would without doubt be the last major investment for the community.
4.2. Abuí: A successful integration within global dynamics?
Faced with the devaluing of extractive products and the rise in monetary needs, the Quilombolas of Abuí need to find new activities. A modification of the spaces frequented by members of the community can thus also be seen, tied to new social functions.
The study of the frequency and reasons for mobility reveal two principal modes of circulation outside the village. The short distance visits to the surrounding villages arise from “tradition” motivated by religious festivals, sporting events, and occasional visits to relatives. Displacement towards the towns deal above all with economic activities. These essentially concern Oriximiná: throughout the history of extractive activities in the region, the town has been a place of exchange and sale of extractive products for manufactured ones. But the frequency of displacements to Oriximiná seems to have increased these past few years, as the acquisition of a community boat as well as individual motorboats allow people to travel the 250 km of river in a single day, in contrast to many days in a pirogue. In 71% of the cases, people from Abuí say they go there at least once a month. This increase in the frequency of travelling to town is motivated by the growth of social benefits (accessible in town) since the Lula government (2003) as well as opportunities for salaried work. These are essentially jobs for women: the majority of young women from Abuí take their chances as house workers while pursuing their studies in Oriximiná, whereas the young children stay with their grandparents in Abuí. This growing interaction with Oriximiná is thus expressed in the construction of multi-sited residential systems (or multi-sited households) between town and forest
The residential system is an articulated group of places of residence for the members of an extended family (Le Bris, 1986}.
.
On the other hand, Porto Trombetas, located halfway between Abuí and Oriximiná, is much less frequented: most visits occur fewer than four times a year. Porto Trombetas essentially fulfils a function of access to health services. It is in effect a town built in the 1970s for skilled workers from the mining industry, and which had no role in the extractive economy. Visiting Porto Trombetas and the settling of families in nearby quilombola villages (such as Boa Vista) are strictly regulated and limited to avoid urbanization along the river in proximity to the mines (Nasuti, 2005). Faced with protests from the quilombola communities, the mining industry made the hospital at Porto Trombetas accessible in case of emergency, which explains such unusual displacements to this town. Porto Trombetas is also a destination for temporary work, but as opposed to Oriximiná, it is essentially work for men, tied to the mines. The regional towns, further away, such as Óbidos, Santarém, and Manaus, are less often cited, since they are visited only occasionally. Manaus is cited only as a place to visit relatives, who have left Abuí for good to work there.
Thus, the effects of recent urbanization in Abuí reflect in the extension of kinship networks in regional towns. Figure 3 shows that Abuí is where the majority of relatives reunite. The family network also links Abuí to other quilombola villages in the region (Tapagem, Sagrado Coração, Boa Vista, Erepecu), which reveals, as opposed to Cunani, the anchoring of this social structure in the rural setting. However, most of the people surveyed are situated between these three poles (Abuí, Oriximiná, and Manaus), which means they have close relatives in the two towns, notably Oriximiná, where they have older relatives as well as some younger ones (secondary school students, house workers). It can thus be said that most of the inhabitants of Abuí belong to multi-sited residential systems that link
Figure 3.
Spatial dispersion of the kinship network for the inhabitants of Abuí(76 surveys)
the legalized quilombola territory with regional towns offering economic alternatives to the crisis of extractivism. Instead of engaging in a process of rural exodus, the people of Abuí seek out available resources in different spaces by intensifying their movements into the towns. The polarized movements to towns are thus superimposed on the “traditional” movements between the other quilombola villages without replacing them.
5. Conclusion
The two quilombola communities studied are confronted with the contradictory effects of globalization: while they are subject to increasing environmental restrictions because of the proximity to and juxtaposition with conservation areas, they are increasingly integrated within a globalized market and a formal education system. In this way, our research brings into evidence the increasing disjunction between territory and identity produced by globalization (Appadurai, 1995). In effect, as with other traditional populations in Amazonia (Eloy and Lasmar, in press; Moreira, 2003 ; Padoch et al., 2008), there is a growing gap between, on the one hand, a demarcated territory, associated with a specific identity, and on the other, the socio-economic reality anchored in towns and articulated around individual strategies. These manifestations of globalization are expressed in a change in the use of resources but also in the extension of family networks in the regional towns. However, the function and form of these networks differ between the two communities.
In Cunani, after the construction of the BR and the creation of the National Park, the decade from 1980 – 90 was marked by migratory circulation and dual residency between Cunani and Calçoene. With the restrictions imposed by the IBAMA on river transport, most of the inhabitants opted for a definitive migration to Calçoene, as individual transport by road became too onerous. The perspective of the creation of a quilombola community at Cunani was not enough to halt the rural exodus. In addition, the local production of açaí, being seasonal, was not enough to keep the new generations in place. In this context, swidden cultivation is increasingly replaced by plantations of açaí requiring less labour, confirming a process of deagrarisation already observed in other communities in Amapá (Pinedo-Vasquez and Padoch, 2009). At present, the periodic and seasonal movements that link Cunani to Calçoene are motivated essentially by festive events and the production/commercialization of açaí. The social and commercial network of Cunani is thus centred around Calçoene and other regional towns.
In contrast, in Abuí, because of the devaluing of extractive products, land tenure security functions as a resource to free up new revenues that are complementary to or even dependent on urban resources (e.g. share breeding, social benefits, and paid employment). Despite the distance that separates Abuí from Oriximiná (250 km), the inhabitants have constructed multi-sited households between town and forest that rely on intensive river transport. The improvement in the level of livelihoods and the collective organization of river transport has been an essential factor in these socio-demographic adaptations. The mobility thus constitutes a “circulatory resource” (Cortes, pers. comm.) for the rural populations of Amazonia.
In both cases, the emergence of productive values brings with it the individual appropriation of resources (açaí plantations and pasture lands) and a certain concentration of wealth in the hands of a few families, and this even without private property. Thus, the recognition of collective quilombola lands would not be enough to halt the tendency towards socio-economic differentiation. The introduction of ranching in the quilombola villages of Trombetas, driven by the urban political elite through share breeding, indicates that land is not a privileged factor in the concentration of capital (Cochet et al., 2010).
Nevertheless, we cannot affirm that the land tenure security accorded to the Quilombolas of Trombetas explains and justifies in itself the introduction of cattle ranching. The fact that the quilombola lands are not under conservation restrictions leaves the owners free to exploit the resources as they see fit. And yet the introduction of ranching is also explained by the privileged relation that two families from Abuí have with a rancher from Oriximiná, which has allowed them to bring the initial productive capital (cattle). It is this type of network that the other community studied, Cunani, was not able to consolidate.
Thus, while the proximity to roads is known to be the principal factor determining the expansion of cattle ranching (Chomitz et al., 2007; Scouvart and Lambin, 2006), in this case the community that began this activity is precisely the one which is not connected to the road network and is furthest away from town. It seems therefore that the impact of globalization on land use of traditional populations is not uniquely determined by geographic factors (remoteness, land rights), but also depends on the access to mobility and the socio-cultural networks that these populations construct with different agents of development in Amazonia (urban political elites, businesses, NGOs).
Acknowledgments
Our study, financed by the French Agence Nationale de la Recherche, is part of USART program (Uses and transmission of territorial knowledge in traditional Amazonian context). Our fieldwork period was July and August 2010. We are grateful to all the farmers from Cunani and Abuí for their patience and kindness. Thanks to Kevin Frey for his accurate and rapid translation of this text.
