PARK2 gene, while, in sporadic PD, the activity and abundance of this protein can be compromised by stress-related modifications. Intriguingly, research in recent years has shown that parkin depletion is not limited to PD but is also observed in other neurodegenerative diseases—especially those characterized by TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we discuss the evidence of parkin downregulation in these disease phenotypes, its emerging connections with TDP-43, and its possible functional implications.Parkin and PINK1 are key regulators of mitophagy, an autophagic pathway for selective elimination of dysfunctional mitochondria. To this date, parkin depletion has been associated with recessive early onset Parkinson’s disease (PD) caused by loss-of-function mutations in the  Frontotemporal dementia (FTD) is the second most common type of early onset dementia under 65 years of age, characterized by atrophy of the frontal and temporal lobes resulting in behavioral and/or language dysfunction ,2,3. AmyThe common hallmark of sporadic and the majority of the genetic forms of ALS–FTSD is TDP-43 (transactive response DNA-binding protein 43 kDa) pathology, characterized by TDP-43 protein depletion from the nucleus and its cytoplasmic aggregation ,11. Thissubstantia nigra, the brain region producing neurotransmitter dopamine (DA). PD is clinically characterized by bradykinesia, resting tremor, and rigidity [PARK(1–23) genes [Parkinson’s disease (PD) is a neurodegenerative disease with progressive death of dopaminergic neurons in the rigidity . Around 3) genes ,16.PARK2 mutations [Mitochondrial dysfunction has been extensively described in sporadic and genetic forms of ALS–FTSD and PD . In partutations  has gainutations   “a sensor of mitochondrial damage” . Under nIn response to mitochondrial stress, PINK1 normal processing is hindered. As a consequence, it gets anchored to the translocase of the outer mitochondrial membrane (TOMM) complex where subsequent PINK1 autophosphorylation leads to its auto-activation ,33.Further to this, PINK1 recruits parkin along with ubiquitin onto damaged mitochondria and activates them through phosphorylation on Ser65 . To enhaActivated parkin ubiquitinates several mitochondrial outer membrane proteins , tagging them for proteasome degradation with long ubiquitin chains ,34. SubsPARK2 and PARK6 are the most common known causes of autosomal recessive early onset parkinsonism  and account for c.a. 5% of familial PD [Homozygous mutations in ilial PD ,36  with only mild parkinsonism [Finally, biallelic insonism .PARK2 or PARK6 mutations occur with similar frequency in patients with sporadic PD and healthy individuals; their estimated penetrance is around 1–25%, and their role in pathogenesis is still not well understood [PARK2 or PARK6 mutation are usually free of clinical motor symptoms; however, some of them can present clinical signs of parkinsonism [PARK2 or PARK6 mutation show a stronger increase of cortical-motor-related activity during execution of self-initiated movements in functional magnetic resonance imaging (fMRI) studies, thus indicating additional recruitment of motor cortical areas during simple motor tasks, as is suggestive of compensatory response [PARK2 mutation carriers [PARK2 mutation carriers is very low [Single heterozygous derstood ,46,47,48insonism ,50 and minsonism . Asymptoresponse ,53. Therresponse ,55. Subcvery low . FinallyPARK2 or PARK6 mutation is a reduction in enzymatic activity of ubiquitin ligase and kinase, respectively, leading to functional haploinsufficiency, unable to secure normal nigrostriatal activity [A possible molecular explanation for the observed abnormal nigrostriatal dysfunction in heterozygous carriers of activity ,57. Indeactivity . HeterozPARK2/PARK6 variants representing a strong risk factor for Parkinson’s disease [Independently of the mechanism, those mutations likely interfere with the protective functions of the PINK1/parkin-mediated mitochondrial quality control . In conc disease , whetherParkin activity can be compromised by post-translational modifications, such as oxidative, nitrosative, or dopamine-related stress, which has implications for patients with sporadic PD and Lewy body neuropathology, as reviewed in References ,60.TAR DNA-Binding Protein-43 (TDP-43) was first identified in 2001 as a protein able to bind the HIV-1 TAR binding sequence , and in In pathological aggregates, TDP-43 is subject to various post-translational modifications that include ubiquitination, phosphorylation, acetylation, sumoylation and is also cleaved to generate C-terminal fragments . From a Interestingly, apart from Parkinson’s disease, decreased levels of parkin have been found in several TDP-43 proteinopathies C. To thiPARK2 [PARK2 pre-mRNA possesses multiple TDP-43 binding sites, suggesting that the control of its stability depends on TDP-43 RNA binding function, at least partially [At the mechanistic level of RNA processing, TDP-43 has turned out to be crucial for the maintenance of brain enriched mRNAs with long introns (>100 kb) such as PARK2 ,21. Indeartially   brains compared to controls and a few cellular TDP-43 overexpression models [Supporting the notion of parkin being a direct target for TDP-43, a significant increase in n models ,93,94. Tn models ,94,96  insoluble aggregates in the cytoplasm via the mechanism of TDP-43 overexpression–related impairment of the proteasomal activity . To confla model .At present, there is no satisfactory explanation for the observed differences between TDP-43 overexpression experiments. In contrast to TDP-43 knockdown, it should nonetheless be considered that TDP-43 overexpression levels may vary substantially between different labs/experimental systems. At the cellular level, this may result in the overexpressed TDP-43 binding/interacting with different partners, depending on the absolute level of overexpression reached during the study. If this could be the case, it would not be surprising that different overexpression levels could even have opposite effects on parkin expression. Of course, such a possibility would have to be experimentally tested and this is an area that certainly deserves further investigation.Notwithstanding the fact parkin levels are regulated by TDP-43, it has been shown that parkin, in turn, can affect the state of TDP-43 within cells. In particular, Hebron et al. have shown that parkin promoted Lys-48- and Lys-63-linked ubiquitination of TDP-43 and formed a multi-protein complex with histone deacetylase 6 (HDAC6) inducing sequestration of TDP-43 into cytosolic inclusions . Co-exprPARK2 mutations lead to complete parkin depletion in patients with PD [PARK2 mutations remains yet to be determined , did not change any mitochondrial parameters, thus indicating the importance of the dose [While biallelic  with PD ,99 , cases with behavioral and/or cognitive impairment without dementia , ALS–parkinsonism/dementia complex , and other mixed variants .ALS–FTSD is predominantly associated with TDP-43 proteinopathy , ALS beiC9orf72, PGRN, and TARDBP [First of all, it is important to keep in mind that cases of ALS–FTSD that have not been genetically defined may present other types of pathology . For this reason, in this review we focus on parkinsonism in genetic forms of ALS–FTSD with confirmed TDP-43 proteinopathy, caused by mutations in d TARDBP ,112,113.MAPT mutation, so the term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was coined [Regarding FTLD it is interesting to note that the first links between this disease and parkinsonism extend before the recognition of TDP-43 proteinopathies. Indeed, until a few decades ago parkinsonian symptoms were regarded as a rare manifestation of FTLD associated with s coined . More res coined ,116,117 s coined .PGRN mutations) or with MND .Usually, FTLD is associated with either parkinsonian symptoms  [with MND ,123. In of cases . ImportaAT-Scan) . UnfortuTARDBP mutations may have a broader symptomatic spectrum than other gene mutations in FTLD, as they may be associated with all three conditions: ALS, FTLD, and parkinsonism [It seems that insonism .At the clinical level, parkinsonism in FTLD syndromes is typically characterized by akinetic–rigid phenotype   and may PGRN mutations and is rather uncommon in C9orf72 mutations and VCP  mutations and rare in TARDP mutations cases. PSP-like features may be rarely observed in both C9orf72 and PGRN mutation carriers, CBS-like features are uncommon in PGRN and rare in C9orf72 [Akinetic–rigid parkinsonism, as far as TDP-43 proteinopathies are concerned, occurs commonly in  C9orf72 . Of note C9orf72 ,130.C9orf72 or TARDBP gene mutations, but also those with DCTN1 (Dynactin Subunit 1) and VCP gene mutations.Among inherited FTLD cases, MND is observed mainly in patients carrying DCTN1 mutation, TDP-43 pathology is predominant [In some very rare clinical entities, such as Perry disease, caused by dominant . In othedominant . In Perrdominant  are accodominant .Another example of the complex relationship between ALS and parkinsonism is the rare variant of ALS: ALS and parkinsonism/dementia complex (ALS/PDC) in which TDP-43 pathology may be accompanied by alpha-synuclein pathology. In ALS/PDC three types of pathology were described: the tauopathy-dominant type, the TDP-43 proteinopathy-dominant type, and the synucleinopathy-dominant type .C9orf72 is a relatively recently described mutation as are Strong et al.’s criteria [The frequency of parkinsonism in ALS–FTSD with TDP-43 proteinopathy cannot be easily established. Parkinsonism may be an under-diagnosed phenomenon in ALS–FTSD with TDP-43 proteinopathy due to several reasons. First, genetic testing and/or neuropathological examination is not routinely performed worldwide, remaining unproven in many cases. Secondly, In conclusion, the theme of parkinsonism in ALS–FTLD guarantees further research since at present there are a lot of gaps that need to be filled, specifically regarding parkinsonism in sporadic forms of ALS–FTSD with defined neuropathology and its clinical subgroups. Finally, it would be interesting to investigate whether parkinsonian symptoms observed in ALS–FTLD could be mediated by TDP-43-associated parkin decrease.TDP-43 related mitochondrial dysfunction has been observed in genetic and sporadic forms of TDP-43 proteinopathies and in several cellular and animal models ,135. In PARK2 by TDP-43 , TBK1 (TANK Binding Kinase 1), SQSTM1/p62, and VCP ) that cause genetic forms of ALS–FTSD with TDP-43 proteinopathy encode proteins involved in mitophagy/autophagy [In addition, a majority of genes  levels has been confirmed in Parkinson’s disease patients with utations . The lacC9orf72, PGRN, and TARDBP itself, that cause familial forms of ALS–FTSD.While it is well documented that TDP-43 pathology represents one of the main mechanisms underlying various aspects of mitochondrial dysfunction, its actions can also be modulated by different genetic backgrounds, such as mutations in In this section, we discuss sporadic ALS–FTSD cases where, apparently, TDP-43 proteinopathy is not modified by additional genetic factors.First, it is important to note that induced pluripotent stem cells (iPSCs) and postmortem samples derived from patients with sporadic ALS and FTLD have demonstrated the destabilization of ribosomal and mitochondrial transcripts with decreased levels of corresponding mitochondrial proteins, as well as altered morphology and respiration ,154. A sSecondly, transcriptomic analysis of frontal cortex in 16 patients with sporadic FTLD–TDP followed by mRNA and protein level validation has demonstrated downregulation and decreased activity of several mitochondrial subunits of electron transport chain  .The results of these functional studies are supported by ultrastructural and morphological analyses which have revealed abnormal mitochondrial and lysosomal phenotypes in brain samples derived from patients with sporadic FTLD or ALS ,156. In Finally, it has been observed that TDP-43 aggregation-driven oxidative stress in mouse and human neurons depleted mitochondrial proteins encoded by nuclear-genome, leading to global mitochondrial dysfunction oxidative stress .In conclusion, TDP-43-induced mitochondrial impairment certainly represents a critical aspect in TDP-43 proteinopathy.C9ORF72 hexanucleotide repeat expansion, TDP-43 pathology is accompanied by dipeptide repeat (DPR) protein aggregates arising from the unconventional repeat-associated non-ATG translation [C9ORF72 pathology may act through loss-of-function (C9orf72 haploinsufficiency) and gain-of-function mechanisms. The latter one is associated with the generation of long G4C2 expansions that may sequester cellular proteins from their normal functions and even generate toxic dipeptide repeat proteins [In patients with nslation ,159. Simproteins .C9ORF72 and TARDBP have shown similar