Haut PDF Sténose postopératoire de la voie biliaire principale

Role of Apoptosis in the final outcome of DNA damage

Role of Apoptosis in the final outcome of DNA damage

Damage to DNA is intrinsic to life, as the cell continuosly suffers from numerous exogenous agents, including radiation and chemicals, and from endogenous sources, such as free radicals generated during essential metabolic processes. The broad spectrum of DNA lesions induced by these agents includes damage to nucleotide bases, DNA protein cross- links and DNA single- and double-strand breaks (DBSs). Because of their high cytotoxicity (unrepaired or misrepaired DNA DSBs can kill a cell) and their ability to induce chromosomal aberrations (that may ultimately lead to carcinogenesis) cell survival and mantenaince of genome integrity are critically dependent on efficient repair of DNA DSBs. When the burden of genomic insult is too large to be effectively repaired, cells are able to initiate apoptosis (programmed cell death). On the basis of these considerations, the aim of this thesis has been to investigate the role of apoptosis in the final outcome of DNA damage.
More...

En savoir plus

Role of Bim and p53 in transcription- independent apoptosis induced by Combretastatin A-4 in human non-small lung cancer cells

Role of Bim and p53 in transcription- independent apoptosis induced by Combretastatin A-4 in human non-small lung cancer cells

The Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized by chromo- somal instability and hypersensitivity to ionizing radiations (IR). The N-terminus of nibrin (NBN) contains a tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one of the major mediators of phosphorylation-dependent protein-pro- tein interactions in processes related to cell cycle checkpoint and DNA repair functions. Patients with NBS compound heterozygous for the 657del5 hypomorphic mutation and for the Arg215Trp missense mutation (corresponding to the 643C[T gene mutation) display a clinical phenotype more severe than that of patients homozygous for the 657del5 mutation. Here, we show that both the 657del5 and Arg215Trp mutations, occurring within the tan- dem BRCT domains of NBN, although not altering the assembly of the MRE11/RAD50/NBN (MRN) complex, affect the MRE11 IR-induced nuclear foci (IRIF) formation and the DNA double- strand break (DSB) signaling via the phosphorylation of both ataxia-telangiectasia-mutated (ATM) kinase and ATM down- stream targets (e.g., SMC1 and p53). Remarkably, data obtained indicate that the cleavage of the BRCT tandem domains of NBN by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. Indeed, the 70-kDa NBN frag- ment, arising from the 657del5 mutation, maintains the capability to interact with MRE11 and c-H2AX and to form IRIF. Alto- gether, the role of the tandem BRCT domains of NBN in the localization of the MRN complex at the DNA DSB and in the
More...

En savoir plus

PLK1 and NOTCH1 at the interface of DNA Damage Checkpoint and tolerance to genotoxic stress

PLK1 and NOTCH1 at the interface of DNA Damage Checkpoint and tolerance to genotoxic stress

Wang et al, 2011). Additionally, inhibition of NOTCH or HEY1 significantly decreased cell growth of primary tumor-derived cells, indicating their potential involvement in HNSCC development (Agrawal N et al, 2011; Wang N.J. et al, 2011; Sun W et al, 2014). We have recently reported that the clinical manifestation of Hailey–Hailey disease, a hereditary skin disease, is associated with NOTCH1 downmodulation as a consequence of increased oxidative stress (Biolcati G et al, 2014; Cialfi et al, 2010; Manca S et al, 2011). Much recent interest has focused on the role of ROS in normal and malignant cell biology (Jaramillo MC, Zhang DD, 2013; Naviaux RK, 2012). Organisms living in aerobic conditions are continuously subjected to ROS, and the response to ROS influences central cellular processes such as proliferation, apoptosis, and senescence, and elevated levels of ROS are associated with various human diseases including various cancers (Gorrini C et al, 2013). Of note, NOTCH1 contributes to leukemia-initiating cells’ maintenance through
More...

