Citation: Jennifer L. Wood, Wuxing Liu, Caixian Tang, Ashley E. Franks. Microorganisms in heavy metal bioremediation: strategies for applying microbial-community engineering to remediate soils[J]. AIMS Bioengineering, 2016, 3(2): 211-229. doi: 10.3934/bioeng.2016.2.211
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Transglutaminases (TGs, E.C. 2.3.2.13) are Ca2+-dependent enzymes which catalyze post-translational modifications of proteins. Examples of TG-catalyzed reactions include: (Ⅰ) acyl transfer between the γ-carboxamide group of a protein/polypeptide glutaminyl residue and the e-amino group of a protein/polypeptide lysyl residue; (Ⅱ) attachment of a polyamine to the γ-carboxamide of a glutaminyl residue; (Ⅲ) deamidation of the γ-carboxamide group of a protein/polypeptide glutaminyl residue (Figure 1) [1,2]. The reactions catalyzed by TGs occur by a two-step mechanism (ping-pong type) (Figure 2). The transamidating activity of TGs is activated by the binding of Ca2+, which exposes an active-site cysteine residue. This cysteine residue reacts with the γ-carboxamide group of an incoming glutaminyl residue of a protein/peptide substrate to yield a thioacyl-enzyme intermediate and ammonia (Figure 2, Step 1). The thioacyl-enzyme intermediate then reacts with a nucleophilic primary amine substrate, resulting in the covalent attachment of the amine-containing donor to the substrate glutaminyl acceptor and regeneration of the cysteinyl residue at the active site (Figure 2, Step 2). If the primary amine is donated by the ε-amino group of a lysyl residue in a protein/polypeptide, a Nε-(γ-L-glutamyl)-L-lysine (GGEL) isopeptide bond is formed (Figure 1, example Ⅰ). On the other hand, if a polyamine or another primary amine (e.g. histamine, serotonin and others) acts as the amine donor, a γ-glutamylpolyamine (or γ-glutamylamine) residue is formed (Figure 1, example Ⅱ). It is also possible for a polyamine to act as an N, N-bis-(γ-L-glutamyl)polyamine bridge between two glutaminyl acceptor residues either on the same protein/polypeptide or between two proteins/polypeptides [3]. If there is no primary amine present, water may act as the attacking nucleophile, resulting in the deamidation of glutaminyl residues to glutamyl residues (Figure 1, example Ⅲ). Regarding the physiological roles played by the transglutaminase activity, recently transglutaminase-catalyzed polyamination of tubulin has been shown to stabilize axonal microtubules, suggesting an important role for these reactions also during some physiological processes, such as neurite outgrowth and axon maturation [4]. The reactions catalyzed by TGs occur with little change in free energy and hence should theoretically be reversible. However, under physiological conditions the cross-linking reactions catalyzed by TGs are usually irreversible. This irreversibility partly results from the metabolic removal of ammonia from the system and from thermodynamic considerations resulting from altered protein conformation. Some scientific reports suggest that TGs may be able to catalyze the hydrolysis of Nε-(γ-L-glutamyl)-L-lysine cross-links (GGEL) isopeptide bonds in some soluble cross-linked proteins. Furthermore, it is likely that TGs can catalyze the exchange of polyamines onto proteins [2]. In TG2 other catalytic activities, such as the ability to hydrolyze GTP (or ATP) into GDP (or ADP) and inorganic phosphate (Figure 1, example Ⅳ), a protein disulfide isomerase activity (Figure 1, example Ⅴ), and a kinase activity which phosphorylates histones, retinoblastoma (RB) and P53 (Figure 1, example Ⅵ), are present, while only some of these activities have been identified also in other TGs [5,6,7,8].
Figure 1. Examples of reactions catalyzed by TG: (Ⅰ) acyl transfer between the γ-carboxamide group of a protein/polypeptide glutaminyl residue and the ε-amino group of a protein/polypeptide lysyl residue; (Ⅱ) attachment of a polyamine to the γ-carboxamide of a glutaminyl residue; (Ⅲ) deamidation of the γ-carboxamide group of a protein/polypeptide glutaminyl residue; (Ⅳ) GTPase activity; (Ⅴ) protein disulfide isomerase activity; (Ⅵ) protein kinase activity.
Figure 2. Schematic representation of a two-step transglutaminase reaction. Step 1: In the presence of Ca2+, the active-site cysteine residue reacts with the γ-carboxamide group of an incoming glutaminyl residue of a protein/peptide substrate to yield a thioacyl-enzyme intermediate and ammonia. Step 2: The thioacyl-enzyme intermediate reacts with a nucleophilic primary amine substrate, resulting in the covalent attachment of the amine-containing donor to the substrate glutaminyl acceptor and regeneration of the cysteinyl residue at the active site. If the primary amine is donated by the ε-amino group of a lysyl residue in a protein/polypeptide, a Nε-(γ-L-glutamyl)-L-lysine (GGEL) isopeptide bond is formed.Numerous experimental data indicate that some TGs are multifunctional proteins with distinct and regulated enzymatic activities. In fact, under physiological conditions, the transamidation activity of TGs is latent [9,10], while other activities, recently identified, could be present. For example, in some physiological states, when the concentration of Ca2+ increases, the crosslinking activity of TGs may contribute to important biological processes. As previously described, one of the most intriguing properties of some TGs, such as TG2, is the ability to bind and hydrolyze GTP and furthermore, to bind to GTP and Ca2+. GTP and Ca2+ regulate its enzymatic activities, including protein cross-linking, in a reciprocal manner: the binding of Ca2+ inhibits GTP-binding and GTP-binding inhibits the transglutaminase cross-linking activity of the TG2 [5]. Interestingly, TG2 shows no sequence homology with heterotrimeric or low-molecular-weight G-proteins, but there is evidence that TG2 (TG2/Ghα) is involved in signal transduction, and, therefore, TG2/Ghα should also be classified as a large molecular weight G-protein. Other studies, along with ours, showed that TG2/Ghα can mediate the activation of phospholipase C (PLC) by the α1b -adrenergic receptor [10] and can modulate adenylyl cyclase activity [11]. TG2/Ghα can also mediate the activation of the δ1 isoform of PLC and of maxi-K channels [12]. Interestingly, the signaling function of TG2/Ghα is preserved even with the mutagenic inactivation of its crosslinking activity by the mutation of the active site cysteine residue [13].