effects on various mitochondrial parameters, such as increased oxidative and endoplasmic reticulum (ER) stress, impaired mitochondrial transport in axons, abnormal morphology, reduced ATP production, Ca2+ signaling, mitochondrial membrane potential, and activity of mitochondrial respiratory complexes [C9ORF72- or TARDBP-linked ALS–FTSD, Drosophila and mouse models [From a pathological point of view, ALS- and FTLD-associated mutations in omplexes ,166,167,omplexes ,140. Expe models ,171,172.Drosophila expressing TDP-43 A315T mutant [Abnormal mitochondrial phenotypes have been described in spinal motor neurons from patient-derived iPSCs with TDP43 S393L and G294V mutations , mice anT mutant ,156.Drosophila muscle and patient fibroblasts with C9ORF72 hexanucleotide repeat expansion, poly(GR) was observed to enter mitochondria and interfere with the function of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), which led to abnormal mitochondrial inner membrane structure, metabolism, and ion homeostasis [C9orf72 is crucial for effective mitochondrial complex I assembly [C9orf72 hexanucleotide repeat expansion in astrocytes deregulated metabolism of adenosine, fructose, and glycogen, and the transport of mitochondria-specific energy substrates, thus increasing toxicity upon starvation [In eostasis . In iPSCeostasis ,170. Thieostasis . In addiassembly . Finallyarvation ,174.C9ORF72 in mitochondrial complex assembly might be one of the reasons for observation of parkinsonisms in FTLD–C9ORF72 cases, since mitochondrial complex dysfunction is one of the best-documented Parkinson’s disease molecular mechanisms [In conclusion, it can therefore be speculated that the involvement of chanisms .PGRN mutations [As it has been well established in many previous studies, PGRN haploinsufficiency always leads to TDP-43 pathology ,177. Regutations . ConsideRegarding the potential role played by PGRN in mitophagy, it has been recently reported that a decrease in PGRN exacerbated mitochondrial damage and dysfunction in podocytes from diabetic mice and that PGRN administration was able to restore mitophagy and mitochondrial biogenesis in podocytes challenged with high glucose through upregulation of Sirt1-PGC-1α/FoxO1 pathway .PGRN mutations which could not be rescued by TDP-43 overexpression, suggesting that established life-long TDP-43 pathology effects cannot be simply resolved through manipulation of TDP-43 level [Finally, as described in 43 level .In summary, while the evidence on mitochondrial dysfunction in TDP-43 proteinopathies is substantial, it is not known whether TDP-43-related decrease of parkin could contribute to some of the observed mitochondrial phenotypes. To address this issue, it might be recommended that future studies on mitochondrial function in TDP-43 pathology model systems could test whether parkin is involved mechanistically, and, if yes, at which specific stage.PARK2 or PARK6 mutations, as reviewed in Reference [PARK2 mutation carrier that protected this individual from developing Parkinson’s disease even in his 80s [Mitophagy-enhancing therapies designed to increase PINK1 and parkin activity and/or inhibit ubiquitin-specific peptidase 30 (USP30) seem to be a plausible solution to rescue parkin/PINK1 deficiency in Parkinson’s disease caused by eference . Notably his 80s . The pat his 80s .Drosophila expressing h-TDP-43 in neurons [In TDP-43 proteinopathies, it has been shown that drugs increasing endogenous parkin levels were also able to decrease nuclear TDP-43 levels and prevent the neuronal loss and cognitive and motor decline in transgenic mice expressing either wild-type human TDP-43 or mutant A315T ,183,184. neurons .PGRN mutations derived from FTLD patients, even if it increased PGRN levels [While parkin upregulation could ameliorate deleterious effects of TDP-43 proteinopathy in these cases, an opposite approach—overexpression of TDP-43—could not rescue decreased parkin levels in fibroblasts with N levels . MoreoveIn contrast to precise targeting of the PINK1/parkin pathway, global mitophagy boost seems to aggravate phenotypes in TDP-43 proteinopathies. For example, in mice co-expressing TDP-43WT and mutant Q331K, rilmenidine administration induced autophagy and mitophagy, promoting accelerated nuclear TDP-43 clearance, but worsening the neurodegenerative phenotype, resulting in enhanced motor neuron death, and shortened lifespan .Finally, in some genetic forms of ALS and FTLD with elevated basal levels of autophagy ,186,187,


The virtual brand community has become an important marketing tool for companies. A successful brand community marketing strategy should attract a large number of consumers. Although past studies have revealed consumer motivations for participating in virtual brand communities, they fail to answer an important question: Why is it so easy for some virtual brand communities to attract users while others have such difficulty? In this study, product characteristics are hypothesized to be important factors that determine consumer motivation to participate in brand communities. Product characteristics  can directly affect how actively consumers participate in brand communities. The results of questionnaires show that product complexity, product symbolism, and product satisfaction have a positive influence on consumers’ willingness to participate in brand communities. Notably, the duration of product use has a regulating effect on the influence of product satisfaction and product symbolism. A long period of product use weakens the influence of product satisfaction on consumers’ willingness to participate in brand communities. On the contrary, a long period of product use strengthens the influence of product symbolism on consumers’ willingness to participate in brand communities. This study enriches the literature on brand community participation and has implications for companies that aim to utilize brand communities for marketing. Renren.com, as well as those constructed by the companies independently, such as Meizu Community  The results show that product characteristics are important factors that determine whether consumers are willing to continuously participate in communities. Unlike past research, which either studied the psychological aspects of consumer motivations to participate in brand communities or discussed the sociological aspects of community performance of virtual brand communities, this study reveals the influence of product characteristics on brand community participation, enriching the literature on brand community participation. (2) This study reveals that brand community participation and the consumer–brand relationship interact as both causes and effects. Past research has found that community participation can promote the consumer–brand relationship , but this study also reveals that product satisfaction can promote brand community participation, which indicates that satisfied consumers are more likely to engage in social media marketing. (3) Our research suggests that the motivations of consumers participating in brand communities continue to change. We find that the duration of product use is connected with brand community participation. As the duration of use increases, the relationship between product satisfaction and community participation is weakened, but the relationship between product symbolism and community participation is strengthened. This indicates that as consumers become familiar with products, their focus shifts to the symbol that the products represent. This research can help companies to tailor the focus of their brand communities according to the characteristics of their product in order to promote user participation.A brand community is the product of the combined influences of a market-oriented economy, consumerism, and mass media, and its connotations are still expanding. The initial purpose of establishing brands was for companies to differentiate themselves from others so as to increase their competitiveness. With the help of widespread mass media, companies attract consumers by highlighting their brand image and brand connotations to imply that their products possess not only physical qualities but also spiritual qualities. Brand communities are groups of consumers who gather out of their love for particular brands; participants form specific connections, rituals, and traditions among themselves and show a sense of responsibility toward the community . With thWillingness to engage is the likelihood that users will be willing to respond to a company’s activities once they have entered a virtual brand community. Existing research shows that user engagement is fundamental to the long-term survival and growth of user innovation communities . TherefoIn this part, we identify product characteristics related to consumers’ participation in brand communities. With the development of the economy and the improvement of people’s living standards, modern consumer requirements have transcended physical qualities. Their attention has shifted from the functions of the products to the social significance and emotional satisfaction that they derive from them. Studies on marketing suggest that consumers not only become dependent on the products that they buy but also become fixated on the brands. Some researchers argue that this fixation can strengthen consumers’ willingness to participate in brand communities ; in otheBased on past research, this study divides consumer motivations to participate in brand communities into three types : functioThe Internet is one of the means by which consumers acquire information about products, brands, and services. Virtual communities can provide a wide range of benefits , such asProduct complexity can strengthen consumer motivation to acquire information, so it might be a factor that drives consumers to participate in brand communities. The dictionary defines the word “complexity” as something composed of interconnected parts. The complexity of products can exert profound effects on consumers’ purchasing and use behaviors. Some scholars define product complexity as the difficulty that consumers have in understanding or using the products . If consBrand communities are groups of consumers who share the same preference for certain brands. Recognition is a key factor that drives consumers to participate in brand communities . As a tyAs suggested by product value theory, symbolic value is part of the product value. According to symbolic interactionism, a product is endowed with symbolic meaning, and people will appreciate its connotations through learning . AppreciThis can help product users to find people who are similar to themselves and acquire social experience and social values.In essence, a brand is a concept with emotional factors. Researchers have pointed out that brand communities are groups of consumers who love and admire certain brands. Thus, emotional factors are key in driving consumers to join virtual brand communities .Emotional factors allow consumers to establish stable relationships with brands. Product satisfaction might be an important emotional factor that drives consumers to participate in brand communities, as it renders consumers fixated on the brand . It is aSearching for information about products or brands is an important motivation for joining virtual brand communities . AnswersIn the wake of scientific, economic, and social development, products are becoming increasingly complex, which makes it increasingly difficult for consumers to use them. Some researchers have found that companies need to provide customer education activities to help consumers to learn to use the products on their own and enhance their loyalty. Therefore, the more complex the products, the more knowledge that consumers require. In the era of social media, brand communities are the main channels through which consumers acquire information about products. On the one hand, consumers can directly acquire knowledge about products by reading the content in communities. On the other hand, consumers can view feedback from other consumers through their interactions. The more complex the products, the more information that consumers need, and thus, the more dependent they become on virtual communities. In other words, if the community can provide useful information to consumers, then they are more likely to think it is useful and are more willing to continuously participate in the community. On this basis, we propose the following hypothesis:H1: The higher the product complexity, the stronger consumers’ willingness to participate in the virtual brand community.There are two aspects of social recognition of an individual: the individual perception of his or her identity in the community and the importance of emotions and assessments of this identity . InspireH2: The stronger the product symbolism, the stronger consumers’ willingness to participate in the virtual brand community.Some researchers suggest that consumer satisfaction can establish an emotional connection between consumers and brands . Other rH3: The higher the consumer satisfaction, the higher the consumers’ willingness to continuously participate in the virtual brand community.The duration of product use has a regulating effect on the influence of product symbolism on consumers’ willingness to continuously participate in communities. According to consumer self-concept theory, consumers tend to see their possessions as an extension of themselves . The morH4: The longer the duration of product use, the stronger the consumers’ willingness to participate in the brand community.The duration of product use also has a regulating effect on the influence of product satisfaction on consumers’ willingness to continuously participate in communities. In previous research, subjects were asked about their degree of satisfaction with a theft-proof watch and their willingness to purchase the product. Two weeks later, they were asked the same questions again . The resH5: The longer the duration of product use, the weaker the consumers’ willingness to participate in the brand community.Using questionnaires, data were collected from 427 consumers from brand communities of four types of products: automobile, computer, mobile phone, and sneakers. The questionnaires include three parts: (1) Identification of the brands of the products used by consumers, the duration of use, and their assessment of the product characteristics ; (2) Investigation of consumers’ willingness to participate in brand communities based on the brand communities that they are in; and (3) Collection of demographic information from the interviewees. To encourage community members to complete the questionnaires, we gave 5 yuan to each interviewee and provided them with a chance to win a 50-yuan raffle.We applied the following measures to ensure the quality of the questionnaires: (1) Questionnaires from the same IP address and the same computer were considered invalid; (2) Questionnaires that were finished within 30 s were excluded; and (3) In the end, 375 of the samples met the criteria. The statistical characteristics of valid samples are shown in This study involves four constructs: product complexity, product symbolism, product satisfaction, and willingness to continuously participate in communities. The scale for product symbolism is from , the scaχ2(38) = 106.854, χ2/df = 2.811, p < 0.001, RMSEA = 0.079, CFI = 0.965, NFI = 0.951, IFI = 0.965, and GFI = 0.943, which indicate that convergent validity is high.Reliability and validity tests. Reliability tests include internal consistency reliability and composite reliability tests. As shown in To prevent the common method variance caused by questionnaires filled out by the same person, discriminative reverse expressions were added to the observation items of some constructs. With these discriminative reverse expressions, we can exclude self-contradictory samples. Furthermore, the data were examined using two methods. The first method was Harman’s one-factor test, which was used to conduct exploratory factor analysis on all observation items of the constructs. If the first factor’s variance before rotation accounts for over 50%, it means that the common method has high variance. The results in this research were calculated using SPSS19.0. The variance of the first factor accounts for 39.43%, which is below 50%. This indicates that the common method variance of the data is within a good range. The second method involved examining the correlation coefficients between the constructs. If it is higher than 0.9, it means that there is high common method variance. A result less than 0.9 is acceptable. From β = 0.124**), which supports H1. In other words, when consumers perceive a product as complex, they are more willing to continue participating in the community. The influence of product symbolism on consumers’ willingness to continuously participate in communities is significant , which supports H2. This means that consumers are willing to interact with other consumers who share the same preference for certain brands because of their symbolic value. The influence of product satisfaction on consumers’ willingness to continuously participate in communities is significant , which supports H3. Past research has found that product satisfaction can generate a positive reputation among consumers, prevent the loss of consumers, and increase the brand loyalty of consumers. In this research, however, we discovered that product satisfaction can also affect consumers’ participation in brand communities, which is a dependent variable that should not be ignored. All companies want to conduct community marketing, but they might fail to realize that community marketing is more effective for satisfied consumers (compared to consumers with a low or medium degree of satisfaction).Hierarchical stepwise regression was applied to examine the hypotheses, and the results are shown in β = 0.246***), which supports H4. This means that for products with a high degree of symbolism, a long duration of use can help to develop a psychological bond between the consumers and the brands, and thus, consumers will have a strong desire to strengthen their relationship with the brands. Finally, as we expected, the duration of product use has a negative regulating effect on the influence of product satisfaction on consumers’ willingness to participate in communities (β = −0.159***), which supports H5. This means that the influence of product satisfaction on consumers’ willingness to participate in communities will decline over time as consumers use the product. This is consistent with the conclusion drawn in past research that the effectiveness of using product satisfaction to predict consumer behaviors declines with the passage of time. In addition, it is also discovered that income has a positive correlation with consumers’ willingness to continuously participate in virtual communities, whereas educational background has a negative correlation. Pragmatists might join communities when they have just purchased products but will leave shortly thereafter. Age does not have a significant influence on consumers’ willingness to continuously participate in virtual communities.We arrived at an interesting conclusion on the regulating effect of the duration of product use. The influence of the duration of product use on consumers’ willingness to participate in communities is positively significant  characteristics with consumers’ willingness to participate in virtual brand communities. It explores the role of the brand in driving consumers to participate in virtual brand communities and enriches the literature on consumers’ participation in these communities. Many studies have investigated the motivations of consumers to participate in virtual brand communities, but most of them have been carried out purely from the perspective of consumer motivations . One of Secondly, this study enriches the literature on the influence of product satisfaction. Past research has proven that product satisfaction can increase the brand loyalty of consumers so that they voluntarily contribute to the brand reputation. This study, however, proves that product satisfaction can promote consumers’ willingness to participate in brand communities. In this study, the influence of product satisfaction is extended to consumers’ participation on social media. As the results suggest, satisfied customers are more likely to engage in social media marketing. Past research has revealed that community participation can improve the quality of the relationship between consumers and brands , but this study also reveals that product satisfaction can promote brand community participation. Therefore, brand community participation and the consumer–brand relationship interact as both causes and effects. Their relationship is not a one-way street, as suggested in past research. Therefore, this research contributes to the literature on the association between brand relationship and brand community participation.Finally, this study also reveals dynamic factors that affect consumers’ participation in brand communities. As we observed, the duration of product use is connected with brand community participation. When consumers use products for a long time, the relationship between product satisfaction and community participation weakens, but the relationship between product symbolism and community participation strengthens. Therefore, consumers’ relationship with communities is constantly changing and is closely related to the duration of product use. With this discovery, scholars will be able to observe consumers’ community participation more dynamically.This study provides some implications for companies seeking to establish virtual brand communities.Firstly, past research has discovered that more than half of virtual brand communities have failed due to the lack of content and interaction. Then, we should ask a question: What kind of brand is suitable for a brand community, or will brand characteristics affect consumers’ willingness to participate in brand communities? The research in this study suggests that products with a high degree of symbolism and complexity are suitable for community marketing because community marketing can best satisfy consumer demand for social interaction and information.Secondly, consumer satisfaction is still very important in the era of social media. Consumer satisfaction can strengthen consumers’ desire to establish relationships with brands and increase their brand loyalty. Therefore, the success of community marketing should not be focused solely on its operation but also on consumers’ product satisfaction. This requires companies to consider whether their products are suitable for a brand community from a strategic perspective and how to conduct community marketing from the perspective of the product. Only in this way can they increase the probability of successful community marketing.Thirdly, different brands can apply different strategies to establish their brand communities. For example, for brands with a low degree of complexity , consumers participate in their online communities not because they seek useful information but because of the unique symbols that these brands represent . This symbolic value can help to drive loyal customers to participate in the associated brand communities. This means that consumer requirements for brand communities depend on product characteristics. Brands whose products feature specific functions and have a high degree of complexity can highlight the functional value  of their brand communities. On the contrary, brands with strong symbolism should emphasize the similarity of their values to those of consumers and resonate with them so as to encourage their participation in brand communities.Lastly, managers of brand communities should realize that consumer motivations to participate in brand communities are dynamic. Consumers gain more knowledge about products as they use them, and thus, the influence of product symbolism on the willingness to participate in communities is strengthened over time, but the influence of product satisfaction is weakened. Therefore, for new users, brand communities should provide them with content about information and functions to make the community more attractive to them. For experienced consumers, the communities should emphasize intangible values of the products, such as their symbolic value, to increase brand recognition. Moreover, the passage of time has a negative regulating effect on the influence of product satisfaction on consumers’ willingness to participate. Hence, to liven up virtual brand communities, companies should continuously attract new users to participate.This paper also has certain limitations. Firstly, the source of the data in this study was a questionnaire and the findings of the study would be more convincing in future studies if secondary data could be used to validate the findings. For example, crawlers were written using programming languages, such as python to collect behavioral data from users in various brand communities. However, this requires a certain technical threshold. Secondly, the products involved in this study are more technologically complex , while some studies have pointed out that there is a difference in the choice preferences of men and women on more technologically advanced products. Female consumers are more concerned with the appearance of the product, while male consumers are more concerned with the performance of the product. This has therefore led to the sample participating in this study being mostly male users. And in future studies, we can also expand to products that female consumers care about  to further test the findings of this study. Thirdly, this study discusses the influence of brand characteristics on consumers’ participation in virtual brand communities based on consumer motivation theory, but it fails to reveal the rationale behind the influence of each brand characteristic on consumer motivation to participate. Future studies can explore this issue with both experiments and surveys. Lastly, although this study discusses the influence of three major product characteristics on consumers’ participation in brand communities, the influence of other brand or product characteristics  on consumers’ participation in virtual brand communities still remains to be studied.