En savoir plus

The role of mitotic spindle alterations in the induction of apoptosis

The role of mitotic spindle alterations in the induction of apoptosis

Mitotic catastrophe has been first described in Schizosaccharomyces pombe as a temperature-sensitive lethal phenotype, linked to gross abnormalities of chromosome segregation, that was observed in some mutant strains (Ayscough et al, 1992;Castedo et al, 2004). Some authors view mitotic catastrophe of mammalian cells as the failure to undergo complete mitosis which usually ends in the formation of large cells with multiple micronuclei and decondensed chromatin (Swanson et al, 1995;Ianzini and Mackey, 1997;Roninson et al, 2001;Castedo et al, 2004). However, reports describing mitotic catastrophe frequently show cells with some phenotypic characteristic of apoptosis (Castedo et al, 2004). Mitotic catastrophe would be a type of cell death occurring during mitosis, as a result of DNA damage or deranged spindle formation coupled to the debilitation of different checkpoint mechanism that would normally arrest progression into mitosis and hence suppress catastrophic events until repair has been achieved. (Castedo et al, 2004;Tait and Green, 2008). Damage leading to mitotic catastrophe can be induced, in particular, by microtubules damaging agents. So, mitotic catastrophe can be considered as a type of cell death occurring during mitosis or resulting from mitotic failure.
More...

En savoir plus

Role of the MUTYH protein in the response to oxidative damage to DNA

Role of the MUTYH protein in the response to oxidative damage to DNA

transcriptional activation and apoptosis by phosphorylating critical targets (Guan et al., 2007). Chk1 and Chk2 are targets of regulation by two signal transducers proteins, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related protein) kinases, respectively. ATM and ATR are PIKK (phosphoinositide three- kinase-related kinases) that share a number of phosphorylation substrates, even if they respond to different type of DNA damage. ATR plays a central role in the response to certain types of genotoxic agents, including hydroxyurea and UV and seems to have a central function in the S and G2 checkpoints. On the contrary, ATM has a major function for management of the G1 checkpoint and in contrast to ATR, provides a rapid protective response to an extremely lethal form of DNA damage, the DSBs. (Abraham, 2001). The main relevance for cell and organism life of this “network of genome surveillance” is reflected in the evidence that a major mechanism whereby tumor cells acquire genetic instability is through the acquisition of mutations that modify checkpoints. This feature renders them more dependent on the remaining intact pathways to promote repair and arrest the cell cycle, representing an important approach for the development of therapeutic strategies in the personalized cancer treatment (Medema and Macurek, 2011).
More...

En savoir plus

The DNA repair proteins CSA and CSB play a key role in the regulation of cellular division and differentiation

The DNA repair proteins CSA and CSB play a key role in the regulation of cellular division and differentiation

CSA and CSB are proving more and more to be key proteins at the crossroad in the management and response to DNA damage. Firstly, they have a fundamental role in DNA repair; both CSA and CSB, in fact, are involved in a subpathway of Nucleotide Excision Repair known as Transcription-Coupled Repair (TCR), which removes transcription blocking DNA lesions, located on the transcribed strand of active genes; inefficiency or lack of TCR triggers an apoptotic signal, which depends on the functional status of CSB. This protein, in fact, also plays a critical role in cell robustness negatively modulating p53 activity after cellular stress, including DNA damage and hypoxia and counteracting p53-independent apoptosis. Also, CSB mediates the transcriptional programs following exposure to cellular stressors such as UV, oxidative damage, inflammation and hypoxia. Evidently, it seems to be that the repair is tuned with the cell-cycle progression and / or induction of death. During my PhD activity I have studied an unexpected new role for CSA and CSB proteins. They not only participate in DNA repair and / or adjust the trigger of apoptosis but also regulate cell fate decision by taking part in the last step of mitosis, cytokinesis, or cell differentiation. So, my aim was to better understand the key role of these proteins, that seem to be the judges of cell life or death in response to genotoxic agents and of cell differentiation. These studies have given rise to the drafting of two scientific papers below reported.
More...

En savoir plus

Studying the role of chromatin remodelers during cell division

Studying the role of chromatin remodelers during cell division

Two alternative hypotheses could be considered to explain how the knock-down chromatin remodelling proteins affects cell divisions: i) the recruitment of chromatin remodelling proteins to the mitotic apparatus only reflects a passive accumulation of protein to be disposed of, and cell division defects after their depletion/loss is merely the consequence of general chromatin perturbations, that in turn result in deregulation of genes involved in cell division; ii) chromatin remodelling proteins are functional components of centrosome, spindle and MB and their depletion/loss results in disfunctions of mitotic apparatus, thus giving rise to mitosis and cytokinesis failure. This hypothesis implies specific roles of remodelers in the organization/function of mitotic apparatus and regulation of cell division;
More...