At least eight different TGs, distributed in the human body, have been identified up to now (Table 1) [14,15,16,17,18,19]. Complex gene expression mechanisms regulate the physiological roles that these enzymes play in both the intracellular and extracellular compartments. In the Nervous System, for example, several forms of TGs are simultaneously expressed [20,21,22]. Moreover, in these last years, several alternative splice variants of TGs, mostly in the 3'-end regions, have been identified [23]. Interestingly, some of them are differently expressed in human pathologies, such as Alzheimer's Disease (AD) [24]. On the basis of their ubiquitous expression and their biological roles, we may speculate that the absence of these enzymes would be lethal. However, this does not always seem to be the case, since, for example, null mutants of the TG2 are usually phenotypically normal at birth [12,25,26]. This result may be explained by the expression of other TG genes that may substitute the TG2 missing isoform, although other TG isoform mutations have been associated with severe phenotypes, such as lamellar ichthyosis for TG1 isoform mutations. Bioinformatic studies have shown that the primary structures of human TGs share some identities in only few regions, such as the active site and the calcium binding regions. However, high sequence conservation and, therefore, a high degree of preservation of secondary structure among TG2, TG3 and FXⅢa indicate that these TGs all share four-domain tertiary structures which could be similar to those of other TGs [27].
| TG | Physiological role | Gene map location | Reference |
| Factor XⅢa | Blood clotting | 6p24-25 | [14] |
| TG 1 (Keratinocyte TG, kTG) | Skin differentiation | 14q11.2 | [15] |
| TG 2 (Tissue TG, tTG, cTG) | Apoptosis, cell adhesion, signal transduction | 20q11-12 | [16] |
| TG 3(Epidermal TG, eTG) | Hair follicle differentiation | 20p11.2 | [17] |
| TG 4 (Prostate TG, pTG) | Suppression of sperm immunogenicity | 3q21-2 | [18] |
| TG 5 (TG X) | Epidermal differentiation | 15q15.2 | [19] |
| TG 6 (TG Y) | Central Nervous System development | 20p13 | [19] |
| TG 7 (TG Z) | Unknown function | 15q15.2 | [19] |
DownLoad: CSVNumerous scientific data suggest that the transglutaminase activity is involved in the pathogenesis of neurodegenerative diseases, but to date, however, still controversial experimental findings about the role of the TGs enzymes in these diseases have been obtained [28,29,30]. Protein aggregates in affected brain regions are histopathological hallmarks of many neurodegenerative diseases [31]. More than 20 years ago Selkoe et al. suggested that TG activity might contribute to the formation of protein aggregates in AD brain [32]. In support of this hypothesis, tau protein has been shown to be an excellent in vitro substrate of TGs and GGEL cross-links have been found in the neurofibrillary tangles and paired helical filaments of AD brains [33,34,35]. Interestingly, a recent work showed the presence of bis γ-glutamyl putrescine in human CSF, which was increased in Huntington's Disease (HD) CSF [36]. This is an important evidence that protein/peptides crosslinking by polyamines does indeed occur in the brain, and that this is increased in HD brain. TG activity has been shown to induce also amyloid β-protein oligomerization [37] and aggregation at physiologic levels [38]. By these molecular mechanisms, TGs could contribute to AD symptoms and progression [38]. Moreover, there is evidence that TGs also contribute to the formation of proteinaceous deposits in Parkinson's Disease (PD) [39,40], in supranuclear palsy and in HD, a neurodegenerative disease caused by a CAG expansion in the affected gene [41,42,43]. For example, expanded polyglutamine domains have been reported to be substrates of TG2 and therefore aberrant TG activity could contribute to CAG-expansion diseases, including HD (Figure 3) [45,46]. However, although all these studies suggest the possible involvement of the TGs in the formation of deposits of protein aggregates in neurodegenerative diseases, they do not indicate whether aberrant TG activity per se directly determines the disease progression. For example, several experimental findings reported that TG2 activity in vitro leads to the formation of soluble aggregates of α-synuclein or polyQ proteins [47,48,49]. To date, as previously reported, at least ten human CAG-expansion diseases have been described (Table 2) and in at least eight of them their neuropathology is caused by the expansion in the number of residues in the polyglutamine domain to a value beyond 35–40 [50,51,52,53,54,55,56,57,58,59]. Remarkably, the mutated proteins have no obvious similarities except for the expanded polyglutamine domain. In fact, in all cases except SCA 12, the mutation occurs in the coding region of the gene. However, in SCA12, the CAG triplet expansion occurs in the untranslated region at the 5' end of the PPP2R2B gene. It has been proposed that the toxicity results from overexpression of the brain specific regulatory subunit of protein phosphatase PP2A [56]. Most of the mutated proteins are widely expressed both within the brain and elsewhere in the body. A major challenge then is to understand why the brain is primarily affected and why different regions within the brain are affected in the different CAG-expansion diseases, i.e., what accounts for the neurotoxic gain of function of each protein and for a selective vulnerability of each cell type. Possibly, the selective vulnerability [60] may be explained in part by the susceptibility of the expanded polyglutamine domains in the various CAG-expansion diseases to act as cosubstrates for a brain TG (Figure 4). To strengthen the possible central role of the TGs in neurodegenerative diseases, a study by Hadjivassiliou et al. showed that anti-TG2 IgA antibodies are present in the gut and brain of patients with gluten ataxia [61], a non-genetic sporadic cerebellar ataxia, but not in ataxia control patients. Recently, anti-TG2, -TG3 and -TG6 antibodies have been found in sera from CD patients, suggesting a possible involvement also of other TGs in the pathogenesis of dermatitis herpetiformis and gluten ataxia, two frequent extra intestinal manifestations of gluten sensitivity [62,63]. These last findings could suggest also a possible role of the "gut-brain axis" for the etiopathogenesis of human neurodegenerative diseases, in which the TG enzymes, in particular the TG2 enzyme, could play an important role [64,65,66].