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.ZS is responsible for article writing and model building, LJ for literature translation, WH for building research ideas and models, WL for data collection, LB for data analysis, and SD and PJ for revising the paper critically for important intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Transparent conductive film on a plastic substrate is a critical component in low cost, flexible and lightweight optoelectronics. CVD graphene transferred from copper- to ethylene vinyl acetate (EVA)/polyethylene terephthalate (PET) foil by hot press lamination has been reported as a robust and affordable alternative to manufacture highly flexible and conductive films. Here, we demonstrate that annealing the samples at 60  Ever since its discovery , graphengraphene . This sugraphene . DespiteHigh intrinsic carrier mobility . A 25-μm thick copper foil was treated with acetic acid to remove surface oxides prior to CVD growth. The Cu foil was then mounted in a CVD chamber and the temperature inside the chamber was increased to 950 We used hot-press lamination and chemical etching to transfer graphene grown on Cu to EVA/PET . Cu foiln). Given these two value, the carrier mobility q is the electron charge. The Raman spectroscopy measurement were performed using the Horiba Raman XploRA™ microscope with a 638 nm laser. The Zeiss Supra 55VP system with 5 kV accelerating voltage was used to acquire scanning electron microscope (SEM) images of the samples. The XPS measurements were performed on PHI5000 VersaProbe III Scanning XPS Microprobe™ system with monochromatic AlKElectrical characterization of ∼1 × 1The adsorption of chemical species on the surface of graphene during its treatment with various chemicals has been known to introduce defects and dopants in graphene lattice , which retup see  for overV−1s−1) ,24,25,26r groups ,12. As eups [3 , which ihttps://imagej.nih.gov/ij/index.html (accessed on 13 January 2022)). In order to check the surface morphology of our sample, SEM images were captured. Atomic force microscopy (AFM) is inherently difficult to conduct on our samples, which lack the required smoothness see . SEM imaThe Raman spectra of EVA/PET, graphene transferred to EVA/PET and CVD graphene on Cu are shown in p-doping in graphene [p-type donors in graphene due to its strong oxidizing nature [p-doping region of the map. However, due to the volatility of such dopants, they are removed upon annealing, resulting in a shift of spectral points in the opposite direction. These Raman findings are consistent with our Hall-effect measurements.The strain and doping lines cross at a point corresponding to a suspended exfoliated graphene with neither doping nor strain . Almost 420 ∘C . The comgraphene . It has g nature ,16. Thisp-doping. Concentration of the functional groups, however, is reduced upon annealing (XPS measurements were carried out to quantify the chemical composition of our samples after etching and after annealing.The sample composition before annealing consists of 91.6 at.% of carbon and 8.4 at.% of oxygen and becomes 93.6 at.% of carbon and 6.4 at.% of oxygen afterwards see . The intsisorbed . Hence, nnealing . These Xp-doping of graphene. The increased dopant concentration causes charge carrier scattering and lower carrier mobility. However, due to the volatility of these functional groups, they easily desorb from the surface of graphene at 60 p-doping and oxygen functional groups respectively before and after annealing.We demonstrate that HNO


In recent years, philosophical-legal studies on neuroscience (mainly in the fields of neuroethics and neurolaw) have given increasing prominence to a normative analysis of the ethical-legal challenges in the mind and brain sciences in terms of rights, freedoms, entitlements and associated obligations. This way of analyzing the ethical and legal implications of neuroscience has come to be known as “neurorights.” Neurorights can be defined as the ethical, legal, social, or natural principles of freedom or entitlement related to a person’s cerebral and mental domain; that is, the fundamental normative rules for the protection and preservation of the human brain and mind. Although reflections on neurorights have received ample coverage in the mainstream media and have rapidly become a mainstream topic in the public neuroethics discourse, the frequency of such reflections in the academic literature is still relatively scarce. While the prominence of the neurorights debate in public opinion is crucial to ensure public engagement and democratic participation in deliberative processes on this issue, its relatively sporadic presence in the academic literature poses a risk of semantic-normative ambiguity and conceptual confusion. This risk is exacerbated by the presence of multiple and not always reconcilable terminologies. Several meta-ethical, normative ethical, and legal-philosophical questions need to be solved in order to ensure that neurorights can be used as effective instruments of global neurotechnology governance and be adequately imported into international human rights law. To overcome the shortcomings above, this paper attempts to provide a comprehensive normative-ethical, historical and conceptual analysis of neurorights. In particular, it attempts to (i) reconstruct a history of neurorights and locate these rights in the broader history of idea, (ii) outline a systematic conceptual taxonomy of neurorights, (iii) summarize ongoing policy initiatives related to neurorights, (iv) proactively address some unresolved ethico-legal challenges, and (v) identify priority areas for further academic reflection and policy work in this domain. Neurotechnology is the umbrella term typically used to describe this broad and heterogenous spectrum of methods, systems and instruments that establish a direct connection pathway to the human brain through which neuronal activity can be recorded and/or influenced. As a result of this growing academic and public interest, whole new disciplines and subdisciplines have emerged. These include neuroethics and neurolaw. Neuroethics was defined by Safire as “the examination of what is right and wrong, good and bad about the treatment of, perfection of, or unwelcome invasion of and worrisome manipulation of the human brain” , has resulted in growing public interest and academic reflection on the ethical and societal implications of technologies that intercommunicate with the human brain. n brain” . The tere system . In the e system . The fouThroughout the 1990s and early 2000s, the dominant discourse in public opinion and academic reflection on neuroethics and neurolaw focused mainly on four main thematic families:A.via nootropics , freedoms, entitlements and associated obligations.The point of departure of their analyses, however, is normative-theoretical in nature: both authors posited that the concept of cognitive liberty should be interpreted not simply as a neurophilosophical description or a moral desideratum but as a “fundamental right” , p. 223.neuroright” was first introduced by neurorights, that, in their view, may offer suitable conceptual ground for normative analysis in this domain: the right to cognitive liberty (which they interpreted in agreeance with Sententia and Bublitz), the right to mental privacy, the right to mental integrity, and the right to psychological continuity. This article sparked a debate on public media and in the academic community. Among others, The term “Around the same time Nature and authored by a team of 25 researchers coordinated by Rafael Yuste and Sara Goering reignited and amplified the debate on neurorights , free will was originally conceptualized as a descriptive ontological statement about the lack of necessity of human will. This descriptivist account of free will was rooted in the late ancient Greek philosophy, especially among the Stoics. The Stoic philosopher Epictetus, for instance, regarded it as a “fact that nothing hindered us from doing or choosing something that made us have control over them” , which is legally binding on member states of the International Covenant on Civil and Political Rights (ICCPR). Particularly, the right to freedom of thought is listed under Article 18, which states the following:Everyone has the right to freedom of thought, conscience and religion; this right includes freedom to change his religion or belief, and freedom, either alone or in community with others and in public or private, to manifest his religion or belief in teaching, practice, worship and observance.prima facie link between freedom of thought and freedom of religion. In addition, the United Nations Human Rights Committee (UNHRC) emphasized that the scope of the right to freedom of thought is “far-reaching and profound; it encompasses freedom of thoughts on all matters” . Although the Amendment does not mention freedom of thought explicitly, U.S. courts have explicitly referred to a “First Amendment right to freedom of thought” . Furthermore, the U.S. Supreme Court has stated that “at the heart of the First Amendment is the notion that an individual should be free to believe as he will” .Many authors have considered freedom of thought as a precursor and progenitor of other freedoms, such as freedom of religion and freedom of expression. This fundamental role of freedom of thought as a substratum for other freedoms was recognized by, among others, US Supreme Court Justice Benjamin Cardozo whose reasoning in Palko v Connecticut (1937) was as follows: “Freedom of thought…is the matrix, the indispensable condition, of nearly every other form of freedom. With rare aberrations a pervasive recognition of this truth can be traced in our history, political and legal” . Sententin nuce in the notions of freedom and personal autonomy, the first consistent conceptualization of the modern right to privacy dates back to a seminal article, published in 1890, by Warren and Brandeis. In this article, privacy was conceptualized as “a right to be let alone”  states that “no one shall be subjected to arbitrary interference with his privacy, family, home or correspondence, nor to attacks upon his honor and reputation. Everyone has the right to the protection of the law against such interference or attacks” (Article 12). Similarly, the 1950 European Convention on Human Rights (ECHR) stipulates that “everyone has the right to respect for his private and family life, his home and correspondence” (Article 8 para 1) and specifies that this right involves “protection against telephone tapping, collection of private information by a state’s security services and publications infringing privacy” (Article 8).In today’s digital world, the right to privacy has become relevant to whole new domains and methods of information processing that were unthinkable at the time of Warren and Brandeis or even of the UDHR; among them: the brain-mind sphere and data processing techniques aimed at revealing information about a person’s mental processes or neurological health. This category of privacy challenges includes both the predictive analysis of primary neural data, such as brain recordings and inferences based on secondary data  through techniques, such as affective computing. For example, A somewhat surprising historical antecedent of the right to mental privacy is reported by philosopher and statesman Francis Bacon, who chronicled that Queen Elisabeth I revoked a thought censorship law in the late sixteenth century, because, allegedly, she did “not [like] to make windows into men’s souls and secret thoughts” .While freedom of thought protects the human mind from external interference and the right to privacy protects personal information  from external intrusion, other normative principles protect the human mind from harm. In the history of ideas, the ethical principle of “non-maleficence” is the most comprehensive conceptual construct postulating the protection of a person’s integrity and the avoidance of harm.primum non-nocere,’’ that is ‘‘first do no harm’’.1 Although the principle of avoiding harm embedded in the ethos of medicine and biomedical research, the characterization of harm is not always semantically