En savoir plus

<<The>> role of intrinsic and extrinsic signals in the regulation of brest cancer stem cell activity

<<The>> role of intrinsic and extrinsic signals in the regulation of brest cancer stem cell activity

In the last years, multiple reports have shown that a subpopulation of cancer cells displaying stem cell properties and named as cancer stem cells (CSCs) plays a crucial role in sustaining tumor growth and progression. These cells are characterized by their ability to undergo self-renewal, a process that drives tumorigenesis, and to differentiate into the non-self-renewing cells forming the tumor bulk [2, 3]. From a clinical point of view, the main concern with CSCs is related to their resistance to conventional treatments (e.g. endocrine-, chemo- and radio-therapy), a feature that might be the underlying cause of tumor recurrence and metastases [4–6]. Similar to embryonic and somatic stem cells, the self-renewal and differentiation of CSCs are regulated by both intrinsic and extrinsic pathways whose dysregulation may be a key event initiating carcinogenesis. Among the intrinsic pathways, an important role is displayed by developmental signals such as Wnt, Hedgehog, Janus kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) and Notch pathways that are frequently deranged in cancers [7]. Extrinsic signals that regulate stem cell behaviour originate in the surrounding stem cell microenvironment, termed as cancer stem niche. This niche contains a number of cell types, including mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), adipocytes, endothelial and immune cells, all of which, through networks of cytokines and growth factors, have been shown to influence tumor growth and metastasis [8]. Thus, strategies aimed to specifically target the interaction between CSCs and their microenvironment may represent an important approach to improve patient outcome.
More...

En savoir plus

Angiotensin II and mechanisms of oxidative damage in HUVECs

Angiotensin II and mechanisms of oxidative damage in HUVECs

In conclusion we can say that with little effect on cell viability peptide, Angiotensin II induces a significant increase in ROS levels and lipid oxidation products in both thermal conditions, but more effectively in Hypothermia. Considering the eNOS inhibitor ADMA in our experimental data we obtained an intracellular response of increased superoxide radical levels. This happens also after thermal treatment by both Angiotensin II pathways. This effect is mainly due to the interaction of selective e NOS inhibitor ADMA and Angiotensin II, mainly in reference to the mechanisms for the generation of reactive oxygen species. The contribution of Nitric Oxide and combination products of ROS are negligible in the presence of ADMA [10 -4 M]. Only at a lower concentrations of ADMA is possible to observe a decrease in the production of Superoxide. Overall, the action of the main changes due to thermal damage and the action of Angiotensin II is mediated by AT1 receptor, the recovery of such damages has been accomplished through the action of the reducing natural agent ECG even at relevant concentrations. Once again we can confirm that the peroxidative damage is primarily mediated via AT 1 R in all tested (thermal and chemical) treatment combinations. The way to reduce the effect is to add reducing agents of natural origin. If the levels used in vitro reproduced in vivo ones, however, high doses of this flavonoid should be required . Only the use of many reducing agents from different sources could achieve the equivalent effect without causing collateral damages due to the means of conveyance (e.g. alcohol). On the basis of the described data, Angiotensin IV [10 -8 M] is an effective binding agent and AT 4 R improves the functionality of the HUVECs. This suggests that its action is optimal in vitro at that same concentration. By using Angiotensin II inhibitors of AT 1 R and AT 2 R we confirmed the data, further suggesting that AT IV is effective at concentration of this order. Even under conditions similar to those of endothelial dysfunction (Yang, 2011) the range of Angiotensin IV remains at current levels lower than concentrations studied as effective in
More...