Figure 3. Possible physiopathological effects of the mutated huntingtin. Some of the physiopathological roles of mutated huntingtin, including the formation of nuclear inclusions, have been described in the Figure AP2 = adipocyte Protein 2; BAX = bcl-2-like protein 4; BDNF = brain-derived neurotrophic factor; CALM = calmodulin; CASP = caspases; CASP3 = caspase 3; CASP8 = caspase 8; CBP = CREB binding protein; CBS = cystathionine-β-synthase; DCTN1 = dynactin subunit 1; GAPD = glyceraldehyde-3-phosphate dehydrogenase; GRB2 = growth factor receptor-bound protein 2; HAP1 = huntingtin associated protein 1; HIP1 = huntingtin interacting protein 1; HIP2 = huntingtin interacting protein 2; Hippi =; HIP1 protein interactor;
NCOR1 = nuclear receptor corepressor 1; RasGAP = p21Ras protein and GTPase-activating protein complex; TGs = transglutaminases; TP53 = tumor protein 53.| Disease | Sites of neuropathology | CAG triplet number | Gene product (Intracellular localization of protein deposits) | Reference | |
| Normal | Disease | ||||
| Corea Major or Huntington's Disease (HD) | Striatum (medium spiny neurons) and cortex in late stage | 6–35 | 36–121 | Huntingtin(n, c) | [50] |
| Spinocerebellar Ataxia Type 1 (SCA1) | Cerebellar cortex (Purkinje cells), dentate nucleus and brain stem | 6–39 | 40–81 | Ataxin-1(n, c) | [51] |
| Spinocerebellar Ataxia Type 2 (SCA2) | Cerebellum, pontine nuclei, substantia nigra | 15–29 | 35–64 | Ataxin-2 (c) | [52] |
| Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph disease (MJD) | Substantia nigra, globus pallidus, pontine nucleus, cerebellar cortex | 13–42 | 61–84 | Ataxin -3 (c) | [53] |
| Spinocerebellar Ataxia Type 6 (SCA6) | Cerebellar and mild brainstem atrophy | 4–18 | 21–30 | Calcium channel Subunit (α 1A)(m) | [54] |
| Spinocerebellar Ataxia Type 7 (SCA7) | Photoreceptor and bipolar cells, cerebellar cortex, brainstem | 7–17 | 37–130 | Ataxin-7 (n) | [55] |
| Spinocerebellar Ataxia Type 12 (SCA12) | Cortical, cerebellar atrophy | 7–32 | 41–78 | Brain specific regulatory subunit of protein phosphatase PP2A (?) | [56] |
| Spinocerebellar Ataxia Type 17 (SCA17) | Gliosis and neuronal loss in the Purkinje cell layer | 29–42 | 46–63 | TATA-binding protein (TBP) (n) | [57] |
| Spinobulbar Muscular Atrophy (SBMA) or Kennedy Disease | Motor neurons (anterior horn cells, bulbar neurons) and dorsal root ganglia | 11–34 | 40–62 | Androgen receptor (n, c) | [58] |
| Dentatorubral-pallidoluysian Atrophy (DRPLA) | Globus pallidus, dentato-rubral and subthalamic nucleus | 7–35 | 49–88 | Atrophin (n, c) | [59] |
| Cellular localization: c, cytosol; m, membrane; n, nucleus; ?, unknown localization. | |||||
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Figure 4. Possible mechanisms responsible for protein aggregate formation catalyzed by TGs. Transglutaminase activity could produce insoluble aggregates both by the formation of Ne-(γ-L-glutamyl)-L-lysine (GGEL) isopeptide bonds (left side of the figure) and by the formation of N, N-bis-(γ-L-glutamyl)polyamine bridges (right side of the figure) in the mutated huntingtin.In support of the hypothesis of the toxic effect of TG activity in other neurodegenerative diseases, such as Alzheimer's disease and Parkinson's Disease, TG activity has been shown to induce amyloid beta-protein and α-synuclein oligomerization and aggregation at physiologic levels [67,68,69]. In fact, TG activity induces protofibril-like amyloid beta-protein assemblies that are protease-resistant and inhibit long-term potentiation [38]. Therefore, by these molecular mechanisms, TG activity could also contribute to Alzheimer's disease symptoms and progression. Very recently, TG2 and its product isopeptide have been found increased in Alzheimer's disease and APPswe/PS1dE9 double transgenic mice brains [70], while catalytically active TG2 colocalizes with Aβ pathology in Alzheimer's disease mouse models [71]. Interestingly, other works are suggesting that also other TGs could be involved in the molecular mechanisms responsible for neurodegenerative diseases [72]. In particular, a recent work by Basso et al. found that in addition to TG2, TG1 gene expression level is significantly induced following stroke in vivo or due to oxidative stress in vitro [73]. Moreover, structurally diverse inhibitors, used at concentrations that inhibit TG1 and TG2 simultaneously, are neuroprotective. Together, these last studies suggested that multiple TG isoforms, not only TG2, participate in oxidative stress-induced cell death signalling, and that isoform nonselective inhibitors of TG will be most efficacious in combating oxidative death in neurological disorders. These are interesting and worthwhile studies, suggesting that multiple TG isoforms can participate in neuronal death processes. Therefore, all these studies suggest that the involvement of brain TGs could represent a common denominator in several neurological diseases, which can lead to the determination of pathophysiological consequences through different molecular mechanisms (Table 3).
| Associations/cause | Effects |
| Gluten intolerance | Gluten ataxia |
| Neuroinflammation | Alzheimer's disease and other neurodegenerative diseases |
DownLoad: CSVNeuroinflammation plays an important role in various chronic neurodegenerative diseases, characterized also by the pathological accumulation of specific protein aggregates. In particular, several of these proteins have been shown to be substrates of transglutaminases. Interestingly, it has recently been demonstrated that transglutaminase 2 (TG2) may also be involved in molecular mechanisms underlying inflammation. In the central nervous system, astrocytes and microglia are the cell types mainly involved in this inflammatory process. The transcription factor NF-κB is considered the main regulator of inflammation and it is activated by a variety of stimuli including calcium influx, oxidative stress and inflammatory cytokines. Recently, in addition to these stimuli, TG2 has been shown to activate NF-κB both via a canonical pathway [74] and via a non-canonical pathway [75]. On the other hand, NF-κB regulatory response elements are present also in the Transglutaminase 2 promoter [76]. Under these conditions, the over-expression of TG2 results in the sustained activation of NF-κB. Severalκ findings emphasize the possible role of the TG2/NF-κB activation pathway in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Together, these evidences suggest that TG2 could play a role in neuroinflammation and could contribute to the production of compounds that are potentially deleterious to neuronal cells [77].
In consideration to the fact that up to now there have been no long-term effective treatments for the human neurodegenerative diseases previously reported, then the possibility that selective TG inhibitors may be of clinical benefit has been seriously considered. In this respect, some encouraging results have been obtained with TG inhibitors in preliminary studies with different biological models of CAG-expansion diseases. For example, cystamine (Figure 5) is a potent in vitro inhibitor of enzymes that require an unmodified cysteine at the active site [78]. Inasmuch as TGs contain a crucial active-site cysteine, cystamine has the potential to inhibit these enzymes by a sulfide-disulfide interchange reaction. A sulfide-disulfide interchange reaction results in the formation of cysteamine and a cysteamine-cysteine mixed disulfide residue at the active site. Recent studies have shown that cystamine decreases the number of protein inclusions in transfected cells expressing the atrophin (DRPLA) protein containing a pathological-length polyglutamine domain [79]. In other studies, cystamine administration to HD-transgenic mice resulted in an increase in life expectancy and amelioration of neurological symptoms [80,81]. Neuronal inclusions were decreased in one of these studies [81]. Although all these scientific reports seem to support the hypothesis of a direct role of transglutaminase activity in the pathogenesis of the polyglutamine diseases, cystamine is also found to act in the HD-transgenic mice by mechanisms other than the inhibition of TGs, such as the inhibition of caspases [82], suggesting that this compound can have an additive effect in the therapy of HD. Currently, cysteamine is already in phase Ⅰ studies in humans with HD [83], but several side effects, such as nausea, motor impairment and dosing schedule have been reported as reasons for non-adherence during phase Ⅱ studies in human patients affected by cystinosis [84,85]. Another critical problem in the use of TG inhibitors in treating neurological diseases relates to the fact that, as previously reported, the human brain contains at least four TGs, including TG1, 2, 3 and TG6, and a strong non-selective inhibitor of TGs might also inhibit plasma Factor XⅢa, causing a bleeding disorder [22,86]. Therefore, from a number of standpoints it would
Figure 5. Chemical structure of cystamine.seem that a selective inhibitor, which discriminates between TGs, would be preferable to an indiscriminate TG inhibitor. In fact, although most of the TG activity in mouse brain, at least as assessed by an assay that measures the incorporation of radioactive putrescine (amine donor) into N, N-dimethyl casein (amine acceptor), seems to be due to TG2 [87], no conclusive data have been obtained by TG2 gene knock-out experiments about the involvement of this TG in the development of the symptoms in HD-transgenic mice [26,88,89]. Moreover, a recent scientific report showed that cystamine reduces aggregate formation in a mouse model of oculopharyngeal muscular dystrophy (OMPD), in which also the TG2 knockdown is capable of suppressing the aggregation and the toxicity of the mutant protein PABPN1 [90], suggesting this compound as a possible therapeutic for OMPD.