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Introduction",level:"1"},{id:"sec_2",title:"2. Globalization and the access to land rights: The ethnic strategy",level:"1"},{id:"sec_2_2",title:"2.1. The splendor and misery of Cunani",level:"2"},{id:"sec_3_2",title:"2.2. Abuí, a quilombola community in the Trombetas valley",level:"2"},{id:"sec_5",title:"3. Globalization and market access: Economic strategies and their impact on forms of development",level:"1"},{id:"sec_5_2",title:"3.1. Açaí, an expanding global market in Cunani",level:"2"},{id:"sec_6_2",title:"3.2. Brazil nuts and introduction of cattle ranching in Abuí",level:"2"},{id:"sec_8",title:"4. Migration routes and urbanization",level:"1"},{id:"sec_8_2",title:"4.1. The decline of Cunani, an irreversible phenomenon?",level:"2"},{id:"sec_9_2",title:"4.2. Abuí: A successful integration within global dynamics?",level:"2"},{id:"sec_11",title:"5. Conclusion",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'AlexiadesM. 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C.\n\t\t\t\t\t1996\n\t\t\t\t\tO Mito moderno da Natureza intocada, São Paulo, Editora Hucitec- NUPAUB/USP.'},{id:"B14",body:'DomenachH.Picouet\n\t\t\t\t\t1987 1987. «Le caractère de réversibilité dans l’étude de la migration », Population, 3\n\t\t\t\t\t469484 .'},{id:"B15",body:'EloyL.\n\t\t\t\t\t2008 «Diversité alimentaire et urbanisation. Le rôle des mobilités circulaires des Amérindiens dans le Nord-Ouest Amazonien». Anthropology of food,S4 p. http://aof.revues.org/document2882.html'},{id:"B16",body:'EloyL.Le tourneauF. M.,«L’urbanisation.provoque-t-elle ladéforestation.enAmazonie. ?.Innovationsterritoriales.etagricoles.dans lenord-ouest.Amazonien.Brésil».2009 Annales de géographie (Paris), 118 n° 667 : 204-227. search.ebscohost.com/login.aspx?direct=true&db=fcs&AN=21936449&lang=fr&site=ehost-live'},{id:"B17",body:'Geffray, C., ,Chroniques de la servitude en Amazonie brésilienne.1995 Essai sur l’exploitation paternaliste. Paris, Editions Karthala.'},{id:"B18",body:'GranchampF. L.200Urbanisationstratégies.familialeset.multipolaritérurale-urbaine.la transamazonienneà.l’ouestd’Altamira. .ParáBrésil. Thèse de doctorat. Paris: EHESS, Centre de Recherche sur le Brésil Contemporain, 386 p.'},{id:"B19",body:'GreissingA.KohlerF.Le TourneauF. M.PicançoJ. R. A.\n\t\t\t\t\t2008 «Iratapuru et la noix du Brésil: une expérience de durabilité en Amazonie brésilienne », Cybergeo, Environment, Nature, Landscape, Article 432, http://cybergeo.revues.org/20763'},{id:"B20",body:'HarrisM.\n\t\t\t\t\t2006 “Presente ambivalente: uma maneira amazônica de estar no tempo”, in: Sociedades Caboclas Amazônicas: Modernidade e Invisibilidade. C. Adams, R.S.S. Murrieta, and W.A. Neves (eds.). São Paulo, Ana Blume: 81108 .'},{id:"B21",body:'KramerD. B.UrquhartG.SchmittK.\n\t\t\t\t\t2009\n\t\t\t\t\tGlobalization and the connection of remote communities: A review of household effects and their biodiversity implications, Ecological Economics\n\t\t\t\t\t68\n\t\t\t\t\t2009\n\t\t\t\t\t28972909 .'},{id:"B22",body:'LebrisE.\n\t\t\t\t\t1986 «Synthèse des travaux sur la mobilité interne et externe dans le Sud-Est Togo».In E. Le Bris, G. Pontié, A. Quesnel, J. Gregory, M. T.Duquette-Ahado and K. Vignikin (eds.), Migrations togolaises: bilan et perspectives. Lomé: Université du Bénin. Unité de Recherche Démographique (TGO) : 255282 .'},{id:"B23",body:'McsweeneyK.JokischB.\n\t\t\t\t\t2007 «Beyond Rainforests: Urbanisation and Emigration among Lowland Indigenous Societies in Latin America ». Bulletin of Latin American Research, 26 n° 2 : 159 EOF180 EOF .'},{id:"B24",body:'MoreiraE. L.\n\t\t\t\t\t2003 «Amazônia em movimento: Redes e Percursos de Desenvolvimento dos Índios Ye’kuana, Roraima». Cadernos de Campo (USP),11\n\t\t\t'},{id:"B25",body:'NasutiS.\n\t\t\t\t\t2005 Infrastructures industrielles et communautés: stratégies territoriales. Vallée de Trombetas, Etat du Pará- Brésil, Master. Paris: Université Sorbonne Nouvelle-Paris III, IHEAL.'},{id:"B26",body:'PadochC.BrondizioE.CostaS.Pinedo-vasquezM.SearsR. R.SiqueiraA.\n\t\t\t\t\t2008 Urban forest and rural cities: multi-sited households, consumption patterns, and forest resources in Amazonia. Ecology and Society 13(2): 2. [online] URL: http://www.ecologyandsociety.org/13 iss2/art2/)'},{id:"B27",body:'PantojaM. C.CostaE.PostigoA.\n\t\t\t\t\t2009 “A presença do gado em Reservas Extrativistas: algumas reflexões”. Caderno Pós Ciências Sociais.\n\t\t\t\t\t6 n.12 jul/dez, São Luis/MA: UFMA.'},{id:"B28",body:'Pinedo-VasquezM.PadochC.\n\t\t\t\t\t2009 «Urban and rural and in-between: Multi-sited households, mobility and resource management in the Amazon floodplain», In M. ALEXIADES (ed.), Mobility and migration in indigenous Amazonia. Oxford, Berghahn books : 8696 .'},{id:"B29",body:'Porró, A., ,“Notas sobre o antigo povomaento indígena do Alto Trombetas e Mapuera”,Boletim do Museo Paraense Emílio Goeldi,\n\t\t\t\t\t20083\n\t\t\t\t\t3 n°3, 387397 .'},{id:"B30",body:'RicardoF.rolla\n\t\t\t\t\t2009 2009. Amazonia brasileira. Sao Paulo: InsitutoSocioambiental.'},{id:"B31",body:'ScouvartM.LambinE. F.\n\t\t\t\t\t2006 «Approche systémique des causes de la déforestation en Amazonie brésilienne. Syndromes, synergies et rétroaction», Espace Géographique, 35 n° 3 : 241-254.'},{id:"B32",body:'UNESCO,\n\t\t\t\t\t2003\n\t\t\t\t\tCultural Diversity and Biodiversity for Sustainable Development: a jointly convened UNESCO and UNEP high-level Roundtable held on 3 September 2002 in Johannesburg, South Africa during the World Summit on Sustainable Development:\n\t\t\t\t\thttp://unesdoc.unesco.org/images/0013/001322/132262e.pdf'},{id:"B33",body:'VeranJ.F.\n\t\t\t\t\t2002 «Quilombos: des ‘lieux de mémoire’ bien vivants », Cahiers du Brésil Contemporain n° 49-50 : 87-96.'}],footnotes:[{id:"fn1",explanation:"Ludivine Eloy2, François-Michel Le Tourneau3, Claire Couly4, Stéphanie Nasuti3, Dorothée Serges5, Sophie Caillon6, Guillaume Marchand1 and Anna Greissing3."},{id:"fn2",explanation:"The communities of Paraná do Abuí, Tapagem, Sagrado Coração, and Mãe Cué."},{id:"fn3",explanation:"Arrangement in which a big rancher, having productive capital and generally living in town, places his cattle in several small ranchers’ fields, who, in exchange for half of the production, plant and maintain the pasture (Cochet et al., 2010)."},{id:"fn4",explanation:"Considered as relatives in this graphic: father, mother, brothers and sisters, children, step-brothers and adopted children included, as well as current spouses."},{id:"fn5",explanation:"The residential system is an articulated group of places of residence for the members of an extended family (Le Bris, 1986}. 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1. Introduction
A consensus agreement on the definition of cellular senescence may be stated as a viable but non-proliferative condition distinct from the G0 quiescent phase of the cell cycle and postmitotic terminal differentiation [1, 2]. While aged living organisms accumulate senescent cells, aging and senescence are not synonymous terms—the cellular and molecular pathways that eventuate in the senescent state can be activated by diverse mechanisms, not necessarily chronologic aging nor the limit of replicative cell division. It was the latter phenomenon, in fact, that led early investigators to the original concept of cellular senescence as an in vitro observation; that replicating fetal “skin tissue cells” stop dividing at a certain passage number, the so-called “Hayflick Limit” [3]. This review focuses on our current understanding of how cellular senescence occurs in the skin, its irreversible (and possibly reversible) characteristics, description of known trigger points involving genetic and epigenetic factors and their clinical implications in health and disease.
Cellular senescence is characterized by cell cycle arrest [4], the expression of senescence associated secretory phenotype (SASP) [5, 6], damage to DNA [7, 8, 9], deregulated metabolic profile [2, 10], changes to the epigenome [11] and transcriptome [12], resistance to apoptosis [13, 14], and altered immune surveillance [15, 16]. It can be triggered by multiple factors [2], the mechanisms of which appear to categorize the ‘type’ of senescence into two main groups; so-called replicative senescence (RS) due to shortened telomeric DNA resulting from excessive cell division cycles [17, 18, 19, 20]; and a state generally termed ‘premature senescence’ (PS), in which both oncogene-induced senescence (OIS), triggered by activation of oncogenes such as ras [21], and several other ‘molecular stresses’ [4] also eventuates in the senescent phenotype.