En savoir plus

DNA damage and genetic polymorphisms : influence on individual radiosensitivity

DNA damage and genetic polymorphisms : influence on individual radiosensitivity

In order to examine whether differences in the radiation response could influence the development of normal tissue reactions, we checked the relationship between the repair capacity and the adverse side effects. An interesting outcome was obtained showing a relation between higher degrees of adverse reactions (as evaluated on the basis of ROTG scale) and the residual DNA damage: in patients showing acute skin reactions (20 patients from G1 to G3 grade) DNA damage did not significantly decrease from 30 to 60 min of repair times. This result is particularly evident in 6 over-reactors who showed G2 and G3 reactions. A similar result was reported by Alapetite et al. (1999) in 3 over-reacting BC patients but not by Popanda et al. (2003) who failed to find any significant association between the clinical signs of radiation sensitivity and DNA repair parameters measured in vitro. It will be interesting to follow our over-reacting patients (particularly those showing G2 and G3 grades) for late clinical symptoms which can develop several months after therapy (Bentzen, 2006).
More...

En savoir plus

Experimental study of the phase behaviour of limited valence particles in DNA nano-aggregate systems

Experimental study of the phase behaviour of limited valence particles in DNA nano-aggregate systems

The observed behaviour of the scattering intensity is consistent with this scenario. Since the investigated range of salt concentrations is rather limited, we only have slightly modifications of the instability region and samples at 50, 70, 100 mM NaCl result all located outside the phase boundary where they do not undergo phase separation. Anyhow, the effects of the salt are evident in the sample with the higher ionic strength which, despite being prepared at the same DNA concentration as the others, falls close (and perhaps even inside) the phase boundary. Moreover, the T -dependence of the scattering intensity at different salt concentrations confirms the role played by the ionic strength in shifting the melting temperatures of the systems. Indeed, by comparing the intensities scattered by the different samples at the same temperature value, one can easily observe how the scattering intensity progressively increases on increasing the ionic strength (i.e. at the same T, the sample with the higher ionic strength scatters more light than the others do). In fact, at the same T value, the number of bonded overhangs it is supposed to be larger in samples with higher ionic strength (since, as shown by the UV measurements discussed in chapter 4, the melting temperature of the sticky ends is shifted upward on increasing the salt concentration), thus giving rise to large clusters of bonded nanostars. Besides giving important indications on how the system behaviour is affected by the ionic strength, the scattering intensity can be further exploited to investigate the approach to the equilibrium gel states. Indeed, neglecting the sample at 150 mM NaCl which is affected by the phase-separation, a closer look at the T -dependence of the scattering intensity for the other samples reveals a very interesting behaviour.
More...

En savoir plus

Effects of adiponectin on the progression of breast cancer: role of Estrogen Receptor alpha

Effects of adiponectin on the progression of breast cancer: role of Estrogen Receptor alpha

Breast cancer is stimulated by estrogens that activating the classical ERs modulate cell proliferation, adhesion, migration, and invasion in estrogen-sensitive tumors (2, 3). In addition, estrogens promote the formation of new blood vessels within the tumor mass (35), hence suggesting that these steroids elicit a stimulatory role not only in cancer cells but also in compo- nents of the surrounding stroma in accordance with the results obtained in this study. As the complex process of angiogenesis is required for tumor progression, it represents a central biological target in cancer (36). VEGF is one of the most potent proangiogenic factor playing a paramount role in the forma- tion of blood vessels in the development of different types of tumors, including breast cancer (23). Accordingly, VEGF is highly expressed in breast cancer specimens compared with normal breast tissue (37) and its suppression leads to the
More...

En savoir plus

The role of intestinal inflammation on the gut-liver axis

The role of intestinal inflammation on the gut-liver axis

The intestinal mucosal chemical barrier refers to the gastric secretion of gastric acid, mucus, mucin, bile, glycoproteins, mucopolysaccharides, digestive enzymes, lysozymes, and other substances, which can alter the attack sites of pathogenic bacteria and act as a chemical barrier. The mucus layer contains AMPs, which help prevent contact between bacteria and the epithelium. The chemical barrier can protect the intestinal mucosa from erosion as a result of enzymes and acidic and alkali conditions. Gastric acid and bile can inactivate bacteria. The pH of gastrointestinal mucus and digestive juice is not conducive to the growth of bacteria. Gastric acid is the best bactericide in the gastrointestinal tract [72]. BAs can be combined with endotoxin; cholic acid can degrade endotoxin molecules; and lysozyme can destroy bacterial cell walls, destroying bacteria. The digestive juice secreted by the intestines can dilute the toxin and clean the intestinal cavity, making it difficult for the potentially pathogenic bacteria to adhere to the intestinal epithelium [73]. In addition, there are some complementary components in the intestinal secretion, which can help intestinal immune cells clear pathogens [38]. BAs can maintain the stability of the intestinal environment by inhibiting bacterial growth and translocation in the small intestine [74]. By activation FXR, bile acid negatively regulates the expression of sterol regulatory element binding protein 1c (SREBP-1c) [75] and reduces the expression of fat- related genes, reducing the occurrence of NAFLD [76].
More...