Numerous scientific reports have implicated aberrant TG activity in neurodegenerative diseases, but still today we are looking for experimental findings which could definitely confirm the direct involvement of TGs in the pathogenetic mechanisms responsible for these diseases. However, as result of the putative role of specific TG isoforms, such as TG2, in some human diseases, there is a considerable interest in developing inhibitors of these enzymes [91,92]. Of those currently available, cystamine is the most commonly used experimentally to inhibit TG2 activity. In addition to cystamine, several types of TG2 inhibitors have been developed up to now [93]. Interestingly, some of these inhibitors have shown promising results in experimental diabetic models [94]. Therefore, the use of these inhibitors of TGs could be then useful also for other clinical approaches. To minimize the possible side effects, however, more selective inhibitors of the TGs should be required in the future. Progress in this area of research could be achieved, if possible, also through pharmaco-genetic approaches.
This work is supported by the Italian Education Department and the Regione Campania (L.R. n.5 del 28.03.2002, finanziamento 2008) entitled: Identificazione e caratterizzazione di geni della transglutaminasi nel Sistema Nervoso in relazione allo sviluppo di malattie neurodegenerative (Identification and characterization of transglutaminase genes in the Nervous System in relationship to the development of neurodegenerative diseases).
Authors do not have any conflict of interest.
| [1] | Lum AF, Ngwa ESA, Chikoye D, et al. (2014) phytoremediation potential of weeds in heavy metal contaminated soils of the Bassa industrial zone of Douala, Cameroon. Int J Phytoremediation 16: 302–319. |
| [2] | Rajkumar M, Prasad MNV, Freitas H, et al. (2009) Biotechnological applications of serpentine soil bacteria for phytoremediation of trace metals. Crit Rev Biotechnol 29: 120–130. |
| [3] | Dalcorso G, Manara A, Furini A (2013) An overview of heavy metal challenge in plants: From roots to shoots. Metallomics 5: 1117–1132. |
| [4] | Liu H, Probst A, Liao B (2005) Metal contamination of soils and crops affected by the Chenzhou lead/zinc mine spill (Hunan, China). Sci Total Environ 339: 153–166. |
| [5] | Wasi S, Tabrez S, Ahmad M (2013) Toxicological effects of major environmental pollutants: An overview. Environ Monit Assess 185: 2585–2593. |
| [6] | Nagajyoti PC, Lee KD, Sreekanth TVM (2010) Heavy metals, occurrence and toxicity for plants: A review. Environ Chem Lett 8: 199–216. |
| [7] | Lebeau T, Braud A, Jézéquel K (2008) Performance of bioaugmentation-assisted phytoextraction applied to metal contaminated soils: A review. Environ Pollut 153: 497–522. |
| [8] | Agency for Toxic Substances and Disease Registry (2015) Priority List of Hazardous Substances. Atlanta: Agency for Toxic Substances and Disease Registry |
| [9] | Clemens S (2006) Toxic metal accumulation, responses to exposure and mechanisms of tolerance in plants. Biochimie 88: 1707–1719. |
| [10] | Järup L (2003) Hazards of heavy metal contamination. Br Med Bull 68: 167–182. |
| [11] | Tongesayi T, Fedick P, Lechner L, et al. (2013) Daily bioaccessible levels of selected essential but toxic heavy metals from the consumption of non-dietary food sources. Food Chem Toxicol 62: 142–147. |
| [12] | Khan S, Shahnaz M, Jehan N, et al. (2013) Drinking water quality and human health risk in Charsadda district, Pakistan. J Clean Prod 60: 93–101. |
| [13] | Martin R, Dowling K (2013) Trace metal contamination of mineral spring water in an historical mining area in regional Victoria, Australia. J Asian Earth Sc 77: 262–267. |
| [14] | Salt D E, Smith RD, Raskin I (1998) Phytoremediation. Annu Rev Plant Physiol Plant Mol Biol 49: 643–668. |
| [15] | Rascio N, Navari-Izzo F (2011) Heavy metal hyperaccumulating plants: How and why do they do it? And what makes them so interesting? Plant Sci 180: 169–181. |
| [16] | Anderson CWN, Brooks RR, Chiarucci A, et al. (1999) Phytomining for nickel, thallium and gold. J Geochem Explor 67: 407–415. |
| [17] | Robinson BH, Brooks RR, Gregg PEH, et al. (1999) The nickel phytoextraction potential of some ultramafic soils as determined by sequential extraction. Geoderma 87: 293–304. |
| [18] | Sheoran V, Sheoran AS, Poonia P (2011) Role of hyperaccumulators in phytoextraction of metals from contaminated mining sites: A review. Crit Rev Environ Sci Technol 41: 168–214. |
| [19] | Alford ÉR, Pilon-Smits EAH, Paschke MW (2010) Metallophytes-a view from the rhizosphere. Plant Soil 337: 33–50. |
| [20] | Finneran KT, Anderson RT, Nevin KP, et al. (2002) Potential for Bioremediation of Uranium-Contaminated Aquifers with Microbial U(VI) Reduction. Soil Sediment Contam 11: 339–357. |
| [21] | Gadd GM (2009) Biosorption: Critical review of scientific rationale, environmental importance and significance for pollution treatment. J Chem Technol Biotechnol 84: 13–28. |
| [22] | Aracic S, Manna S, Petrovski S, et al. (2015) Innovative biological approaches for monitoring and improving water quality. Front Microbiol 6: 826. |
| [23] | Das N, Vimala R, Karthika P (2008) Biosorption of heavy metals - An overview. Indian J Biotechnol 7: 159–169. |
| [24] | Vijayaraghavan K, Yun YS (2008) Bacterial biosorbents and biosorption. Biotechnol Adv 26: 266–291. |
| [25] | Ahluwalia SS, Goyal D (2007) Microbial and plant derived biomass for removal of heavy metals from wastewater. Bioresour Technol 98: 2243–2257. |
| [26] | Aryal M, Liakopoulou-Kyriakides M (2015) Bioremoval of heavy metals by bacterial biomass. Environ Monit Assess 187: 4173. |