There are a variety of biomarkers for cellular senescence but not all senescent cells express the same biomarkers due to these differential molecular induction pathways. Several senescent biomarkers have been identified in the skin [22]; however, it is currently unclear how the multitude of cell types that comprise this tissue respond to senescence-inducing triggers and how this correlates with skin aging, other than the fact that senescent cells accumulate in all skin compartments with age, just like other organ systems. What is becoming clear, however, is that cellular senescence plays critical roles in the pathobiology of skin aging and disease [23].
2. Aging of the skin
Both intrinsic (time, genetic and hormonal) and extrinsic (environmental) factors contribute to skin aging. Old skin not only appears clinically different from young skin but has altered physiology due to a combination of molecular, cellular, and biochemical processes, and tracing the pathogenic origin of the ‘skin aging phenotype’ remains a work in progress. From a clinical perspective however, the skin of most people older than 6–7 decades of life, particularly in photo-exposed areas, is thinner, looser, less tethered to underlying tissue, more wrinkled, more translucent with more visible capillary vessels, more discolored, drier, and less padded by the subcutaneous layer [24, 25]. Scalp skin also ages, commonly observed as pigment loss (graying), and most people experience hair loss as another inevitable esthetic problem.
Anatomically, the structure of human integument tissue we call ‘skin’ is composed of ectodermal-derived epithelial cells layered as stratified squamous epithelium on top of mesenchymal-derived dermis separated by a specialized basement membrane zone (BMZ) called the dermal-epidermal junction (DEJ). Directly below the dermis is the fatty hypodermis (or subcutaneous layer) separating fascia and muscle from the skin. Epithelial-mesenchymal interactions that occur during embryogenesis (and wound repair) contribute to the formation of glandular structures buried within these compartments (called adnexa) which are comprised of eccrine, apocrine, sebaceous and hair follicle structures. Peripheral nerves and blood vessels traverse the subcutaneous and dermal layers and together with all other structures of the integument, serve the functions of barrier protection, retention of heat and water, sensation, contractility, and lubrication [26].
This multi-compartmental system is the largest organ of the body and is composed of about 20 different cell types responsible for skin function and its stratification [27], all of which also change with age to contribute to the overall ‘skin aging phenotype’. At the microscopic level, skin tissues of older individuals exhibit common characteristics regardless of whether sun protected or chronically exposed to ultraviolet (UV) light [28]. The most obvious and well documented structural changes include epidermal thinning, loss of rete ridges and flattening of dermal papillae [29, 30], keratinocyte and melanocyte architectural changes [31, 32], BMZ/DEJ alterations [33], less dense and altered reticular dermal collagen structure [34], accumulation of altered elastin and elastic fiber structural abnormalities [35], altered shape and loss of papillary dermal capillary loops [36, 37, 38], and size and structural alterations in glandular structures of the eccrine, apocrine and sebaceous units [39]. Concomitant with morphologic changes observed in aged skin, senescent cell populations increase in all skin compartments.
2.1 Effects of aging on epidermal structure and function
The epidermis, consisting of 5 different layers of keratinocytes, continuously renews itself on an approximate 27-day cycle by a differentiation program involving basal cells which are maintained and replenished by stem cells residing in the bulge region of the hair follicle and the interfollicular epidermis [40]. Of particular importance to aging of the epidermal compartment is the general concept that the cellular microenvironment (or niche) of stem cell populations plays a critical role in homeostatic resupply of transient amplifying basal cells [41]. The epidermis maintains a dynamic equilibrium by proliferating in the basal layer that is attached to the DEJ, then cell division ceases and basal keratinocytes undergo terminal differentiation while spatially migrating towards the top of the epidermis. During this transition, keratinocytes acquire specialized cytoskeletal components and create an intercellular diffusion barrier, eventually forming the outermost epidermal layer called the stratum corneum (SC). The SC is a specialized acidic, hydrophobic, protein-lipid-carbohydrate flexible ‘shell’ resistant to wear and tear, water loss, and invasion of microbes [42]. The “barrier function” of the skin is derived from the SC.
The epidermal compartment appears to deal with the ravages of extrinsic aging in a fundamentally different way than the dermal compartment because terminally differentiated (cell cycle arrested) keratinocytes are continuously shed, thus removing accumulated DNA and other macromolecular damage that otherwise trigger the senescent phenotype. But since the epidermis is continuously replenished by stem cells arising from the interfollicular niche, its alteration can affect epidermal biology in profound ways. In fact, epidermal stem cell niche can be affected during aging by both basal keratinocytes [43] and dermal fibroblasts [44]. Niche microenvironments can be altered by intrinsic and extrinsic aging at cell-cell, cell-matrix and paracrine signaling levels, leading to stem cell depletion and the ‘atrophic epidermal phenotype’ observed in intrinsic aged skin [45].
Many other cell types localize to the epidermis, including pigment-producing melanocytes found in the basal layer that protect against UV radiation. Pigment is synthesized within the melanocyte but transferred to neighboring basal keratinocytes (and specialized hair follicle-associated keratinocytes) via a complex melanosomal exo/phagocytosis mechanism localizing at the dendritic tips of melanocytes which interdigitate with up to 20 keratinocytes [46]. Melanocyte dysfunction associated with extrinsic aging (mostly photoaging) manifests clinically as abnormally dispersed and/or diminished melanin pigment (i.e., dyschromia, lentigines, and in the scalp, canities). Senescence of the melanocyte has been observed both in vitro and in vivo and the molecular pathways involved identified [47]. In fact, based on biomarker (e.g., P16) expression, senescent melanocytes appear to represent most senescent cells in aged epidermis [48] and their contributions to development of the epidermal atrophic phenotype via autocrine and paracrine (i.e., SASP) mechanisms have been identified [49].
The epidermal immune system is a network of resident antigen-presenting dendritic Langerhans cells (LC) thought to function as immune sentinels [50] together with trafficking lymphoid immune cells including resident memory T cells as CD8+ and CD4+ cells [51]. Of interest, a specialized CD4 + T cell (Treg) residing near the hair follicle bulge areas (located in the dermis) has been shown to play a role in hair growth cycling [52]. Skin aging is associated with variable deterioration of both adaptive and innate immune function, generally referred to as cutaneous ‘immunosenescence’. This term has become controversial in the literature [16] because immune cell senescence is, in part, a physiologic adaptive response to survival and fitness of the organism. Its use to describe altered skin immune responses with age appears appropriate in the context of inflammaging [53], since the concept of immunosenescence encompasses both systemic chronic, low-grade inflammation [i.e., elevated serum levels of interleukins IL-6 and IL-8 and increased tumor necrosis factor alpha (TNF-α), etc.] and the presence of dysfunctional immune responses in various skin compartments apparently related to both tissue level RS and PS. Currently unknown, however, is whether cutaneous inflammaging is a cause or an effect of dysfunctional innate immune responses observed in the elderly and whether cellular senescence is responsible.
Examples of cutaneous aged-related immune dysfunction include reported reductions in the number and functionality of LC in aged skin and this correlates with both age related defective epidermal barrier function and inflammaging [54]. Likewise, defective physiologic immune clearance of senescent cells that contribute to aged skin pathologies have been demonstrated in dermal fibroblasts by the observation that these cells express a nonclassical major histocompatibility antigen (HLA-E). Its increased expression appears to block activation of natural killer (NK) cells and CD8+ cells responsible for clearing damaged cells, suggesting that evasion of dermal immunosurveillance leads to persistence of senescent dermal fibroblasts [55].
Aging is a clinical comorbidity in many skin diseases pathogenically linked to defective cutaneous innate and adaptive immune responses [53]. The incidence and prevalence of autoimmune blistering disorders such as bullous pemphigoid (BP), pemphigus vulgaris, and epidermolysis bullosa acquisita are all increased in older populations, BP being the most common example [56]. Likewise, aging is a comorbidity in the development of skin cancers, and the loss of immunosurveillance due to dysfunctional LCs is thought to contribute to progression of both non-melanoma skin cancer (NMSC) [57] and melanoma [58].
Another unique cell type scattered along the DEJ, considered part of the epidermal compartment, and possessing mixed neuronal, endocrine, and immunologic functions (as well as embryonic origin) is the Merkel cell (MC) [59]. Its involvement in the skin’s somatosensory system is key to the sense of fine touch discrimination, which is decreased in the elderly [60]. In glabrous skin MC form complexes with intraepidermal sensory neurites found at the DEJ termed ‘touch domes’ or Merkel’s discs. Digital skin of aged humans contains less of these complexes, lower density of MC and decreased expression of the stretch-activated ion-channel component Piezo2 [61]. Occurring mainly in aged humans, a rare but very aggressive skin cancer, Merkel cell carcinoma (MCC) has attracted recent attention due to its mysterious etiopathogenesis. 80% of MCC is associated with integration of a newly identified polyoma virus (MCPyV) [62], whereas 20% appear linked to accumulation of UV light-induced somatic mutations [63]. As detailed in the next section on epigenetics, it is of interest that the majority of MCC display expected chronologic age but DNA methylation patterns of epigenetically youthful cells [64].