straightforward. The medical ethics literature classifies harm according to its magnitude, severity, duration, and reversibility  defines the conditions under which people who have a mental disorder may or may not be subjected to an intervention without their consent. Finally, mental integrity offers potentially suitable normative ground for protecting people from discrimination based on their neural and/or mental characteristics, a type of discrimination called “neurodiscrimination” .In philosophy, particularly in the philosophy of mind, personal identity is the unique identity of a person−who is considered subject of consciousness−over time. Personal identity is often referred to as the set of properties that define someone as an individual person or make someone the person he or she is, and which distinguish them from others. Consequently, the notion of personal identity often presupposes a notion of personhood, i.e., the status of being a person as opposed to a non-person. Most philosophers interpret personhood in terms of a certain set of mental properties . However2In legal theory, the right to personal identity is everyone’s right to form an individual identity, develop a conscience, and protect such individual identity and conscience from external limitations, manipulation, or erasure. It is believed that the right to personal identity begins with the right to life, since it is only through existence that individuals can cultivate their identity. This right is recognized in international law through a range of declarations and conventions. For example, the European Court of Human Rights (ECHR) interpreted Article 8 of the European Convention on Human Rights as to include ‘‘personal identity’’ within the meaning of ‘‘private life,’’ which is explicitly protected from unwanted intrusion by third parties.3It is notable that reflections on neurorights have received extensive coverage in the mainstream media. However, the presence of such reflections in the academic literature is still relatively scarce. Although it has rapidly become a mainstream topic within neuroethical discourse, this area of study is still in a germinal stage of theoretical maturity. This is attested by the fact that the number of publications about neurorights in mainstream media largely outnumbers the quantity of scholarly publications on this topic.While the prominence of the debate on neurorights in public opinion is crucial to ensure public engagement and democratic participation in deliberative processes on this issue, its relative sporadic nature in the academic literature raises a risk of semantic-normative ambiguity and conceptual confusion. This risk is exacerbated by the presence of multiple and not always reconcilable terminologies. Above all, several meta-ethical, normative ethical and legal questions need to be solved. For these reasons, in this section we will try to provide a systematic classification of the neuro-rights proposed so far. Finally, in the next section, we will discuss the main conceptual issues still open.First of all, let us consider the very notion of “neurorights.” Neurorights can be defined as the ethical, legal, social or natural principles of freedom or entitlement relating to a person’s cerebral and mental domain; that is, the fundamental normative rules for the protection and preservation of the human brain and mind. Consequently, neuroright studies are a subfield of neuroethical and neurolegal inquiry that deals with the ethical, legal, social or natural principles of freedom or entitlement related to a person’s cerebral and mental domain; that is, the fundamental normative rules for the protection and preservation of the human brain and mind. We can identify at least five families of neurorights, depending on the normative ethical principles from which they derive: derivatives of freedom of thought, derivatives of privacy, derivatives of mental integrity, derivatives of personal identity and other ethical corollaries. Four neurorights conceptually derived from freedom of thought have been proposed in the literature. These are: cognitive liberty, the right to agency and free will, mental freedom, and freedom of thought itself.via social media and online manipulation, irrespective of whether they result in enhancement, diminishment or no change in brain function.As we have seen earlier, cognitive liberty was a precursor to the neuro-rights debate. Albeit there are differences in its formulation, there is a general consensus in the literature that cognitive liberty entails a person’s autonomous, unhindered control over their mind. This is well-captured by A “right to agency, or the freedom of thought and free will to choose one’s own actions” has been advocated by Mental freedom is used seldom in the literature. ceteris paribus more parsimonious to adopt this normative terminology compared to multiplying the number of normative entities by introducing cognitive liberty, mental freedom and the rights to agency and free will. In that event, however, it should be clarified that “the protection of a person’s self-determination over her mind should comprise the entire forum internum . However, there are differences on how this right is interpreted. Some authors have argued for the recognition of a fourth family of neurorights related to the protection of personal identity. Borrowing the terminology from the psychological-continuity account of personal identity , Ienca aFinally, some authors have proposed the recognition of rights that are not directly related to the protection of the mental domain but rather to the promotion of some socio-technical requirements that are instrumentally necessary for the realization of the rights above. Two of these normative ethical corollaries have been proposed: the right to fair access to mental augmentation and the right to protection from algorithmic bias. The former is defined by Several governmental, intergovernmental and non-governmental actors are currently actively involved in the governance of neurotechnology. Some of these governance initiatives have included the promotion of neurorights, or the consideration thereof, within their agenda. A first important step was marked in 2019, when the Council of the Organization of Economic Development and Cooperation (OECD) adopted a “Recommendation on Responsible Innovation in Neurotechnology,” which set the first international standard in neurtechnology governance . While tAlthough (or perhaps precisely because) neurorights have moved in a relatively short time from the domain of ethical-legal reflection to that of advocacy and policy, many questions still remain unanswered. The first question is to determine whether neurorights should interpreted as rights in the philosophical sense , as rights in the sense of international human rights law  or all the above.The second and most pressing question is to determine whether neurorights in the sense of international human rights law are to be interpreted as brand new human rights or as evolutionary interpretations of existing rights. Two problem-solving principles may offer guidance in this regard. First, as we have seen, Occam’s razor or law of parsimony requires that entities should not be multiplied without necessity. Second, the principle of avoiding “rights inflation,” i.e., the objectionable tendency to label everything that is morally desirable as a “human right,” postulates that the unjustified proliferation of new rights should be avoided. The unjustified proliferation of human rights is problematic because it may spread skepticism about all human rights, as it dilutes them to mere moral desiderata or purely rhetorical claims. In other words, rights inflation is to be avoided because it dilutes the core idea of human rights and distracts from the central goal of human rights instruments, which is to protect a set of truly fundamental human interests, and not everything that would be desirable or advantageous in an ideal world.From this perspective, the most parsimonious approach would be considering neurorights by default as evolutionary interpretations of existing rights, while at the same time imposing justificatory tests to assess whether they actually constitute new human rights. Several justificatory tests to prevent rights inflation have been proposed. For example, A third question regards how neurorights can be adequately implemented and enforced. If in the future some of the neurorights described in this paper were to pass several justificatory tests and obtain strong democratic and deliberative support, how should they be enforced? There are two types of human rights instruments: declarations and conventions. Declarations are not legally binding but do have political impact, whereas conventions are legally binding under international law. Both declarations and conventions can become customary international law over time, which makes them universally legally binding . Future As the analysis above attests, for the field of neurorights to progress and have consistent impact on policy, it would need to overcome the current semantic variations and ambiguities in how these neurorights are denominated, defined, and interpreted. Without a common terminology, semantic disambiguation and conceptual harmonization, it is unlikely that neurorights-based initiatives will lead to effective national and international policies. This harmonization process should not obliterate divergent views, but include them in a pluralistic and deliberative democratic manner. However, it should ensure that neuroright proposals are adequately vetted, conceptually demarcated, normatively justified and rooted in both moral philosophy and existing regulations.inter alia health law, data protection law, consumer protection law and criminal law.Finally, future scholarship should discuss the place of neurorights within the governance of neurotechnology. Unless one commits to the unlikely thesis that neurorights are sufficient for neurotechnology governance (hence that neurotechnology governance can be entirely reduced to neurorights promotion), it is critical to clarify how neurorights relate to other governance mechanisms, such as self-regulation by neurotechnology actors, ethical guidelines, and binding regulations in areas, such as The above analysis suggests that neurorights reflect fundamental human interests that are deeply rooted in the history of ideas. These rights introduce normative specifications related to the protection of the person’s mental and neural domain that are not merely repetitive of existing human rights frameworks. Moreover, it corroborates the view that the fundamental rights and freedoms relating to the human mind and brain are the fundamental substrate of other rights and freedoms. Therefore, protecting neurorights is a fundamental task of international human rights law and may contribute to expanding the protection of other rights and freedoms.This overview indicates that there is still no complete consensus regarding the conceptual-normative boundaries and terminology of neurorights. Divergences exist in relation to how these rights are interpreted, formulated, and conceptually articulated. However, a certain degree of convergence is emerging around three families of neurorights.First, the right to mental integrity appears to have the highest degree of theoretical consensus and legal entrenchment. This is because it is already enshrined in international human rights law and provides a solid legal framework that prioritizes protection from harm. Second, the need for specific provisions on the protection of private mind-related information  also seems to share a high degree of acceptance and recognition. Three, a variety of neurorights candidates have been proposed to preserve and promote the freedom of the human mind and thereby prevent external manipulation. These include evolutionary interpretations of the right to freedom of thought, the right to cognitive liberty, and the right to personal identity. This third family of neurorights is of foundational importance as it largely considered a substrate of all other neurorights and derived freedoms.forum externum  and the protection of the forum internum . Further research is also needed to explore the relationship between freedom of thought and the bundle of rights that fall under the cognitive liberty domain. Clarifying the status of brain data and mental information from a data protection perspective is necessary to define the scope of the right to mental privacy. Finally, the notion of manipulation—which is often invoked as a risk scenario to which the rights to freedom of thought, mental integrity and cognitive liberty could respond—appears elusive to a clear definition, hence requires further analysis to clearly determine the conditions for (il)legitimate influence into a person’s mind. The results of the Council of