| [27] | Gadd GM (2004) Microbial influence on metal mobility and application for bioremediation. Geoderma 122: 109–119. |
| [28] | Lovley DR, Holmes DE, Nevin KP (2004) Dissimilatory Fe(III) and Mn(IV) reduction. Adv Microb Physiol 49: 219–286. |
| [29] | Bolan N, Kunhikrishnan A, Gibbs J (2013) Rhizoreduction of arsenate and chromate in Australian native grass, shrub and tree vegetation. Plant Soil 367: 615–625. |
| [30] | Kashefi K, Lovley DR (2000) Reduction of Fe(III), Mn(IV), and toxic metals at 100°C by Pyrobaculum islandicum. Appl Environ Microbiol 66: 1050–1056. |
| [31] | Williams KH, N'Guessan A, Druhan J, et al. (2010) Electrodic voltages accompanying stimulated bioremediation of a uranium-contaminated aquifer. J Geophys Res (G Biogeosci) 115. |
| [32] | Zhuang K, Ma E, Lovley DR, et al. (2012) The design of long-term effective uranium bioremediation strategy using a community metabolic model. Biotechnol Bioeng 109: 2475–2483. |
| [33] | Anderson RT, Vrionis HA, Ortiz-Bernad I, et al. (2003) Stimulating the In Situ Activity of Geobacter Species to Remove Uranium from the Groundwater of a Uranium-Contaminated Aquifer. Appl Environ Microbiol 69: 5884–5891. |
| [34] | Gadd GM (2010) Metals, minerals and microbes: Geomicrobiology and bioremediation. Microbiology 156: 609–643. |
| [35] | N'Guessan AL, Vrionis HA, Resch CT, et al. (2008) Sustained removal of uranium from contaminated groundwater following stimulation of dissimilatory metal reduction. Environ Sci Technol 42: 2999–3004. |
| [36] | Finneran KT, Housewright ME, Lovley DR (2002) Multiple influences of nitrate on uranium solubility during bioremediation of uranium-contaminated subsurface sediments. Environ Microbiol 4: 510–516. |
| [37] | Sheoran V, Sheoran AS, Poonia P (2016) Factors affecting phytoextraction: A review. Pedosphere 26: 148–166. |
| [38] | Ernst WHO (1996) Bioavailability of heavy metals and decontamination of soils by plants. Appl Geochem 11: 163–167. |
| [39] | Blaylock MJ, Salt DE, Dushenkov S, et al. (1997) Enhanced accumulation of Pb in Indian mustard by soil-applied chelating agents. Environ Sci Technol 31: 860–865. |
| [40] | Cooper EM, Sims JT, Cunningham SD, et al. (1999) Chelate-assisted phytoextraction of lead from contaminated soils. J Environ Qual 28: 1709–1719. |
| [41] | Tandy S, Bossart K, Mueller R, et al. (2004) Extraction of heavy metals from soils using biodegradable chelating agents. Environ Sci Technol 38: 937–944. |
| [42] | Mulligan CN (2005) Environmental applications for biosurfactants. Environ Pollut 133: 183–198. |
| [43] | Freitas EV, Nascimento C (2016) Degradability of natural and synthetic chelating agents applied to a lead-contaminated soil. J Soils Sed 1–7. |
| [44] | Liu D, Islam E, Li T, et al. (2008) Comparison of synthetic chelators and low molecular weight organic acids in enhancing phytoextraction of heavy metals by two ecotypes of Sedum alfredii Hance. J Hazard Mater 153: 114–122. |
| [45] | Karimzadeh L, Heilmeier H, Merkel BJ (2012) Effect of microbial siderophore DFO-B on Cd accumulation by Thlaspi caerulescens hyperaccumulator in the presence of zeolite. Chemosphere 88: 683–687. |
| [46] | Gunawardana B, Singhal N, Johnson A (2011) Effects of amendments on copper, cadmium, and lead phytoextraction by Lolium perenne from multiple-metal contaminated solution. Int J Phytoremediation 13: 215–232. |
| [47] | Angle JS, Linacre NA (2005) Metal phytoextraction - A survey of potential risks. Int J Phytoremediation 7: 241–254. |
| [48] | Bolan N, Kunhikrishnan A, Thangarajan R, et al. (2014) Remediation of heavy metal(loid)s contaminated soils - To mobilize or to immobilize? J Hazard Mater 266: 141–166. |
| [49] | Robinson BH, Chiarucci A, Brooks RR, et al. (1997) The nickel hyperaccumulator plant Alyssum bertolonii as a potential agent for phytoremediation and phytomining of nickel. J Geochem Explor 59: 75–86. |
| [50] | Dell'Amico E, Cavalca L, Andreoni V (2008) Improvement of Brassica napus growth under cadmium stress by cadmium-resistant rhizobacteria. Soil Biol Biochem 40: 74–84. |
| [51] | Hernlem BJ, Vane LM, Sayles GD (1996) Stability constants for complexes of the siderophore desferrioxamine b with selected heavy metal cations. Inorg Chim Acta 244: 179–184. |
| [52] | Neilands JB (1995) Siderophores: Structure and function of microbial iron transport compounds. J Biol Chem 270: 26723–26726. |
| [53] | Kim JO, Lee YW, Chung J (2013) The role of organic acids in the mobilization of heavy metals from soil. KSCE J Civ Eng 17: 1596–1602. |
| [54] | Li WC, Ye ZH, Wong MH (2010) Metal mobilization and production of short-chain organic acids by rhizosphere bacteria associated with a Cd/Zn hyperaccumulating plant, Sedum alfredii. Plant Soil 326: 453–467. |
| [55] | Abhilash PC, Powell JR, Singh HB, et al. (2012) Plant-microbe interactions: Novel applications for exploitation in multipurpose remediation technologies. Trends Biotechnol 30: 416–420. |
| [56] | Sessitsch A, Kuffner M, Kidd P, et al. (2013) The role of plant-associated bacteria in the mobilization and phytoextraction of trace elements in contaminated soils. Soil Biol Biochem 60: 182–194. |
| [57] | Glick BR (2010) Using soil bacteria to facilitate phytoremediation. Biotechnol Adv 28: 367–374. |
| [58] | Lugtenberg B, Kamilova F (2009) Plant-growth-promoting rhizobacteria. Annu Rev Microbiol 63: 541–556. |
| [59] | Rajkumar M, Ae N, Prasad MNV, et al. (2010) Potential of siderophore-producing bacteria for improving heavy metal phytoextraction. Trends Biotechnol 28: 142–149. |