2.2 Aging and the dermis
The dermal compartment is divided into superficial, reticular, and deep dermis with unique cellular, vascular, extracellular matrix (ECM), and adnexal components that define each space. Much of the ‘business-end’ of the dermis is localized to the superficial dermal compartment and the DEJ is central to its structure and functionality. It is considered part of both the epidermis and the superficial dermis because cellular components of each layer contribute to its synthesis, maintenance, and renewal. Serving as an adhesive scaffolding for basal keratinocytes, a shear-resistant Velcro-like surface securing the dermis to the epidermis, a complex paracrine factor-sequestering and mechano-transducer signaling layer, the DEJ modulates a remarkable number of cutaneous cellular processes involved in skin structure, function, regeneration, and resistance to trauma [33]. Comprised mainly of Type IV collagen and laminin, like other BMZs, DEJ complexity has been dissected at the molecular level to reveal a complex network of other collagens (VII, XVII and XVIII), 4 different isoforms of laminin (511, 521, 311 and 332), perlecan, nidogens, SPARC, fibrulins-1 and -2, dystroglycans, and integrins a3b1 and a6b4. All of these DEJ components are altered during aging and these changes correlate with age dependent increases in both DEJ thickness and stiffness [65].
Immediately beneath the DEJ, forming nipple-like structures projecting into the epidermal compartment and containing unique ECM, microvasculature, specialized fibroblasts, and dermal mesenchymal stem cells is the papillary dermis (PD). Here, undulating dermal protrusions interdigitate with epidermal rete ridges (pegs) to increase surface area for nutrient transfer, trafficking of immune cells, and increased tensile strength. The transition of superficial to reticular dermis is static and defined mostly by changes in ECM structure but dynamic during repair and disease. The majority of space in reticular dermis is occupied by thick bundles of interstitial collagens I and III, elastin and fibrillin fibers, and amorphous ‘ground substance’ comprised of hyaluronic acid, proteoglycans and glycoproteins. Like the DEJ, most if not all these dermal ECM components are altered and/or dysfunctional due to aging [35]. Both intrinsic and extrinsic aging correlate with the loss of rete ridges and flattening of dermal papillae [29, 30]. Compared to young, non-exposed and old photo-protected skin, the PD of chronically photodamaged skin displays marked structural changes, the most dramatic feature of which is the presence of “solar elastosis” in the superficial dermis. Solar elastosis consists of pathologically altered elastin fibrils [66] that present as dense accumulations of amorphous material best visualized with trichrome staining.
The cellular composition of these dermal sub-compartments is a complex mix of fibroblasts, endothelial cells, myofibroblasts, macrophages, mast cells, trafficking immune cells, adipocytes, various stem cells, sensory neurites, and the differentiated cellular components of dermal adnexa (including the hair follicle). An example of such cellular complexity, the significance of which continues to evolve, is the apparent postnatal plasticity of the dermal fibroblast. Single cell RNA sequencing has revealed at least four different subpopulations of human dermal fibroblasts [67, 68], and skin aging has been demonstrated to have a strong effect on both dermal ‘fibroblast’ phenotype and functionality. For example, young papillary dermal fibroblasts can direct reformation of youthful DEJ and epidermal structure and function, whereas old papillary and/or reticular dermal fibroblast populations cannot [69]. Furthermore, it is the senescent PD fibroblast and CD271+, laminin 332-expressing interfollicular stem cells that contribute to age-associated pathologic remodeling of the DEJ [33, 70]. Recent attention has focused on specific dermal fibroblast subpopulations and their involvement in wound healing, fibrosis, and loss of epidermal stem cell ‘stemness’ due to niche signaling dysfunction. The homeobox gene engrailed-1 (EN-1) expression appears to distinguish two types of fibroblasts; those cells expressing EN-1 are associated with fibrotic healing phenotype whereas EN-1 negative fibroblasts promote physiologic remodeling [71, 72]. Epigenetic modulation of the fibrotic phenotype is reviewed in the next section.
2.3 Subcutaneous layer involvement in skin aging dysfunction
The subcutaneous compartment (hypodermis) is composed mainly of cellular lipid storage units (adipocytes) separated by thin weblike networks of specialized ECM stroma containing microvasculature, adipose derived mesenchymal stem cells (ADSC) and immune cells. It functions as a thermoregulatory and shock-resistant barrier, as well as a reservoir of bioactive factors involved in systemic lipid metabolism, energy balance, and endocrine function [73]. Subcutaneous fat also undergoes age-related changes that are generally like the epidermal and dermal compartments where an ‘atrophic’ phenotype becomes clinically evident. With aging, subcutaneous fat deposits in various body locations disappear and/or are redistributed to visceral locations elsewhere in the body, causing esthetic concerns; this redistribution is associated with a variety of systemic age-related disease states, including insulin resistance, metabolic syndrome, cardiovascular disease, and obesity [74, 75]. Of note, senescent cells have been shown to accumulate in aged adipose tissue [76], contributing to systemic inflammaging. Experimental clearance of senescent cells can dramatically affect the redistribution of fat from the visceral to the subcutaneous compartment and decrease SASP expression [77]. The mechanism(s) of adipose cell senescence has not been clearly defined; however, ADSC exhaustion, oxidative stress by reactive oxygen species (ROS), and niche disruption appear to play important roles [78].
The influence of adipogenic hormones in skin aging and senescence has received recent attention with the discovery that UVB-light induced PS in human keratinocytes can be rescued by adiponectin via its suppression of inflammatory signaling pathways and human beta defensin-2 (hBD2) expression [79]. Human dermal fibroblasts express adipokine receptors and both leptin and adiponectin have been shown to stimulate expression of the ECM components hyaluronic acid and interstitial collagen [80]. These adipogenic hormones secreted by subcutaneous fat cells thus appear to represent paracrine cutaneous anti-aging factors for both the epidermal and dermal compartments.
‘Fat grafting’ has become a popular procedure in esthetic medicine and a variety of other clinical indications [81, 82] with special attention focused on ADSC. These cells can be isolated from subcutaneous fat removed during liposuction procedures after the stromal vascular fraction (SVF) is either mechanically sorted or enzymatically digested with bacterial collagenase, decanted (or centrifuged), washed, and grafted [83]. SVF is composed of cellular components (pre-adipocytes, adipocytes, histiocytes, endothelial cell progenitor cells and ADSCs) and is a rich source of growth factors (i.e., bFGF, IGF-1, VEGFs, PDGF-BB), matrikines, and other paracrine cellular factors. The ADSC secretome has been well characterized, consisting of soluble protein factors and lipid membrane particles (exosomes and ectosomes) that are used internationally in multiple therapeutic clinical trials for a vast array of indications, including dermatologic conditions (esthetics, wound healing, fibrotic diseases, dermatoporosis, etc). It is the loss of ADSC stemness, decreased proliferative potential, and dysfunctional secretome expression accompanying skin aging that continues to draw intense interest [82].
3. Genetic influences on cutaneous cellular senescence
The two major molecular pathways resulting in RS and PS have been observed in the skin [23]. These are reviewed in the following section by examining first the genetic aspects of cutaneous cellular senescence, followed by epigenetic influences. It should be noted here that acquisition of these cellular senescence phenotypes plays a critical role in both normal organismal and tissue level physiology by, for example, dampening fibrotic responses during the remodeling phase of wound repair or suppressing tumor formation [84]. However, it also appears to be a major pathologic driver in age-related disease states [85].
3.1 DNA damage related to telomere biology
The senescent phenotype can be activated by DNA damage at the ends of all eukaryotic chromosomes, called telomeres, which consist of DNA loops containing noncoding repeats of guanine-rich sequences complexed with protective oligomeric proteins (Shelterins). Discovery that chromosomal replicative machinery responsible for somatic cell division cannot synthesize exact duplicates of these structures led to the concept of the ‘end-replication problem’ during serial passaging [20]; thus, telomeric DNA is subjected to attrition because DNA polymerase fails to replicate the 3′ lagging strands.