Europe’s Strategic Action Plan on human rights and technologies in biomedicine as well as an upcoming report to the UN General Assembly on “Freedom of Thought” may help address these challenges.The three families of neurorights above appear deeply rooted in the history of philosophy, international human rights frameworks, and legal doctrine. However, they are affected by several challenges. First, neurorights are insufficiently specified in current human rights instruments, such as the UDHR, the ECHR and the CFR. For example, although it is enshrined within Article18(1) of the ICCPR, the scope and content of “freedom of thought” is largely underexplored. The same can be said for the notion of “mental integrity” as addressed in the CFR. Therefore, a process of either normative interpretation or reform appears to be needed to adequately specify the principles of freedom or entitlement related to a person’s mind and brain domain in the digital era. Further research is needed to investigate the novel challenges for freedom of thought posed by emerging technologies, such as neurotechnologies and AI and clarify the relationship between the protection of the Normative evolution in the light of disruptive technological innovation is not unprecedented in the history of science. For example, the development of the mechanical ventilator produced the concept of brain death and required the law to specify more clearly what functions are integral to life and what are not . SimilarIt is desirable that neurorights shall follow a similar historical trajectory in a manner that expands and enhances the capacity of our human rights framework to address the profound implications of neurotechnology and AI for human nature, human dignity, and human rights.The author confirms being the sole contributor of this work and has approved it for publication.MI is a member of the Council of the Neurorights Network and a member of the Steering Committee on Neurotechnology of the OECD and has served as an expert advisor to the Council of Europe’s Ad Hoc Committee on Artificial Intelligence on the topic of AI & human rights. He is currently serving as an expert advisor to the Council of Europe’s Committee on Bioethics as part of the Strategic Action Plan on Human Rights and Technologies in Biomedicine.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Sarcoidosis is a multisystem disorder of unknown origin and poorly understood pathogenesis that predominantly affects lungs and intrathoracic lymph nodes and is characterized by the presence of noncaseating granulomatous inflammation in involved organs. The disease is highly heterogeneous and can mimic a plethora of other disorders, making diagnosis a challenge even for experienced physicians. The evolution and severity of sarcoidosis are highly variable: many patients are asymptomatic and their disease course is generally benign with spontaneous resolution. However, up to one-third of patients develop chronic or progressive disease mainly due to pulmonary or cardiovascular complications that require long-term therapy. The diagnosis of sarcoidosis requires histopathological evidence of noncaseating granulomatous inflammation in one or more organs coupled with compatible clinical and radiological features and the exclusion of other causes of granulomatous inflammation; however, in the presence of typical disease manifestations such as Löfgren’s syndrome, Heerfordt’s syndrome, lupus pernio and asymptomatic bilateral and symmetrical hilar lymphadenopathy, the diagnosis can be established with high level of certainty on clinical grounds alone. This review critically examines the diagnostic approach to sarcoidosis and emphasizes the importance of a careful exclusion of alternative diagnoses. Indeed, sarcoidosis can mimic a large number of conditions, including, among others, infection, vasculitis, drug reaction and malignancy. However, a diagnosis of sarcoidosis can be established on clinical ground alone in the following scenarios: asymptomatic patients with bilateral hilar lymphadenopathy , Löfgren’s syndrome, Heerfordt’s syndrome and lupus pernio . In such cases, a histological confirmation of the diagnosis is not required, but close clinical follow-up is advised [Sarcoidosis is a chronic systemic disorder of unknown origin characterized histologically by the presence of noncaseating granulomas in affected organs. Although the disease pathogenesis remains poorly understood, sarcoidosis is believed to result from a complex interaction between host/genetic and environmental/infectious factors leading to an aberrant immune response . The lun advised . Sarcoid advised . However advised , and abo advised ,8,9.This review aims to summarise recent advances in the diagnosis of sarcoidosis, with emphasis on the role of imaging and the importance of a careful exclusion of alternative diagnoses.Sarcoidosis occurs worldwide and most commonly affects young and middle-aged individuals of all races and genders. The precise annual incidence and prevalence of the disease are unknown, mainly due to the variable methods of cases ascertainment, lack of consistent case definition and heterogeneous disease manifestations. In addition, in a minority of cases, sarcoidosis remains undiagnosed unless radiographic screening is undertaken . With thOverall, the average age of onset in most studies is between 47 and 51 years, with the peak ages of onset closer to 30–55 years . SarcoidSarcoidosis has numerous clinical manifestations, but respiratory tract involvement occurs at some point in nearly all patients. Dry cough, dyspnea and chest discomfort are the most common symptoms and are generally more prominent in patients with significant endobronchial or parenchymal involvement . The skiSome forms of sarcoidosis are characterized by specific constellation of manifestations: Löfgren’s syndrome, which is generally acute, benign and self-limiting, is characterized by fever, BHL, erythema nodosum, and periarthritis , whereasPulmonary function tests (PFTs) are useful to assess the severity of respiratory involvement and to monitor the disease course. Different from other interstitial lung disease such as idiopathic pulmonary fibrosis, pulmonary function tests in sarcoidosis do not provide an accurate estimate of the extent of parenchymal disease nor can they predict response to treatment; in fact, some patients could present an extended parenchymal radiological impairment with normal or minimally altered PFT.CO) [The majority of patients with sarcoidosis have a normal lung function . In patiCO) ,23. FurtCO) .Pulmonary imaging has a key role in the diagnosis of sarcoidosis, and all patients evaluated for suspected sarcoidosis should have a chest X-ray. This is abnormal in more than 90% of cases, with bilateral hilar lymphadenopathy and parenchymal changes being observed in 50 to 85% and 25 to 60% of cases, respectively . In the Radiographic resolution occurs in three-quarters of patients with stage I and two-thirds of patients with stage II. Patients with higher radiographic stages tend to have more pulmonary symptoms, greater functional impairment and lower likelihood of remission. However, due to the significant overlap between stages, the Scadding system alone cannot be used to predict outcome in individual patients . In addiChest high resolution CT (HRCT) is more sensitive than chest X-ray and provides a more precise assessment of hilar, mediastinal and parenchymal abnormalities . A typicAdditional HRCT findings include ground glass opacities and septal and nonseptal lines . Up to 2Fluorine 18 fluorodeoxyglucose (FDG) PET/CT is a useful tool for assessing sarcoidosis activity, with a sensitivity of 89 to 100% . In addiIn a small study by Mostard et al., more than 90% of patients with fibrotic lesions (Scadding stage IV) still had active inflammatory disease as measured by FDG-PET . AdditioBecause of the high prevalence of pulmonary involvement, bronchoscopy, with its ancillary sampling techniques, has the highest diagnostic yield in sarcoidosis, unless more easily accessible biopsy sites, such as skin or superficial lymph nodes, are available . BronchoAlthough the main role of BAL in sarcoidosis is to exclude alternative diagnoses, such as, among others, infection and malignancy, it may also provide supportive evidence for a diagnosis of sarcoidosis, provided BAL data are interpreted in the context of clinical and radiological features. An increased cellular count with a lymphocytosis > 25% and an elevated CD4/CD8 ratio are common findings, though they are neither sensitive nor specific for a diagnosis of sarcoidosis. Indeed, the BAL cell count may be normal in approximately 15% of newly diagnosed cases . HoweverMediastinal lymphadenopathy is the most common manifestation of sarcoidosis across all ethnic groups , and difTransbronchial Lung Biopsy (TBLB) has a relatively high diagnostic yield (50 to 75%) in patients with suspected sarcoidosis based on bilateral hilar adenopathy or compatible lung parenchymal abnormalities on HRCT. Conversely, in patients with stage I disease, the diagnostic accuracy of TBLB is suboptimal (12–66%), at least when four to five biopsies per patient are obtained . When coIf less invasive tests are not diagnostic or inconclusive, the next steps to sample the mediastinal lymph nodes are mediastinoscopy , and, inAs with other interstitial lung diseases, diagnostic, prognostic and theragnostic biomarkers are also lacking in sarcoidosis. Angiotensin converting enzyme (ACE) and the soluble interleukin-2 receptor (sIL-2R) are the most widely used biomarkers in sarcoidosis, though with suboptimal sensitivity and specificity. ACE is produced by the epithelioid cells within the sarcoid granuloma, and high levels of serum ACE are believed to reflect the burden of granulomatous inflammation ,64. HowesIL-2R is released by activated mononuclear cells and sIL2R levels correlate with disease activity, particularly in patients with extrapulmonary disease. In addition, sIL2R is more sensitive than serum ACE and lysozyme levels for a diagnosis of sarcoidosis , althougTo date, neither ACE nor sIL2R measurement are recommended as routine tests in the diagnostic work-up, initial assessment or follow up of patients with sarcoidosis .Due to the lack of a diagnostic gold standard and the absence of a specific aetiology, the diagnosis of sarcoidosis remains one of exclusion . In addiInfection, particularly tuberculosis (TB), is always in the differential diagnosis of patients suspected of having sarcoidosis. In countries where TB is endemic, differentiating between the two may be challenging, although a number of differences can also be appreciated. Unlike sarcoidosis, TB is characterized by the presence of a necrotizing granuloma in affected organs and cultures positive for Mycobacterium tuberculosis. It is important to state, however, that both features may be absent. In such cases, a positive Interferon-gamma release assay (IGRA) or tuberculin skin test (TST) associated with a positive PCR on clinical specimens generally suggest the correct diagnosis . Rarely Clinical, radiological and histological features of CBD are virtually indistinguishable from those of sarcoidosis . Indeed,Silicosis represents a spectrum of pulmonary diseases  caused bNon-necrotizing granulomas may be seen in a number of settings, including malignancy, drug toxicity and following medical device implantation . The preCommon variable immunodeficiency (CVID), the most common primary immunodeficiency disorder, is a syndrome characterized by low serum antibody levels, poor antibody response and recurrent bacterial infection . CVID isDue to the heterogenic presentation, sarcoidosis must be careful to also be distinguished from rheumatologic disorders and vasculitis. At presentation, many patients with sarcoidosis could present symptoms similar to autoimmune diseases such as arthralgia/arthritis, parotitis, weight loss, cutaneous lesions, asthenia and fever . LaboratFinally, the usual interstitial pneumonia (UIP) pattern could be present in pulmonary fibrotic sarcoidosis, ILD associated with rheumatoid arthritis and systemic scleroderma ,100.Sarcoidosis is an uncommon disorder of unknown aetiology that can mimic a multitude of other diseases. The diagnosis remains one of exclusion and requires compatible clinical and radiological features together with the evidence of (non-necrotizing) granulomatous inflammation at disease sites, with the exception of some well-defined clinical manifestations such as Löfgren’s syndrome, Heerfordt’s syndromes and lupus pernio. The diagnosis of sarcoidosis may be challenging even for experienced clinicians because multiple other granulomatous disorders can mimic sarcoidosis and need to be excluded. Higher-quality evidence is urgently needed to guide clinical practice with regard to the diagnosis and detection of sarcoidosis.