| [60] | Hayat R, Ali S, Amara U, et al. (2010) Soil beneficial bacteria and their role in plant growth promotion: A review. Ann Microbiol 60: 579–598. |
| [61] | Badri DV, Weir TL, van der Lelie D, et al. (2009) Rhizosphere chemical dialogues: plant-microbe interactions. Curr Opin Biotechnol 20: 642–650. |
| [62] | Onofre-Lemus J, Hernández-Lucas I, Girard L, et al. (2009) ACC (1-aminocyclopropane-1-carboxylate) deaminase activity, a widespread trait in Burkholderia species, and its growth-promoting effect on tomato plants. Appl Environ Microbiol 75: 6581–6590. |
| [63] | De Souza MP, Huang CPA, Chee N, et al. (1999) Rhizosphere bacteria enhance the accumulation of selenium and mercury in wetland plants. Planta 209: 259–263. |
| [64] | Malekzadeh E, Alikhani HA, Savaghebi-Firoozabadi GR, et al. (2012) Bioremediation of cadmium-contaminated soil through cultivation of maize inoculated with plant growth-promoting rhizobacteria. Bioremediation J 16: 204–211. |
| [65] | Abou-Shanab RA, Angle JS, Delorme TA, et al. (2003) Rhizobacterial effects on nickel extraction from soil and uptake by Alyssum murale. New Phytol 158: 219–224. |
| [66] | Abou-Shanab RI, Delorme TA, Angle JS, et al. (2003) Phenotypic Characterization of Microbes in the Rhizosphere of Alyssum murale. Int J Phytoremediation 5: 367–379. |
| [67] | Amprayn KO, Rose MT, Kecskés M, et al. (2012) Plant growth promoting characteristics of soil yeast (Candida tropicalis HY) and its effectiveness for promoting rice growth. Appl Soil Ecol 61: 295–299. |
| [68] | Whiting SN, De Souza MP, Terry N (2001) Rhizosphere bacteria mobilize Zn for hyperaccumulation by Thlaspi caerulescens. Environ Sci Technol 35: 3144–3150. |
| [69] | Lodewyckx C, Mergeay M, Vangronsveld J, et al. (2002) Isolation, characterization, and identification of bacteria associated with the zinc hyperaccumulator Thlaspi caerulescens subsp. calaminaria. Int J Phytoremediation 4: 101–115. |
| [70] | Park JH, Bolan N, Megharaj M, et al. (2011) Isolation of phosphate solubilizing bacteria and their potential for lead immobilization in soil. J Hazard Mater 185: 829–836. |
| [71] | Zhang YF, He LY, Chen ZJ, et al. (2011) Characterization of ACC deaminase-producing endophytic bacteria isolated from copper-tolerant plants and their potential in promoting the growth and copper accumulation of Brassica napus. Chemosphere 83: 57–62. |
| [72] | Zhang S, Reddy MS, Kloepper JW (2004) Tobacco growth enhancement and blue mold disease protection by rhizobacteria: relationship between plant growth promotion and systemic disease protection by PGPR strain 90–166. Plant Soil 262: 277–288. |
| [73] | Shahzad SM, Arif MS, Riaz M, et al. (2013) PGPR with varied ACC-deaminase activity induced different growth and yield response in maize (Zea mays L.) under fertilized conditions. Eur J Soil Biol 57: 27–34. |
| [74] | Wakelin SA, Warren RA, Ryder MH (2004) Effect of soil properties on growth promotion of wheat by Penicillium radicum. Aust J Soil Res 42: 897–904. |
| [75] | Kamnev AA, Tugarova AV, Antonyuk LP, et al. (2005) Effects of heavy metals on plant-associated rhizobacteria: Comparison of endophytic and non-endophytic strains of Azospirillum brasilense. J Trace Elem Med Bio 19: 91–95. |
| [76] | Latour X, Philippot L, Corberand T, et al. (1999) The establishment of an introduced community of fluorescent pseudomonads in the soil and in the rhizosphere is affected by the soil type. FEMS Microbiol Ecol 30: 163–170. |
| [77] | Melent'ev AI, Kuz'mina LY, Galimzyanova NF (2000) Effect of temperature and soil moisture content on the colonization of the wheat rhizosphere by antiphytopathogenic bacilli. Microbiology 69: 351–356. |
| [78] | Gerhardt KE, Huang XD, Glick BR, et al. (2009) Phytoremediation and rhizoremediation of organic soil contaminants: Potential and challenges. Plant Sci 176: 20–30. |
| [79] | Kang Y, Shen M, Wang H, et al. (2013) A possible mechanism of action of plant growth-promoting rhizobacteria (PGPR) strain Bacillus pumilus WP8 via regulation of soil bacterial community structure. J Gen Appl Microbiol 59: 267–277. |
| [80] | Abou-Shanab RAI, Angle JS, Chaney RL (2006) Bacterial inoculants affecting nickel uptake by Alyssum murale from low, moderate and high Ni soils. Soil Biol Biochem 38: 2882–2889. |
| [81] | Abou-Shanab RA, Ghanem K, Ghanem N, et al. (2008) The role of bacteria on heavy-metal extraction and uptake by plants growing on multi-metal-contaminated soils. World J Microbiol Biotechnol 24: 253–262. |
| [82] | Belimov AA, Kunakova AM, Safronova VI, et al. (2004) Employment of rhizobacteria for the inoculation of barley plants cultivated in soil contaminated with lead and cadmium. Microbiology 73: 99–106. |
| [83] | Gao Y, Miao C, Mao L, et al. (2010) Improvement of phytoextraction and antioxidative defense in Solanum nigrum L. under cadmium stress by application of cadmium-resistant strain and citric acid. J Hazard Mater 181: 771–777. |
| [84] | He LY, Chen ZJ, Ren GD, et al. (2009) Increased cadmium and lead uptake of a cadmium hyperaccumulator tomato by cadmium-resistant bacteria. Ecotoxicol Environ Saf 72: 1343–1348. |
| [85] | Lampis S, Santi C, Ciurli A, et al. (2015) Promotion of arsenic phytoextraction efficiency in the fern Pteris vittata by the inoculation of As-resistant bacteria: A soil bioremediation perspective. Front Plant Sci 6: 80. |
| [86] | Li WC, Ye ZH, Wong MH (2007) Effects of bacteria on enhanced metal uptake of the Cd/Zn-hyperaccumulating plant, Sedum alfredii. J Exp Bot 58: 4173–4182. |
| [87] | Liu W, Wang Q, Wang B, et al. (2015) Plant growth-promoting rhizobacteria enhance the growth and Cd uptake of Sedum plumbizincicola in a Cd-contaminated soil. J Soils Sed 1–9. |