En savoir plus

Study of the role of products and enzymes of cholesterol biosynthetic pathway in muscle tissues

Study of the role of products and enzymes of cholesterol biosynthetic pathway in muscle tissues

Reinitzer in 1880, and the right structure and exact steric representation were elucidated between 1900 and 1932, mainly by works from Wieland and Windaus. Meanwhile, Schmidt (1914) measured for the first time high serum cholesterol levels in patients with xanthomatosis, thus recognised it as essential hypercholesterolemia. By the early 1950s, Lynen demonstrated that the acetylation of Coenzyme A is the key first step in a chain of reactions that result in the formation of cholesterol and fatty acids. Together with Bloch, Lynen successively received the Nobel price for medicine (1954) and Nobel price for physiology and medicine (1964) for their discoveries concerning the mechanism and regulation of cholesterol and fatty acids metabolism (pathway from “activated acetic acid” to terpenes and fatty acids). Meanwhile, Tavormina et al. (1956) discovered that mevalonic acid is quantitatively incorporated in cholesterol in cell-free systems with loss of carbon dioxide. The biological function of cholesterol gained insights from work by Fisher (1976) who, by freeze-fracture and biochemical analysis in human erythrocytes, demonstrated that cholesterol is asymmetrically distributed across the plane of the membrane, being more present on the exterior side than on the interior side. Works to elucidate the very nature and metabolism of cholesterol were just starting that it was already pointed for its involvement in atherosclerogenesis. The first hint came from work by Windaus who reported that atherosclerotic plaques from aortas of human subjects contained 20- to 26- fold higher concentrations of cholesterol than did normal aortas. This observation opened nearly a century of research, which leaded to the recognition of the cholesterol carrying low density lipoprotein (LDL) particles as the primary cause of atherosclerosis (Rader et al., 2003) With the discovery of the mevalonic aciduria as first inborn error of cholesterol biosynthesis (Hoffmann et al., 1986), a new era of cholesterol history started, era in which cholesterol was no longer considered just as heart breaking molecule, but also as a key player in developmental processes.
More...

En savoir plus

The right to food: alternative methods of implementation: The Role of Courts and Indicators

The right to food: alternative methods of implementation: The Role of Courts and Indicators

portantly, the document clearly established how to interpret the obligations of States, following the tripartite framework. Respecting the right, therefore not taking action that harms it; protecting it against the action of third parties; fulfilling it in both its dimensions of facilitating it (creating an enabling environment allowing everyone to enjoy the right self-sufficiently) and providing (food supplies to those whom, for reasons beyond their control, are unable to provide for themselves). Vi- olation can both come from actions of commission and of omission, and in the latter case it is up to the State to demonstrate having done all that was in their power to comply with their obligations, including appealing for international assistance. These three obligations were also declined in an in- ternational fashion: respect (in drafting agreements), protect (citizens of other States from the pos- sible harmful action from privates under the State’s jurisdiction), facilitate (cooperate to create an enabling international environment) and provide (aid States facing crises beyond their capabilities). More provisions clarify implementation: national plans must be drafted for the progressive realisa- tion of the right, including appropriate monitoring, benchmarks and frameworks, in a participatory fashion, and providing judicial remedy for infraction. The new millennium saw a flurry of new de- velopments. The non-binding FAO’s Right to Food Guidelines were drafted in 2004, supplementing the PoA of 1996 by guiding the implementation of domestic programmes for the realisation fo the right to food in a way that accounted for the principles of the Vienna Declaration of 1993 (intercon- nectedness, interrelatedness, indivisibility, inalienability and universality of all human rights). The Millennium Declaration and its MDGs, in 2000, and its sequitur, the 2030 Agenda for Sustainable Development, represented
More...