Telomeric DNA are shortened by approximately 50–200 bp per cell division and thus a molecular clock is achieved, reflecting the replicative history of primary cells [86]. A specialized DNA polymerase (telomerase) is responsible for fixing the ‘end replication problem’, maintaining telomeric length, but its expression and function are restricted to immortal postnatal cells; in vivo, comprising stem, progenitor, and cancer cells. When cells reach their ‘Hayflick Limit’ telomeres lose enough DNA [87] to trigger a genomic instability signal and chromosomes become ‘uncapped’ by loss of Shelterin. This genomic instability signal is a specialized DNA damage response (DDR) and generates telomere dysfunction-induced foci (TIFs). Approximately half of all persistent DNA damage foci are localized to telomeres, and these can trigger RS. But senescent cells can harbor many other forms of persistent chromosomal DNA damage foci, called DNA-SCARS (DNA segments with chromatin alterations reinforcing senescence) [9]. These dynamic structures can also trigger cell cycle arrest and SASP induction.
Independent of telomere length or uncapping by loss of Shelterins, guanine-rich telomeric DNA repeats can become damaged by ROS, generating DDR telomere-associated foci (TAFs), which are associated with triggering the senescence phenotype [19]. This observation has particular relevance to the state of chronic inflammation, SASP expression, and tissue aging (Inflammaging) in skin and other tissues [15, 88, 89], as discussed in Section 3.2.
While epidermal, dermal, and subcutaneous cellular compartments all harbor evidence of RS in aged skin tissue, direct evidence that telomeric DNA associated RS is involved in skin aging is supported by experiments involving ectopic expression of human telomerase (hTERT). We reported that neonatal human dermal microvascular endothelial cells (HDMEC) undergo RS in vitro but can become immortalized with viral transfer of the catalytic subunit of hTERT [90]. Furthermore, these telomerized HDMEC formed fully functional microvessels in vivo (perfused with murine blood) that exhibited superior durability with time after xenografting in immunodeficient mice versus vessels created with in vitro-aged primary HDMEC [91]. As previously reviewed, cutaneous microvasculature of aged papillary dermis is markedly reduced and abnormally structured versus young dermis [38], presenting clinically as telangiectasia and senile purpura/dermatoporosis. The roles of RS, OIS, and other senescent pathways on skin vasculature remain to be determined.
3.2 Genotoxic and exposome insults
As noted in the introduction, cellular senescence can be induced in the absence of any telomeric damage or loss and this premature senescence (PS) has similar deleterious effects on aged tissues, including the skin. The triggers for the PS program generally fall into (a) accumulation of subcytotoxic, unrepairable, non-telomeric DNA damage, including mitochondrial DNA (mtDNA), (b) macromolecular insults to cytosolic and secreted proteins and lipids, and (c) metabolic dysfunction involving an altered mitochondrial-lysosomal axis [92]. All of these PS triggers have been demonstrated in skin cells in vitro and in vivo [93].
The molecular and cellular effects of chronic UV light exposure (photoaging) have also been well-documented and, in many ways, more extensively than intrinsically aged human skin. Both UVA (320–400 nm, less energy) and UVB (280–320 nm, more energy) light cause photoaging but UVB is mostly absorbed by the epidermis, where it causes sunburns. UVA penetrates the superficial and reticular dermal compartments and is considered a major factor in photoaging. While both UVA and UVB wavelengths generate reactive oxygen species (ROS), indirectly damaging DNA, UVB is also directly mutagenic, causing DNA defects called cyclobutene pyrimidine dimers and 6–4 photoproducts [94]. Remodeling of dermal ECM favoring an atrophic phenotype is triggered in unwounded skin by UV exposure via the activation of mitogen-activated protein kinase (MAPK) and activator protein 1 (AP-1) signaling pathways which causes downstream expression of matrix metalloproteinases (MMPs) in both the epidermal and dermal compartments [95]. These same pathways block transforming growth factor beta (TGF-β)/SMAD signaling via TGF-b type II receptor down regulation causing decreased collagen synthesis [96, 97]. Dissection of the molecular effects of chronic UV exposure on the DEJ and PD have been recently reviewed [33].
Our understanding of the role senescent cells play in cutaneous aging pathologies continues to evolve. In the past, senescent cells observed in the skin with biomarkers in vivo were believed to be passive, unresponsive bystanders recognized morphologically by their enlarged, seemingly flattened, abnormal shapes and senescence-associated (SA) β-galactosidase staining. But characterization of SASP expression in senescent cells (and their paracrine effects) provided compelling evidence that senescent cells are anything but passive.
It is now widely accepted that senescent cells remarkably influence surrounding non-senescent neighbors and ECM networks via secretion of inflammatory cytokines, chemokines, matrikines, MMPs, tissue inhibitors of metalloproteinases (TIMPs), and other proteinase-inhibitor systems that comprise the tissue ‘proteinase web’ [98]. One such example is the role played by plasminogen activator inhibitor-1 (PAI-1) in modulating senescence. PAI-1 is a soluble and matrix bound serine protease inhibitor with multiple matricellular functions and can be found at increased levels in both dermal fibroblasts from aged donors and premature aging syndrome patients [99, 100, 101]. Ectopic expression of PAI-1 in fibroblasts induces the senescent phenotype and is both necessary and sufficient for RS downstream of p53 [102]. Many other examples of SA ECM alterations have been reviewed [33].
The quintessential example of extrinsic aging involves the postmitotic dermal fibroblast population which responds to ‘expososomal’ damage [103] by activating DDR pathways, triggering PS and subsequent expression of macromolecular damage profiles involving mtDNA damage. One mechanism of mtDNA damage appears to involve UV light-induced deletion of a significant length of mtDNA, termed the ‘common deletion’ (CD) [104]. This 49 kb mtDNA fragment contains codons for electron transport chain (ETC) protein complexes I, IV and V which together express 72 ETC subunits, the loss of which cripples physiologic functions of mitochondrial energy metabolism, ROS protective mechanisms, and calcium homeostasis. Tracking the mtDNA CD in human skin revealed that both intrinsic (photo-protected) and extrinsic (chronic UV-damaged) skin contain this marker [105], and that dermal fibroblasts appear to be the culprit for subsequent age-related tissue damage of ECM [106, 107].
3.3 Genetic skin diseases associated with DNA repair pathway defects
Analysis of progeroid syndromes have provided insights into molecular mechanisms of intrinsic and extrinsic skin aging. Common skin phenotypic signs and symptoms shared by both these premature aging disorders and skin aging in the general population include skin atrophy, alopecia, fibrosis, telangiectasia, poikiloderma, canities and both NMSC and melanoma. Rare autosomal recessive patterns of different mutations in DNA repair genes group these heritable disorders into those involving; (1) multiple defects in nucleotide excision repair (NER) genes [e.g., DNA polymerase eta (POLH) among six others] coding for repair proteins in xeroderma pigmentosum (XP) [108], (2) transcription and transcription-coupled NER genes in Cockayne syndrome (CS) and (3) mutations in the gene family of RecQ helicases involved in DNA double strand break repair in Werner syndrome, Bloom syndrome, and Rothman-Thomson syndrome [109]. In the latter three disorders, mitochondrial defects have been well documented and correlate with cellular senescence phenotypes [110, 111]. In XP-V null mouse models, loss of POLH leads to obesity and marked adipose tissue senescent phenotype expression [112].
3.4 SNPs and transcriptomics
Several genome-wide association studies (GWAS) and meta-analyses performed on young and old populations have identified single nucleotide polymorphisms (SNPs) in genes thought to be correlated with skin aging [113, 114, 115, 116, 117, 118] or ‘perceived’ facial age’ [119]. These large cohort-based studies suggest specific allelic variants of pigmentation gene (MC1R), aryl hydrocarbon receptor gene (AHR), basonuclin 2 gene (BCN2), type-1 collagen alpha-2 gene (Col1A2) or SNPs within or near the DIAPH2, KCND2 and EDEM1 loci all appear to correlate with both intrinsic and extrinsic skin aging phenotypes and/or youthful skin appearance.
Of all these identified genes and their allelic variants, the biology of MC1R gene has received perhaps the most recent attention due to its central role in modulating human (and murine) skin pigmentation systems, the clinical influence of which led to the categorization of Fitzpatrick Skin Phototypes. MC1R signaling is associated with both skin cancer and skin aging via its mixed role in UV induced PS in melanocytes and promotion of efficient DNA damage repair [120]. Genetic variants of MC1R (coding for G protein-coupled transmembrane melanocortin receptor-1 on melanocytes) are strongly linked to increased risk of both NMSC and melanoma in both red and brown Caucasian phototype cohorts [121]. Meta-analysis of several GWAS studies demonstrated SNPs in or near MC1R (and SLC45A2 and IRF4) correlated with different skin aging phenotypes using a skin surface topographic scoring system of solar elastosis [116] and the MC1R gene may also affect inflammaging via generation of ROS independent of its function in melanin production [122].