| [88] | Ma Y, Rajkumar M, Freitas H (2009) Improvement of plant growth and nickel uptake by nickel resistant-plant-growth promoting bacteria. J Hazard Mater 166: 1154–1161. |
| [89] | Ma Y, Rajkumar M, Freitas H (2009) Inoculation of plant growth promoting bacterium Achromobacter xylosoxidans strain Ax10 for the improvement of copper phytoextraction by Brassica juncea. J Environ Manage 90: 831–837. |
| [90] | Ma Y, Rajkumar M, Luo Y, et al. (2011) Inoculation of endophytic bacteria on host and non-host plants-Effects on plant growth and Ni uptake. J Hazard Mater 195: 230–237. |
| [91] | Ma Y, Rajkumar M, Luo Y, et al. (2013) Phytoextraction of heavy metal polluted soils using Sedum plumbizincicola inoculated with metal mobilizing Phyllobacterium myrsinacearum RC6b. Chemosphere 93: 1386–1392. |
| [92] | Płociniczak T, Sinkkonen A, Romantschuk M, et al. (2013) Characterization of Enterobacter intermedius MH8b and its use for the enhancement of heavy metals uptake by Sinapis alba L. Appl Soil Ecol 63: 1–7. |
| [93] | Prapagdee B, Chanprasert M, Mongkolsuk S (2013) Bioaugmentation with cadmium-resistant plant growth-promoting rhizobacteria to assist cadmium phytoextraction by Helianthus annuus. Chemosphere 92: 659–666. |
| [94] | Rajkumar M, Freitas H (2008) Influence of metal resistant-plant growth-promoting bacteria on the growth of Ricinus communis in soil contaminated with heavy metals. Chemosphere 71: 834–842. |
| [95] | Rajkumar M, Ma Y, Freitas H (2013) Improvement of Ni phytostabilization by inoculation of Ni resistant Bacillus megaterium SR28C. J Environ Manage 128: 973–980. |
| [96] | Rani A, Souche Y, Goel R (2013) Comparative in situ remediation potential of Pseudomonas putida 710A and Commamonas aquatica 710B using plant (Vigna radiata (L.) wilczek) assay. Ann Microbiol 63: 923–928. |
| [97] | Sheng X, He L, Wang Q, et al. (2008) Effects of inoculation of biosurfactant-producing Bacillus sp. J119 on plant growth and cadmium uptake in a cadmium-amended soil. J Hazard Mater 155: 17–22. |
| [98] | Yang Q, Tu S, Wang G, et al. (2012) Effectiveness of applying arsenate reducing bacteria to enhance arsenic removal from polluted soils by Pteris vittata L. Int J Phytoremediation 14: 89–99. |
| [99] | Zaidi S, Usmani S, Singh BR, et al. (2006) Significance of Bacillus subtilis strain SJ-101 as a bioinoculant for concurrent plant growth promotion and nickel accumulation in Brassica juncea. Chemosphere 64: 991–997. |
| [100] | Zhang X, Lin L, Chen M, et al. (2012) A nonpathogenic Fusarium oxysporum strain enhances phytoextraction of heavy metals by the hyperaccumulator Sedum alfredii Hance. J Hazard Mater 229–230: 361–370. |
| [101] | Muehe EM, Weigold P, Adaktylou IJ, et al. (2015) Rhizosphere microbial community composition affects cadmium and zinc uptake by the metal-hyperaccumulating plant Arabidopsis halleri. Appl Environ Microbiol 81: 2173–2181. |
| [102] | Muehe EM, Obst M, Hitchcock A, et al. (2013) Fate of Cd during microbial Fe(III) mineral reduction by a novel and Cd-tolerant geobacter species. Environ Sci Technol 47: 14099–14109. |
| [103] | Rodríguez H, Fraga R (1999) Phosphate solubilizing bacteria and their role in plant growth promotion. Biotechnol Adv 17: 319–339. |
| [104] | Ma Y, Prasad MNV, Rajkumar M, et al. (2011) Plant growth promoting rhizobacteria and endophytes accelerate phytoremediation of metalliferous soils. Biotechnol Adv 29: 248–258. |
| [105] | Spaepen S, Vanderleyden J, Remans R (2007) Indole-3-acetic acid in microbial and microorganism-plant signaling. FEMS Microbiol Rev 31: 425–448. |
| [106] | Ryu RJ, Patten CL (2008) Aromatic amino acid-dependent expression of indole-3-pyruvate decarboxylase is regulated by tyrr in Enterobacter cloacae UW5. J Bacteriol 190: 7200–7208. |
| [107] | Sharma SB, Sayyed RZ, Trivedi MH, et al. (2013) Phosphate solubilizing microbes: Sustainable approach for managing phosphorus deficiency in agricultural soils. SpringerPlus 2: |
| [108] | Mattey M (1992) The production of organic acids. Crit Rev Biotechnol 12: 87–132. |
| [109] | Thijs S, Sillen W, Rineau F, et al. (2016) Towards an Enhanced Understanding of Plant–Microbiome Interactions to Improve Phytoremediation: Engineering the Metaorganism. Front Microbiol 7: 341. |
| [110] | Siciliano SD, Fortin N, Mihoc A, et al. (2001) Selection of Specific Endophytic Bacterial Genotypes by Plants in Response to Soil Contamination. Appl Environ Microbiol 67: 2469–2475. |
| [111] | Hamamura N, Olson SH, Ward DM, et al. (2006) Microbial population dynamics associated with crude-oil biodegradation in diverse soils. Appl Environ Microbiol 72: 6316–6324. |
| [112] | Edgar RC (2010) Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26: 2460–2461. |
| [113] | Caporaso JG, Kuczynski J, Stombaugh J, et al. (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7: 335–336. |
| [114] | Cole JR, Wang Q, Fish JA, et al. (2014) Ribosomal Database Project: Data and tools for high throughput rRNA analysis. Nucleic Acids Res 42: D633–D642. |
| [115] | Howe AC, Jansson JK, Malfatti SA, et al. (2014) Tackling soil diversity with the assembly of large, complex metagenomes. Proc Natl Acad Sci USA 111: 4904–4909. |
| [116] | Langille MGI, Zaneveld J, Caporaso JG, et al. (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31: 814–821. |
| [117] | Aßhauer KP, Wemheuer B, Daniel R, et al. (2015) Tax4Fun: Predicting functional profiles from metagenomic 16S rRNA data. Bioinformatics 31: 2882–2884. |
| [118] | Tu Q, Yu H, He Z, et al. (2014) GeoChip 4: A functional gene-array-based high-throughput environmental technology for microbial community analysis. Mol Ecol Resour 14: 914–928. |