We present a detailed study on band structure-dependent properties such as electrical conductivity, the charge of carriers and Seebeck coefficients of graphene nano-ribbons (GNRs) doped with the magnetic impurities Fe and Co since the spin thermopower could be considerably enhanced by impurities. Thermoelectric properties of two-dimensional systems are currently of great interest due to the possibility of heat to electrical energy conversion at the nanoscale. The thermoelectric properties are investigated using the semi-classical Boltzmann method. The electronic band structure of doped nano-ribbons is evaluated by means of density-functional theory in which the Hubbard interaction is considered. Different types of nano-ribbons (armchair-edge and zigzag-edge) and their thermoelectric features such as conductivity and Seebeck coefficient in the presence and absence of magnetic impurities have been studied. We present a detailed study on band structure-dependent properties such as electrical conductivity, the charge of carriers and Seebeck coefficients of graphene nano-ribbons doped with atoms since the spin thermopower could be enhanced by impurities. The last have demonstrated exceptional physical and chemical properties which can be utilized in next generation electronics and optoelectronics. Recently, due to their unique properties, graphene and other 2D graphene-driven nanosheets have been studied both experimentally and theoretically by means of density functional theory (DFT).2–9 The thermoelectric, mechanical, and optical properties of graphene and other graphene-like 2D nanosheets can be promoted by different processes, including doping with other elements as an impurity,10 making ribbons11 and heterostructures,12 creating atomic vacancies,13 and so on. One-dimensional structure of graphene namely graphene nanoribbons (GNRs) are thin ribbons of graphene that have brought additional benefits over graphene monolayer.14 For instance, GNRs have a higher aspect ratio with respect to graphene, which importantly decreases the percolation threshold in polymer composites and conductive films. Two types of nanoribbons can be derived from the graphene monolayer, namely armchair graphene nanoribbons (AGNRs) and zigzag graphene nanoribbons (ZGNRs). The GNRs are perfect for nano-electronic applications,15–20 and numerous researches have been implemented on the electronic properties of GNRs by different methods, including DFT calculations, non-equilibrium Green's function method, mean field theory, and tight-binding calculations.21After the discovery of graphene22 However, the thermal properties of GNRs structure have been studied for thermoelectric applications,23 some researches have revealed that it is possible to promote thermoelectric properties of GNRs by modifying the atomic configuration of the ribbon's edge.24,25 Recently, the GNRs junction structures and their thermoelectric features have been studied.26 In another study, the electronic transport characteristics of GNRs have been simulated by means of nearest-neighbor π-orbital tight-binding Hamiltonian, and the thermal transport has been modeled by the forth-nearest-neighbor force constant model (4-NNFC).27,28The thermoelectric properties arise from a thermoelectric material with the ability to generate electricity from temperature gradients. The Peltier's and Seebeck's effects are the most interesting aspect of materials with thermoelectric properties. The efficiency of a thermoelectric material can be expressed by the power factor, which is one of the characteristics of materials to determine the utility of a thermoelectric cooler or generator. To predict a sufficiently high thermoelectric performance, phenomenologically, calculating the band structure-dependent quantities are needed.29 and the characteristics of graphene can be tuned by dopping impurities by substitutional or adsorbing atoms.30–33Recently, a lot of efforts have been carried out to modify the electronic and magnetic properties of graphene to make it useful for realistic applications. The gapless nature of graphene can be changed by adding a small number of heteroatoms34 Mean-field approximation has been used to model the magnetic impurities through Hubbard term.35,36 It has been demonstrated that cobalt dopping can be used in band gap controlling in graphene.37The effect of impurities on graphene have been studied theoretically using different methods such as tight binding and Green's function methods.38 Understanding the physics of the localized spins on a metal host is significant for the engineering of doped thermoelectric nanoscale devices. Here, the behavior of thermoelectric features around the Fermi level has been investigated using Boltzmann's method.In this paper, the thermoelectric properties of doped GNRs have been studied in detail. For example, in ZGNRs as a host, the configuration of the edges play a pivotal role in conductivity, and the magnetic impurities will change the energy bands of the host dramatically due to the Hubbard effect.2N in the unit cell which is shown as ZGNR(N) and AGNR(N). Atomic structure relaxations were performed using the linear combination of pseudo-atomic orbitals (LCPAO) method within the quasi-Newton scheme till the forces on the atoms become less than 10−5 eV Å−1. The optimized lattice constant and atomic positions for both AGNR (a = 4.28 Å) and ZGNR (a = 2.47 Å) are in agreement with some previous works.39,40 The exchange-correlation energy was taken into account by using the local density approximations (LDA) and a kinetic cutoff energy of 400 eV for the plane-wave basis was adopted. A Monkhorst–Pack mesh (12 × 1 × 1) was set for the Brillouin zone.There are two typical kinds of edges in graphene nanoribbons called armchair-edge and zigzag-edge. The two edges have 30° difference in their cutting direction. Here we briefly discuss the structure and the procedure of calculating band-structure dependent properties. We have considered our system as the one illustrated in 41 Based on the ref. N = 3n, N = 3n + 1, and N = 3n + 2 dimer lines. It is essential to study three groups since AGNRs show a periodic behavior in band gap and other AGNRs with higher width show a similar characteristics.It has been taken into account that all suspended bonds at graphene edges are terminated by hydrogen atoms, and thus give no contribution to the electronic states near the Fermi level. The band-structures of both systems are displayed in f(ε). Based on the Boltzmann theory the conductivity is obtained as follows42τn(εn(k)) is the relaxation time which is energy dependent and can be evaluated from the following equation42νn(k) is the semi-classical velocity of electron defined as a function of band energies as followsIn this section, we are inspired by the semi-classical Boltzmann approximation used in quasi-one-dimensional GNRs. We calculate the conductivity employing the semi-classical motion of the electron in the presence of gradient and disturbing fields. To describe the conduction, we use the equilibrium Dirac distribution function σ, which is a sum of contributions from each bandNote that we need the total conductivity vice versa the Seebeck coefficient can be written as follows:Using the definition of the conversion of heat directly into electricity or τ which is inversely proportional to the scattering probability of the charge carrier from atoms. τ is closely related to the electrical conductivity and other thermoelectric properties of the system. Furthermore, the charge of carriers can be evaluated from the density of states (DOS) g(ε) calculated by DFT. One can calculate the charge of carriers as follows:In the Boltzmann theory, the average free time of flight of a charge carrier is defined as relaxation time 43 Calculating the Boltzmann conductivity needs to evaluate band-structures and energies in which we will utilize the OpenMX software package based on DFT. Atomic structure relaxations and electronic properties calculations were performed employing the OpenMX package44 within the linear combination of pseudo-atomic orbitals (LCPAO) method.45Thermoelectric properties of the system have been calculated using the BoltzTraP.3We studied iron (Fe) and cobalt (Co) as magnetic impurities in which the Hubbard interaction plays an important role in the electronic and spintronic properties of the system. The structure used in DFT calculations is presented in Ueff) for doped GNRs. To achieve this goal we should consider DFT + U corrections in the first-principles calculations46,47 because the on-site Coulomb interactions are not correctly described by the LDA or GGA when we have magnetic impurities. The idea behind the DFT + U is to correct the strong on-site Coulomb interaction of the electrons which are localized with an additional Hubbard term. To increase the accuracy of the Brillouin zone integrations the Monkhorst–Pack mesh is changed to (15 × 1 × 1).As mentioned before, the Hubbard interaction plays an important role in magnetic systems. So, we should find the Hubbard correction  and AGNR(3n + 1) are considerable because only the spin-down band remains near the Fermi level. Although the flat bands do not contribute to the conductivity because of localized electrons around the impurities, they affect the magnetic features of the system. The electrons with zero velocity localized in impurities' orbitals can feed the non-flat states of carbon atoms in the GNRs. Because the electrons in the edge sites contribute to conductivity, the distance of the impurities from the edge of the ribbon plays an essential role in its electronic behavior. The carbon bands near the Fermi level are related to the edge state and so the width of ribbons will change the results of separation of spin up and down. That is why the separation between spin up and down of the flat bands in