Gene expression studies of the skin aging phenotype have revealed several important observations about the complexities of distinguishing intrinsic from extrinsic mechanisms, as they appear to overlap in many important ways. In human skin, gene profiling and transcriptomic analyses [115, 123, 124, 125, 126, 127, 128] have identified thousands of upregulated and downregulated genes in old vs. young and intrinsically aged vs. extrinsically aged (photoaged) skin. One transcriptomic study showed genes associated with mitigating oxidative stress, control of lipid synthesis, and epidermal differentiation were all downregulated in both exposed and photo-protected skin, whereas, elastin expression was increased in exposed skin (consistent with formation of solar elastosis), and interstitial collagen expression decreased in sun protected skin (consistent with intrinsic aging) [127]. Similarly, confirming histologic studies, expression profiling of human aging that spanned subjects between the ages of 24–70 years demonstrated younger-appearing skin upregulated expression of the LAMA5 gene (DEJ component) and epidermal cell-cell adhesion complex (desmosomal) genes DSC3 and CDH1 [126].
Race, sex, and skin tone of subjects also all play a role in the genetic correlates of skin aging. The expression of some aging related genes was found to be sex-dependent in a Caucasian sample [129], and studies in a Han Chinese sample showed distinct genetic variants and phenotypes from that in a Caucasian population [118]. These discrete expression patterns further highlight the complexity of cataloging aging mechanisms in the skin and suggest that much more information would be required from a wider diversity of samples to understand any potential global age-related changes.
Altogether, genetic factors, including telomere DNA loss, genotoxic accumulation of mutations in both genomic and mtDNA, DDR signaling, DNA repair dysfunction, and allelic variations in key cutaneous protective genes controlling pigmentation, inflammation, dermal, epidermal, and subcutaneous physiology all converge on our emerging understanding of the central role cellular senescence plays in skin aging. What follows is a review of how epigenetic factors also influence cellular senescence in cutaneous biology and the aging phenotype.
4. Epigenetic influences on cutaneous cellular senescence
Though the evolution to senescence is usually characterized as a genomically driven phenotype, its manifestation can be largely characterized as an epigenetically entrenched state. The baseline definition of a senescent cell is an otherwise mitotic cell that has entered permanent cell cycle arrest, but this also begets a broader shift in cell behavior and protein production. For these changes to be permanent they must be encoded in long-term gene expression tendencies, i.e., in the cellular epigenome. The epigenome is the composite architecture consisting of chemical and physical modifications to the DNA that do not alter the underlying coding and noncoding sequences but instead modify its oligomeric structure and transcription. These modifications span multiple layers from the local control of specific gene promoters to large scale regulation of entire domains of genes.
Canonically, the epigenome is most strongly associated with cell identity, as it makes accessible the portions of genomic DNA needed for the cell’s functional role while segregating and silencing irrelevant regions. Thus, the most dramatic epigenetic shifts are observed when cells differentiate from stem or progenitor states. In this full and dramatic state transition, the function of the cell is redefined, affecting everything from its morphology to its protein production and factor secretion [130]. For skin this can mean, for instance, a transiently amplifying cell in the basal epidermis fully differentiating to a corneocyte through natural turnover or endothelial progenitor cells differentiating into new endothelium in response to an angiogenic signal. Conversely, cells undergo constant but more minor epigenetic events as they are exposed to regular stimuli from the environment, which can lead to upregulation or downregulation of certain behaviors [131]. For instance, methylation sequencing of the same cell type across patients (e.g., epidermal keratinocytes) will show a distribution with perturbation on the mean population value based on internal and local external stimuli [132]. This heterogeneity evolves with different stressors, and with aging itself becomes more prominent. Eventually the stressors can lead to enough diversity to characterize pseudostates and pseudostate transitions that may by-and-large retain the cell’s identity but with a different grade of functionality across multiple genes. We will discuss a few additional examples of this in the following sections, like fibrotic versions of connective tissue cells and pro-/anti-inflammatory versions of macrophages; however, the focus of this section that could also be considered an epigenetic pseudostate is senescence. It meets the criteria in that it still retains core cell identity but also dramatically affects a multitude of genes to alter protein production and secretion profile, and thus requires a core epigenetic component. In this section we will review the multitude of epigenetic changes that accompanies this pseudostate evolution in skin cells, what role they play in establishing the senescent phenotype and how they may potentially be engaged therapeutically.
4.1 Sequence specific modulation
One modality of epigenetic is sequence specific meaning it targets specific regions of the genetic code—either DNA or RNA. DNA base pair methylation is a well-known example of this modality. Cytosine is the most commonly methylated base in eukaryotic cells and when methylated, often serves to block the activity of RNA polymerase, as in the context of CpG islands. Found in the promoter region of many genes, CpG islands are clusters of methylated cytosine followed by guanine, wherein the methylation inhibits (silences) the transcription of that gene [132]. Widespread hypomethylation has been documented in aging and senescent fibroblasts, and in some cases, impairs cell cycling pathways through the suppression of cyclin pathways. Specifically, a lack of methylated sites leads to the upregulation of p16INK4a which inhibits cyclin D/CDK4 to suppress G1 phase progression, while upregulation of p14ARF leads to activation of p53/p21 and inhibits cyclin E/CDK4 to prevent S phase progression [7]. The global methylation status of fibroblasts is directly and strongly correlated with donor chronological age through regression algorithms known as ‘epigenetic clocks.’ These algorithms calculate a weighted linear combination of the beta coefficients (the percent signal from the methylated out of the total unmethylated and methylated alleles) [133]. When dermal fibroblasts were passaged towards replicative senescence (RS) these epigenetic clocks show aggregated methylomic evolution. The cell cycle was reengaged by overexpressing the telomerase gene hTERT, causing cells to progress to further doubling. However, the epigenetic clock did not reverse and the cells continued to age, bypassing RS, further hinting that a broader epigenetic change was occurring through the progression to senescence rather than just the suppression of a few mitotic arrest genes [134].
Conversely, sequence specific epigenetic regulation on the level of transcribed RNA is accomplished through feedback mechanisms by families of non-coding RNA-including microRNAs, siRNAs, long and short non-coding RNAs, and others. These non-coding RNAs will interact with other DNA, RNA, and proteins to regulate their expression, further enhancing the complexity of the transcriptome over the more rigid landscape of the methylome [135]. Thus, non-coding species are often used to not just reinforce but also propagate the senescence response. The particular influence of miRNAs, short sequences that complement and bind to specific regions of mRNAs to limit their stability and thus their translation likelihood, has been explored in the context of cutaneous cell senescence [136]. For instance, UV-induced senescent fibroblasts are known to produce miR-34 which targets a number of transcripts within these cells for cell cycle regulatory genes like MYC and BCL2 as well as genes for other epigenetic factors such as E2H and SIRT1 [137]. Meanwhile, in wounding-induced senescence the extracellular secretion of miR-21 as part of the SASP phenotype triggers the activation of resident macrophages to drive the local inflammatory response [138], but these represent only a few of a handful of drivers. Senescent keratinocytes, for instance, have displayed upregulation of over a hundred different microRNAs correlated with expression of the senescence biomarkers p16, p53, and senescence-associated β-galactosidase (SA-β-Gal) [136]. Together, these mechanisms represent the precise regulation of specific genomic targets and interfering with transcription machinery as one mode of enforcing the senescent epigenetic state.
4.2 Compaction
For regulation across gene domains (~150 base pairs or greater), the epigenome uses methods of physical compaction to close off regions of the genome from transcription. The negative charge of the DNA attracts it to wrap around the positively charged protein octamer spools called histones, which segregate the sequences away from transcription machinery. Chemical modifications like methylation, acetylation, and ubiquitination of the amino acid residues on the tails of these histone proteins alter the charge interaction with DNA and with other histones influencing oligomeric structure [139]. Senescence engages in this mechanism by modulating the enzymatic activity that regulates these histone tails. For example, the activity of methyltransferases like EZH2, which adds trimethylation to the lysine residue 27 of histone 3 (H2K27me3), is reduced in senescent cells. This reduction in the resulting H3K27me3, especially at the INK4a/ARF locus mentioned previously, reinforces the discontinuation of the cell cycle [8]. Other forms of histone tail modification include acetylation, which tends to promote more transcription. One of the most well-studied classes of deacetylation enzymes is the sirtuin family of proteins. In both fibroblasts and keratinocytes, Sirt1 and Sirt6 directly respond to DNA damage and inflammation, but their expression is diminished in senescent cells [140]. Interestingly, both Sirt1 and Sirt6 also play an active role in regulating collagen balance, thus their downregulation could be conceptually likened to senescence of the dermal ECM and its turnover, just like that of cellular turnover.