| [119] | Andrews SC, Robinson AK, Rodríguez-Quiñones F (2003) Bacterial iron homeostasis. FEMS Microbiol Rev 27: 215–237. |
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Figures(1) / Tables(2)
Jennifer L. Wood, Wuxing Liu, Caixian Tang, Ashley E. Franks. Microorganisms in heavy metal bioremediation: strategies for applying microbial-community engineering to remediate soils[J]. AIMS Bioengineering, 2016, 3(2): 211-229. doi: 10.3934/bioeng.2016.2.211
| TG | Physiological role | Gene map location | Reference |
| Factor XⅢa | Blood clotting | 6p24-25 | [14] |
| TG 1 (Keratinocyte TG, kTG) | Skin differentiation | 14q11.2 | [15] |
| TG 2 (Tissue TG, tTG, cTG) | Apoptosis, cell adhesion, signal transduction | 20q11-12 | [16] |
| TG 3(Epidermal TG, eTG) | Hair follicle differentiation | 20p11.2 | [17] |
| TG 4 (Prostate TG, pTG) | Suppression of sperm immunogenicity | 3q21-2 | [18] |
| TG 5 (TG X) | Epidermal differentiation | 15q15.2 | [19] |
| TG 6 (TG Y) | Central Nervous System development | 20p13 | [19] |
| TG 7 (TG Z) | Unknown function | 15q15.2 | [19] |
DownLoad: CSV| Disease | Sites of neuropathology | CAG triplet number | Gene product (Intracellular localization of protein deposits) | Reference | |
| Normal | Disease | ||||
| Corea Major or Huntington's Disease (HD) | Striatum (medium spiny neurons) and cortex in late stage | 6–35 | 36–121 | Huntingtin(n, c) | [50] |
| Spinocerebellar Ataxia Type 1 (SCA1) | Cerebellar cortex (Purkinje cells), dentate nucleus and brain stem | 6–39 | 40–81 | Ataxin-1(n, c) | [51] |
| Spinocerebellar Ataxia Type 2 (SCA2) | Cerebellum, pontine nuclei, substantia nigra | 15–29 | 35–64 | Ataxin-2 (c) | [52] |
| Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph disease (MJD) | Substantia nigra, globus pallidus, pontine nucleus, cerebellar cortex | 13–42 | 61–84 | Ataxin -3 (c) | [53] |
| Spinocerebellar Ataxia Type 6 (SCA6) | Cerebellar and mild brainstem atrophy | 4–18 | 21–30 | Calcium channel Subunit (α 1A)(m) | [54] |
| Spinocerebellar Ataxia Type 7 (SCA7) | Photoreceptor and bipolar cells, cerebellar cortex, brainstem | 7–17 | 37–130 | Ataxin-7 (n) | [55] |
| Spinocerebellar Ataxia Type 12 (SCA12) | Cortical, cerebellar atrophy | 7–32 | 41–78 | Brain specific regulatory subunit of protein phosphatase PP2A (?) | [56] |
| Spinocerebellar Ataxia Type 17 (SCA17) | Gliosis and neuronal loss in the Purkinje cell layer | 29–42 | 46–63 | TATA-binding protein (TBP) (n) | [57] |
| Spinobulbar Muscular Atrophy (SBMA) or Kennedy Disease | Motor neurons (anterior horn cells, bulbar neurons) and dorsal root ganglia | 11–34 | 40–62 | Androgen receptor (n, c) | [58] |
| Dentatorubral-pallidoluysian Atrophy (DRPLA) | Globus pallidus, dentato-rubral and subthalamic nucleus | 7–35 | 49–88 | Atrophin (n, c) | [59] |
| Cellular localization: c, cytosol; m, membrane; n, nucleus; ?, unknown localization. | |||||
DownLoad: CSV| Associations/cause | Effects |
| Gluten intolerance | Gluten ataxia |
| Neuroinflammation | Alzheimer's disease and other neurodegenerative diseases |
DownLoad: CSV| TG | Physiological role | Gene map location | Reference |
| Factor XⅢa | Blood clotting | 6p24-25 | [14] |
| TG 1 (Keratinocyte TG, kTG) | Skin differentiation | 14q11.2 | [15] |
| TG 2 (Tissue TG, tTG, cTG) | Apoptosis, cell adhesion, signal transduction | 20q11-12 | [16] |
| TG 3(Epidermal TG, eTG) | Hair follicle differentiation | 20p11.2 | [17] |
| TG 4 (Prostate TG, pTG) | Suppression of sperm immunogenicity | 3q21-2 | [18] |
| TG 5 (TG X) | Epidermal differentiation | 15q15.2 | [19] |
| TG 6 (TG Y) | Central Nervous System development | 20p13 | [19] |
| TG 7 (TG Z) | Unknown function | 15q15.2 | [19] |
| Disease | Sites of neuropathology | CAG triplet number | Gene product (Intracellular localization of protein deposits) | Reference | |
| Normal | Disease | ||||
| Corea Major or Huntington's Disease (HD) | Striatum (medium spiny neurons) and cortex in late stage | 6–35 | 36–121 | Huntingtin(n, c) | [50] |
| Spinocerebellar Ataxia Type 1 (SCA1) | Cerebellar cortex (Purkinje cells), dentate nucleus and brain stem | 6–39 | 40–81 | Ataxin-1(n, c) | [51] |
| Spinocerebellar Ataxia Type 2 (SCA2) | Cerebellum, pontine nuclei, substantia nigra | 15–29 | 35–64 | Ataxin-2 (c) | [52] |
| Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph disease (MJD) | Substantia nigra, globus pallidus, pontine nucleus, cerebellar cortex | 13–42 | 61–84 | Ataxin -3 (c) | [53] |
| Spinocerebellar Ataxia Type 6 (SCA6) | Cerebellar and mild brainstem atrophy | 4–18 | 21–30 | Calcium channel Subunit (α 1A)(m) | [54] |
| Spinocerebellar Ataxia Type 7 (SCA7) | Photoreceptor and bipolar cells, cerebellar cortex, brainstem | 7–17 | 37–130 | Ataxin-7 (n) | [55] |
| Spinocerebellar Ataxia Type 12 (SCA12) | Cortical, cerebellar atrophy | 7–32 | 41–78 | Brain specific regulatory subunit of protein phosphatase PP2A (?) | [56] |
| Spinocerebellar Ataxia Type 17 (SCA17) | Gliosis and neuronal loss in the Purkinje cell layer | 29–42 | 46–63 | TATA-binding protein (TBP) (n) | [57] |
| Spinobulbar Muscular Atrophy (SBMA) or Kennedy Disease | Motor neurons (anterior horn cells, bulbar neurons) and dorsal root ganglia | 11–34 | 40–62 | Androgen receptor (n, c) | [58] |
| Dentatorubral-pallidoluysian Atrophy (DRPLA) | Globus pallidus, dentato-rubral and subthalamic nucleus | 7–35 | 49–88 | Atrophin (n, c) | [59] |
| Cellular localization: c, cytosol; m, membrane; n, nucleus; ?, unknown localization. | |||||
| Associations/cause | Effects |
| Gluten intolerance | Gluten ataxia |
| Neuroinflammation | Alzheimer's disease and other neurodegenerative diseases |