AGNR(3n + 2) is less than the others.Both iron and cobalt have an energy level near the Fermi level. The separation of the spin up and down in AGNR and AGNR(3n + 2) Fe atoms play as electron donor dopant which can releases a mobile conduction electron into the crystal lattice if the applied voltage is higher than cut voltage. It should be noted that the donor levels are spin-down electrons. However, it is possible to control the properties of all these categories using an external magnetic field.49From the band structures we can categorize the systems into three groups. ZGNRs are Dirac semiconductors, 2Te3, Sb2Te3 and Bi2Se3 single crystals.50 Furthermore, in the case of AGNR(3n + 2) one can find out that the spin-up and spin-down electrons show different behaviours in flat bands. The dopant states are made of spin-down electron and the spin-up band-structure is a normal semiconductor without any dopant states.It has been also reported that iron impurity acts as a donor in Bi4via an interface to OpenMX,51 one can calculate the thermoelectric properties of such a system. Semi-classical transport coefficients such as Seebeck coefficient and electrical conductivity were calculated under the constant relaxation time at temperature 300 K. Semi-classical transport features are presented as a function of chemical potential (μ) which is an independent variable. Substitution and doping can be used to manipulate μ which plays an important role in the thermoelectric transport properties.52In this section, we present the thermoelectric properties of graphene nanoribbons using first-principle calculations. Using BoltzTraP code n) in terms of chemical potential in different cases. In this figure, we compare the doped GNRs (coloured solid lines) with pure GNRs (dashed black lined). The charge of carriers in the case of doped GNRs increased dramatically in comparison with the pure GNRs. This is completely the correct behaviour of a doped crystal. The current of the GNRs can be evaluated as the product of the average velocity calculated from band structure times the corresponding charge of carriers. σ/τ, is illustrated in Also, conductivity S in terms of chemical potential. It is noticeable that like conductivity, the symmetry between negative and positive energies is broken after taking the Hubbard interaction into account. The most important fact evidenced from N = 3n. Meanwhile, the Seebeck coefficient of AGNRs with N = 3n + 1 and N = 3n + 2 decreases with doping.N = 3n + 2 the Seebeck coefficient of spin-up is negligible. In other words, Co-doped ZGNR and AGNR(5) are good candidates for filtering spin-down and spin-up electrons respectively.Concerning cobalt doped GNRs, the Seebeck coefficient of spin-up ZGNR is dominant in the whole range of chemical potential, but in the case of AGNR 5i.e. Fe and Co on the electronic structure of GNRs with different widths. The energy states of the impurities can act as dopant states in AGNRs. Besides, the Seebeck coefficient of the doped nano-ribbons shows that the Co-doped ZGNR and AGNR (3n + 2) are two candidates for spin filter heat to electricity conversion.Band structure-dependent properties of graphene nanoribbons such as the charge of carrier, conductivity and Seebeck coefficients have been investigated by a powerful combination of the semi-classical Boltzmann theory and DFT. The properties of GNRs doped with application-relevant magnetic impurities are studied in detail and compared with those of pure ones. We studied the effect of magnetic impurities The data that support the findings of this study are available from the corresponding author upon reasonable request.The authors declare that there are no conflicts of interest regarding the publication of this paper.


The discovery of introns over four decades ago revealed a new vision of genes and their interrupted arrangement. Throughout the years, it has appeared that introns play essential roles in the regulation of gene expression. Unique processing of excised introns through the formation of lariats suggests a widespread role for these molecules in the structure and function of cells. In addition to rapid destruction, these lariats may linger on in the nucleus or may even be exported to the cytoplasm, where they remain stable circular RNAs (circRNAs). Alternative splicing (AS) is a source of diversity in mature transcripts harboring retained introns (RI-mRNAs). Such RNAs may contain one or more entire retained intron(s) (RIs), but they may also have intron fragments resulting from sequential excision of smaller subfragments via recursive splicing (RS), which is characteristic of long introns. There are many potential fates of RI-mRNAs, including their downregulation via nuclear and cytoplasmic surveillance systems and the generation of new protein isoforms with potentially different functions. Various reports have linked the presence of such unprocessed transcripts in mammals to important roles in normal development and in disease-related conditions. In certain human neurological-neuromuscular disorders, including myotonic dystrophy type 2 (DM2), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Duchenne muscular dystrophy (DMD), peculiar processing of long introns has been identified and is associated with their pathogenic effects. In this review, we discuss different mechanisms involved in the processing of introns during AS and the functions of these large sections of the genome in our biology. Initially, genes that contained introns were called interrupted and considered to be noncoding; however, this notion has changed over time. The completed sequencing projects of the human genome and other organisms including D. melanogaster and C. elegans have confirmed that all eukaryotes have introns  in cystic fibrosis (CF)  requires the presence of splice donor (5′ss) and splice acceptor (3′ss) sites, in addition to the branch point (BP) site located near the 3′ss. This process involves the formation of a lariat intermediate controlled by specific dinucleotide sequences that border the exon/intron junction, i.e., conserved GU and AG, respectively, at the 5′- and 3′-ends of each intron Fig. A. In humcis-acting elements in RI-mRNAs with nuclear export proteins. Although they were originally thought to be unique to viruses, it was subsequently shown that the mammalian nuclear export factor 1 (NXF1) gene itself contains a constitutive cis-acting transport element in its alternatively spliced mRNA with a retained intron , Fuchs endothelial corneal dystrophy , and amyotrophic lateral sclerosis/ frontotemporal dementia   of pre-RNAs, through the use of alternative promoters and polyA signals and, to some extent, through nucleotide editing. Intron retention (IR), which was originally described in viruses is one type of alternative splicing event (ASE) and is characterized by the inclusion of one or more introns in mature mRNA (RI-mRNA). This class of ASE is distinct from other types in that the mature transcript harboring unspliced introns still contains a potentially spliceable unit  pose challenges during processing and are cut out by splicing of distinct segments in a process known as recursive splicing (RS)  or other structural features that can activate or repress translational initiation efficiency  and contact a host cell karyopherin protein (CRM1), also known as Exportin1 or Xpo1. Subsequently, this complex shuttles to the cytoplasm, where it delivers the RNA cargo     and mouse (CH12 B lymphoma) cell lines focusing on transcription and chromatin components. They detected significant enrichment of RNA Pol II and some of the chromatin regulators, e.g., chromodomain-helicase-DNA-binding protein 2 (CHD2), over retained introns compared to constitutive, and specific chromatin modifications, i.e. acetylation of histone H3 (H3K27ac). Of all the factors analyzed, the strongest enrichment was found for RNA Pol II phosphorylated at serine 2 (Pol II-Ser2P) associated with transcription elongation, indicating that RIs are sites of pausing for Pol II, whose levels appear to be tightly coupled with increased IR events , RNA Pol II processing, and splicing factor recruitment  on genomic DNA from mouse promyelocytes and granulocytes. They measured levels of DNA methylation near the 3’ and 5’ splice junctions and within the body of all introns in these cells. Significantly reduced methylation levels were observed in retained introns than in constitutive introns, particularly near the junctions of RI; however, a weaker reduction was also detected within the body of the unspliced introns Eukaryotic cells responses to stress-related programs are associated with IR  , ALS/FTD (GGGGCCexp), FECD (CTGexp), spinocerebellar ataxias type 10 (ATTCTexp), type 37 (ATTTCexp), and Friedreich’s ataxia (GAAexp)  gene of Drosophila  or ratchet points (RPs). Each RS-site contains an AGGU sequence motif comprising a pair of juxtaposed 3′ and 5′ splice sites  gene contains five recursive sites, two of which were previously unknown. Recursively spliced introns were enriched in first introns, which are longer than non-first introns, relative to subsequent introns in fly genes ite Fig. . Their rUbx gene, correlation that has also been investigated in humans . They represent a large fraction of unstable molecules, as most of them are destroyed within minutes in the nucleus via the DBR1 enzyme. The enzyme hydrolyzes the 2′–5′ phosphodiester bond (branch point) in lariats to give rise to linear molecules promoting their rapid turnover (Ooi et al. Xenopus oocytes, in embryos of Drosophila, and in cells and tissues from humans, mice, chickens and fish (Gardner et al. SciRNAs from a variety of genes have been found in the cytoplasm and nucleus of Only approximately 1.5% of DNA contains protein-coding sequences. The other over 98% consists of nonprotein coding regions (Kapranov et al.