Histones can also be modified through changes within the core octamer proteins themselves and a hallmark example of this phenomenon is the variant species of the H2A protein known as H2A.J. This modified protein is prevalent in a lot of senescent skin cell types where it weakens the binding of another histone in the complex, H1, triggering a signaling cascade that preempts the interferon response and contributes to initiation of SASP expression [141]. In senescent epidermal keratinocytes in particular, the increase in H2A.J variants is correlated with arrested cell cycle and maturation of the basal cells into mature corneocytes, thus it may play a direct role in the morphologic phenomena of epidermal thinning seen with age [142]. The broader contribution of these histone changes, along with local DNA methylation shifts, is the transition to wide-reaching genome compaction in senescent cells, for example the condensation of senescence associated heterochromatin foci, as in H3K9me3 rich regions of nuclease resistant compact facultative heterochromatin [11]. These foci are seen across skin cell types like fibroblasts and keratinocytes and are thought to entrench the senescent state by long term segregation and silencing of mitotic genes [143]. However, the evolution of these foci seems to be specific to the type of senescence induction, most prominent in OIS, suggesting that senescence itself may even be a family of pseudo-states rather than a distinct, singular manifestation [144]. Nevertheless, in general, these forms of epigenetic modification which bias entire regions of genes from active to passive and vice versa truly embody a cell state/pseudostate.
4.3 Alternative epigenetic pseudostates
The natural and prevalent engagement of senescence, even in young tissues, reflects its role as a form of stress response. In fact, a major function of senescence is to prevent the evolution of alternate, more detrimental states of the cells and tissue under these conditions. One such competing epigenetic pseudostate is fibrosis. The fibrotic transition is a common feature in the pathological evolution of many tissues, i.e., hypertrophic scarring and keloids in the skin, idiopathic pulmonary fibrosis in the lung, cirrhosis in the liver [145]. A key component of fibrosis is the differentiation of various cell types including fibroblasts, adipocytes, epithelial cells, and endothelial cells into a population known as myofibroblasts [146]. As mentioned, differentiation is canonically an epigenetic event as cells convert and specify their functional gene regions while silencing other unused regions. It involves the same modalities of control—methylation, histone tags, chromatin structure, etc.—often with more dramatic and permanent modifications. These activated myofibroblasts are critical for the repair response in that they secrete superfluous extracellular matrix (ECM) components (Collagen 1, alpha-smooth muscle actin (α-SMA), fibronectin, etc) that accumulate in the connective tissue [147]. At the same time, these cells diminish the process of anabolic degradation of ECM through reduction of MMPs [148]. Unbridled overgrowth of these myofibroblasts, as evidenced by the overactivation of growth factors like connective tissue growth factor (CTGF), leads to the buildup and disorganization of the connective tissue [149]. Senescence in this context is thought to be a responsive, secondary epigenetic evolution that is engaged to shut down this population and stop the overgrowth [150]. These processes—from the epigenetic cell identity shift (e.g., epithelial-to-mesenchymal or fibroblast-to-myofibroblast transitions, depending on the starting cell types) to the epigenetic proliferation-suppressed state (induction of senescence)—represent relatively fast epigenetic turnovers. As such, a key mediator of this rapid transition is thought to be the slew of non-coding RNAs, like let-7 g to engage TGFbeta driven myoblast conversion and miR-127-3p to induce p53/p21 drivers of senescence [151, 152].
Another alternative pseudostate that competes with senescence is of course cancer and more particularly for skin, melanoma. Like senescence, cancer is a state transition that involves bypassing apoptotic pathways, yet these aberrant cells also bypass the suppression of their cell cycle gene networks [14]. It is thought that melanoma cells are able to undo the senescence epigenetics and re-engage the cell cycle due to the deleterious recruitment of epigenetic enzymes, like histone demethylases and Jumonji proteins [153]. This means a host of pathways whose methylation would otherwise lead to cell cycle suppression, like the p15INK4B or the p27Kip1 pathways, are methylated without cell cycle arrest in melanoma [154, 155, 156]. The use of inhibitors to target these epigenetic enzymes seems to be a promising methodology to restore the cell cycle arrest and control the cancerous growth [157].
An interesting intersection of epigenetic and oncogenic pseudostates is highlighted in Merkel cell carcinoma (MCC). This aggressive, non-melanoma skin cancer is rare but occurs primarily in the elderly and immunosuppressed. Interestingly, methylation clock analysis of MCC cells shows their epigenetic age as significantly younger than the chronologic age of the patients from which they were derived—a stark contrast from the continually progressing epigenetic age of senescent cells. Further analysis of these MCC cells did not indicate any signs of pluripotency [64]. The mechanism by which MCCs reverse their epigenetic age is still unknown, however, it may be related to other epigenetic alterations recently discovered in this cell type, including decreased H3K27me3 expression [158, 159] and overactivity of the lysine-specific histone demethylase 1A [160, 161]. These are just some examples of this fundamental need to tightly control and disengage mitotic networks and why senescence requires a complex regulatory architecture like the epigenome.
4.4 Enablers of senescence
The phenomenon of senescence is promoted by the epigenetics of not just the arrested cells in question, but also that of the other resident cells that enable this transition. Though senescence is thought to be a permanent state, the persistence of senescence in the tissue is only meant to be transient. This is because the key function of this state is to respond to stressors by retaining cells, despite their damage, to maintain the tissue temporarily while preventing them going down the more detrimental alternate routes mentioned, all the while signaling the immune system and other repair mechanisms. When the immune system is young and efficient its cells are recruited to the skin and other tissues to clear out the senescent cells [162]. With aging, however, the number and lifetime of these senescent populations increases due to the altered epigenetic pseudostates of the senescent clearing cells as well, contributing to innate immunosurveillance dysfunction of the skin. One example of this is in the dominance of the pro-inflammatory M1 macrophage pseudostate over the anti-inflammatory M2 macrophage pseudostate [163]. There are a number of histone methylation and acetylation modifiers that play a role in pseudostate fate decision, for instance histone deacetylase 3 promoting M1 macrophages or the SYMD family of methyltransferases promoting M2 macrophages [164]. With the accumulation of stressors over a lifetime, the more pro-inflammatory epigenetic pseudo-states are favored in skin and other tissues, especially in response to factors like SASP or inflammaging [165]. In addition, in some disease states like type 2 diabetes, the wound healing response and inflammation tends to exaggerate the M1 state response with focal DNA methylation components at sites like peroxisome proliferator activated receptor gamma (PPARγ) or and elevation of miR-125b [164]. This epigenetic shift in the balance of macrophage cells then ties back to senescence as the M1 macrophage predominantly engages in more phagocytic clearance of foreign pathogens, while the M2 macrophages carry out more phagocytic clearance of damaged host cells (efferocytosis) [166]. This, coupled with the fact that senescent cells develop ways to better evade apoptosis, means that they are more likely to accumulate [167] in aged tissue. There are additional immune cell types that are similarly driven by the pro-inflammatory transition, yet become impaired at senescent cell clearance, including NK cells and neutrophils [167]. Altogether, this epigenetic evolution of the regulator cells, part of inflammaging, proves just as critical to the manifestation of a sustained senescence pressure in cutaneous tissue as epigenetic changes engaged in the non-dividing cells themselves.
4.4.1 Distinction from temporary cell cycle arrest
Though sometimes associated with senescence, somatic stem cells (as opposed to differentiated cells) are typically associated with another form of cell cycle arrest, known as quiescence. Because their role is to remain as a niched tissue reserve, they often enter periods of temporary cell cycle arrest with a prolonged G0, instead of a permanent one, until they are called to activate, to proliferate and differentiate, by a stressor [168]. One major epigenetic distinction that enables this temporary quiescence vs. permanent senescence is the utilization of bivalent domains. These are regions of genes that are regulated by both a repressive histone tag as well as an activating one, that allows the region to rapidly switch from one state to another depending on stimulus [169]. A prime example of the use of this is in the coinciding utilization of repressive H3K27me3 and activating H3K4me3, which maintains a tenuous baseline suppression of the gene region. This pair forming a bivalent domain is widely used throughout the embryonic stem cell genome, establishing its broad potency as a cell type with the potential to express a lot of different proteins [170]. But when the same domains were searched for in dermal hair follicle stem cells (HFSC), they were found to be substantially restricted to lineage-specific factors like Sox9 and Nfatc1 and growth factor FGF18 [171]. Then, when these HFSC were stimulated to activate, many of the genes with H3K4me3 activating markers, which are located primarily near the gene promoters, were further reinforced by additional H3K79 dimethylation in the gene body, to tip the scale from suppression to activation [171]. These genes included many cell cycle regulators which, when combined with the cell lineage factors, properly executed differentiation. Thus, this mechanism of readily switchable suppression to expression establishes a major distinction in epigenetic regulation from cell cycle in quiescence from that of senescence where the cell cycle genes are more permanently, epigenetically suppressed.