En savoir plus

Behavioral, physiological and neural evidence of the role of political ideology in social cognition

Behavioral, physiological and neural evidence of the role of political ideology in social cognition

statistical computing (R Development Core Team, 2013). Trials in which participants did not recognize the politician were excluded from the analysis (Total valid trials=62%; range: min=13%, max=100% of valid trials per subject). We then performed a multilevel mixed linear regression analysis (LMM or “mixed-effects models”; (Garson 2013; Pinheiro and Bates 2000) through the package lme4 Version 1.1–5 (Bates, D., Maechler, M., Bolker, B., & Walker 2014). Unlike traditional statistical methods, LMM are suitable for (a) analyzing hierarchical data structures (i.e., in which not all levels of a categorical factor co-occur at all levels of another categorical factor); (b) analyzing the whole data set (not just the mean observations for each subject and condition) to better evaluate the data variations that variance-style analyses (ANOVA) often leave out; (c) accounting for the non-independence of observations with correlated error; (d) separately treating the effects caused by the experimental manipulation (fixed effects) and those that were not (random effects) (Pinheiro and Bates 2000). We used Valence as the dependent measure of our model. The fixed effects were the Political Categorization of the stimulus, the Group and their respective interactions. Political categorization of the stimulus was recoded as follows: if the categorization of the stimulus made by the participant matched his/her Group (i.e., left vs right-wing), that stimulus was considered as ingroup (e.g., a stimulus categorized as left-wing by a left-wing participant was considered as ingroup). If the categorization did not match, that stimulus was considered as outgroup (e.g., a stimulus categorized as right-wing by a left-wing participant was considered as outgroup). We considered the random intercept over participants and the random slope of Political categorization over participants as random factors. Statistical significance of fixed effects was determined using type III Wald F tests with Kenward-Roger degrees of freedom (Kenward and Roger 1997) and the Anova function from R’s car package. Post hoc pairwise comparisons (FDR corrected) were performed using least squares contrasts (lsc), as employed in R’s lsmeans package. The analysis revealed a significant Group x Political Categorization interaction F (1, 70.025) = 48.31, p< .001. Post hoc analysis showed the slope of left-wing participants to be significantly different from zero (b= 3.11, SE= 0.26, df= 68.75, t.ratio= -11.94, p< .001), while that of right-wing
More...

En savoir plus

Economic crisis, role of public authorities and the commons : Rome and the governance of urban resources

Economic crisis, role of public authorities and the commons : Rome and the governance of urban resources

To be more specific, we might recall with Sturn (2006) that Musgrave‘s perspective on collective goods originated also from Hermann‘s subjectvisim. According to Sturn, ―Musgrave gives impressive overviews of important writers of German Staatswirthschaft such as Hermann and the writers of the aforementioned ‗triad‘ as well as Sax, von Wieser, Wicksell, and Lindahl, who applied marginal utility analysis to the theory of public expenditure‖(Sturn 2006: 41). Hermann is the reference for a ―non-atomistic subjectivism‖ that provide a basis for Musgrave conception of State. Hermann emphasized the role of the subject of action and their development, and his subjectivism was not utilitarian, focusing on how in the process of socio-economic development individuals define and increase cognitive skills, motivations and needs.. According to this author, ―self-preservation was the basic motivational assumption and source of needs‖ (Sturn 2006:52). The family is the basic—social condition of self-preservation, since it primarily addresses specific needs, motivations and activities defining the spectrum of collective needs and joint consumption 20 . The process of civilization enlarges the objective of self-preservation and defines new collective needs beyond the level of the individual or the family. These collective (joint) needs (at least in Sturn‘s perspective) define collective goods. The necessity of this goods at a wider level motivate the intervention of the State and the public sector. Indeed, similarly to Musgrave, collective needs define collective goods that need the existence of State/government. Hermann discussed the conditions under which impure public goods are better supplied on a voluntary basis by some intermediate institutions sustained by the public spirit or the government 20 and Sturn reports in a passage by Hermann an envision of market and State that strongly reminds Musgrave‘s conception and also the literature by Adam Smith, Robbins, and Ropke. ‗Presupposing all the social means of securing and enhancing industry and trade, and assuming moreover sufficiently educated citizens, one may well admit that, as a rule, the individual‘s own advantage is the best guide to the kind and method of his industry, whereas constraints are rather harmful than useful‘ (Hermann (1832: 13))
More...