4.4.2 Manipulability of senescent epigenetics
Earlier, we mentioned how drugs targeting epigenetic enzymes represent one methodology for modulating some of the epigenetic changes that drive senescence, such as senolytic therapies. However, a broader and more dramatic approach of epigenetic evolution is through the process of cellular reprogramming. This technology was inspired by the core epigenetic reset that occurs during the process of reproduction in which sperm and egg, two cells with very precise roles and epigenetic identities, are reprogrammed to make embryonic cells—epigenetically plastic cells that can differentiate into any cell in the body. The isolation and recapitulation of this process in any desired cell type was achieved through the discovery of core transcription factors [172]. When overexpressed in cells, this set of core transcription factors would drive a full epigenetic remodeling to produce embryonic-like cells with all their differentiation potential. This process is called induced pluripotent stem cell reprogramming (iPSC) and has been utilized in a variety of different cell types with dermal fibroblasts being the gold standard for many studies [173]. Even fully senescent fibroblast populations established from 51 population doublings and maintained for two months in culture, successfully showed iPSC reprogramming, as evidenced by revived proliferation, reduced p16 and p21, and re-differentiation after reaching the pluripotent state [174]. Crucially, the re-differentiated progeny were once again able to be passaged into senescence, thus suggesting that malignant transformation was not induced during the entire process. Furthermore, one of the key reprogramming factors Oct4, has been shown to independently re-engage senescent hair follicle mesenchymal stem cells back into cycling by engaging a host of DNA methyltransferase to inhibit the p21 pathway [175]. More recently researchers have shown that the prevalence of senescence in a population can be reduced with even a transient application of the reprogramming factors [176, 177, 178]. Though whether this means a re-engagement of senescent cells in the cell cycle or simply competitive growth advantage of healthy cells remains to be seen. This represents an enticing new possibility in that epigenetic manipulation may possibly counter the accumulation of senescent cells in many aged and diseased tissues, including the skin.
5. Conclusion
The skin represents an excellent organ system in which the effects of cellular senescence manifest as observed clinical changes in organismal health and disease. A myriad of processes drives the genomic erosion that instigates the transition to senescence. Some of these processes are more stereotyped, engineered into the cell by design, and are observed in chronologically aged skin, while others are stochastic and driven by environmental conditions, exemplified by exposomal damage. Either way, the result is an evolution of the entire state of the cell. This means more than just the direct arrestation of the cell cycle, but also entails changes through the cellular transcriptome, proteome, and secretome as encoded by alterations to the core cellular epigenome. This also involves a myriad of changes to the many layers of architecture that encode a cell’s function and identity. The global process is critical for the skin’s ability to retain functional integrity upon stress and insult as the first line of defense for the body, and in many ways, senescence represents the least of multiple evils.
This review gives a glimpse of how and why intrinsic and extrinsic factors trigger cutaneous cellular senescent phenotypes, leaving several important questions unanswered. For example, which genetic and epigenetic factors determine the dominant decision pathways favoring senescence vs. apoptosis or any other disease states for different skin compartments? How are the various types of senescence manifestations comparable in terms of evolution and manipulability? What are the molecular and cellular consequences of therapeutic re-engagement of senescent cells into the cell cycle? As the focus on aging grows as an ever more prominent factor in clinical and investigative dermatology, insights on these questions into the nature of senescence become a critical step towards both dermatologic therapeutic advancement specifically and translational medicine in general.
Acknowledgments
Intellectual and financial support by Turn Biotechnologies, Inc. is gratefully appreciated.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"skin, DNA damage, telomeres, epigenetics, immunosenescence, inflammaging",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/79295.pdf",chapterXML:"https://mts.intechopen.com/source/xml/79295.xml",downloadPdfUrl:"/chapter/pdf-download/79295",previewPdfUrl:"/chapter/pdf-preview/79295",totalDownloads:132,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 10th 2021",dateReviewed:"October 10th 2021",datePrePublished:"November 11th 2021",datePublished:null,dateFinished:"November 11th 2021",readingETA:"0",abstract:"Skin is the largest human organ system, and its protective function is critical to survival. The epithelial, dermal, and subcutaneous compartments are heterogeneous mixtures of cell types, yet they all display age-related skin dysfunction through the accumulation of an altered phenotypic cellular state called senescence. Cellular senescence is triggered by complex and dynamic genetic and epigenetic processes. A senescence steady state is achieved in different cell types under various and overlapping conditions of chronological age, toxic injury, oxidative stress, replicative exhaustion, DNA damage, metabolic dysfunction, and chromosomal structural changes. These inputs lead to outputs of cell-cycle withdrawal and the appearance of a senescence-associated secretory phenotype, both of which accumulate as tissue pathology observed clinically in aged skin. This review details the influence of genetic and epigenetic factors that converge on normal cutaneous cellular processes to create the senescent state, thereby dictating the response of the skin to the forces of both intrinsic and extrinsic aging. From this work, it is clear that no single biomarker or process leads to senescence, but that it is a convergence of factors resulting in an overt aging phenotype.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/79295",risUrl:"/chapter/ris/79295",signatures:"Tapash Jay Sarkar, Maiko Hermsmeier, Jessica L. Ross and G. Scott Herron",book:{id:"10935",type:"book",title:"Mechanisms and Management of Senescence",subtitle:null,fullTitle:"Mechanisms and Management of Senescence",slug:null,publishedDate:null,bookSignature:"Dr. Hassan M. Heshmati",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83969-051-8",printIsbn:"978-1-83969-050-1",pdfIsbn:"978-1-83969-052-5",isAvailableForWebshopOrdering:!0,editors:[{id:"313921",title:"Dr.",name:"Hassan M.",middleName:null,surname:"Heshmati",slug:"hassan-m.-heshmati",fullName:"Hassan M. Heshmati"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Aging of the skin",level:"1"},{id:"sec_2_2",title:"2.1 Effects of aging on epidermal structure and function",level:"2"},{id:"sec_3_2",title:"2.2 Aging and the dermis",level:"2"},{id:"sec_4_2",title:"2.3 Subcutaneous layer involvement in skin aging dysfunction",level:"2"},{id:"sec_6",title:"3. Genetic influences on cutaneous cellular senescence",level:"1"},{id:"sec_6_2",title:"3.1 DNA damage related to telomere biology",level:"2"},{id:"sec_7_2",title:"3.2 Genotoxic and exposome insults",level:"2"},{id:"sec_8_2",title:"3.3 Genetic skin diseases associated with DNA repair pathway defects",level:"2"},{id:"sec_9_2",title:"3.4 SNPs and transcriptomics",level:"2"},{id:"sec_11",title:"4. Epigenetic influences on cutaneous cellular senescence",level:"1"},{id:"sec_11_2",title:"4.1 Sequence specific modulation",level:"2"},{id:"sec_12_2",title:"4.2 Compaction",level:"2"},{id:"sec_13_2",title:"4.3 Alternative epigenetic pseudostates",level:"2"},{id:"sec_14_2",title:"4.4 Enablers of senescence",level:"2"},{id:"sec_14_3",title:"4.4.1 Distinction from temporary cell cycle arrest",level:"3"},{id:"sec_15_3",title:"4.4.2 Manipulability of senescent epigenetics",level:"3"},{id:"sec_18",title:"5. Conclusion",level:"1"},{id:"sec_19",title:"Acknowledgments",level:"1"},{id:"sec_22",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Rodier F, Campisi J. Four faces of cellular senescence. The Journal of Cell Biology. 2011;192(4):547-556'},{id:"B2",body:'Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: Defining a path forward. Cell. 2019;179(4):813-827'},{id:"B3",body:'Hayflick L, Moorhead PS. 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A double take on bivalent promoters. Genes & Development. 2013;27(12):1318-1338'},{id:"B170",body:'Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125(2):315-326'},{id:"B171",body:'Lien W-H, Guo X, Polak L, Lawton LN, Young RA, Zheng D, et al. Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage. Cell Stem Cell. 2011;9(3):219-232'},{id:"B172",body:'Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-872'},{id:"B173",body:'Malik N, Rao MS. A review of the methods for human iPSC derivation. Methods in Molecular Biology (Clifton, N.J.). 2013;997:23-33'},{id:"B174",body:'Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, et al. 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Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nature Communications. 2020;11(1):1-12'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Tapash Jay Sarkar",address:null,affiliation:'
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He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. 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