En savoir plus

Importance of environmental habitats as a reservoir of phytopathogenic bacteria and their role in the evolution of pathogenicity traits

Importance of environmental habitats as a reservoir of phytopathogenic bacteria and their role in the evolution of pathogenicity traits

Different evolutionary strategies seem to have been deployed by strains in the P. syringae complex according to the substrates or life styles that typify them. We demonstrated that strains in phylogroup 7 and 8, previously named P. viridiflava, are widely distributed in the environment and that both environmental and crop strains possess one of either two types of T3SS. However, the evolution of the two T3SS does not seem to be related to the substrate of the origin or with the ability to induce disease. The only correlation with pathogenicity that we could find was that the absence of the conserved effector gene avrE was consistently associated with lack of pathogenicity in our tests. Hence, we speculate that the ability to produce pectolytic enzymes capable of inducing soft rot on potato, found only in phylogroup 7 and 8, might have led to the evolution of a less complex T3SS such as the Single-Partite T3SS (S-PAI). The latter was found in 90% of the P. viridiflava strains isolated from all the substrates. This is consistent with the prevailing view of P. viridiflava as a saprophytic opportunist. In this light, the capacity to produce pectolytic enzymes associated with a potato soft-rot phenotype, in conjunction with the expression of avrE, seems to reflect an important evolutionary strategy in phylogroup 7 and 8 that has involved maintaining both saprophytic and pathogenicity life-styles. In-depth future studies about the role of the avrE gene during host infection may help understanding and predicting pathogenicity of P. viridiflava strains. In fact, although we found a suitable molecular marker for the detection of P. viridiflava strains in general, it cannot discriminate between pathogenic and non-pathogenic strains.
More...

En savoir plus

DNA Methylation changes in the brain white matter of multiple sclerosis patients

DNA Methylation changes in the brain white matter of multiple sclerosis patients

Demyelination areas localise in both the white and grey matter of the brain and spinal cord. The oligodendrocytes, the cells that exert a trophic effect on the axons and maintain the structural integrity of the myelin, are attacked by the immune system in MS. As a direct consequence of the damage, the compromised myelin sheath does not properly propagate the axonal action potential (Patel and Balabanov 2012). At the initial phases of the disease, both axons and neurons are still capable of preserving their functionality as well as their correct structure. With the disease progression, there is a gradual neuro-axonal integrity decline strongly related to the patient's degree of disability (Correale, Marrodan et al. 2019).
More...

En savoir plus

Analysis of the role of werner helicase interacting protein 1 in response to replication stress

Analysis of the role of werner helicase interacting protein 1 in response to replication stress

Base modifications limited to one strand of the DNA template do not produce a physical block for the moving replicative helicase, but can stall polymerases and uncouple helicase unwinding from DNA synthesis. In contrast, lagging-strand DNA lesions are well tolerated because of the inherently discontinuous nature of Okazaki-fragment synthesis and maturation, leading strand lesions represent a major obstacle for processive DNA synthesis (Yeeles et al., 2013). In these cases, DNA-damage tolerance (DDT) mechanisms ensure that replication continues with a minimal effect on fork elongation, either by using specialized DNA polymerases or by postponing repair. Fork progression may be facilitated by specialized polymerases called TLS polymerases, which have the ability to replicate through a damaged template, albeit with lower fidelity (Sale et al., 2012). Alternatively, the replisome may skip the damaged DNA, thus leaving an unreplicated ssDNA gap to be repaired after replication. The bacterial replisome is able to reinitiate DNA synthesis downstream of a leading-strand lesion by de novo priming and recycling or exchange of stalled replicative polymerases (Heller and Marians, 2006; Yeeles et al., 2013). This mechanism also appears to efficiently restart replication in eukaryotes, and proteins capable of ‘repriming’ DNA synthesis beyond a lesion have recently been identified (Elvers et al., 2011; Lopes et al., 2006). The human primase PrimPol ensures resumption of DNA synthesis after UV irradiation and under conditions of dNTPs shortage. Interestingly, PrimPol has also TLS activity, although it is currently uncertain whether its fork-repriming or lesion-bypass activity is important for fork restart (Mourón et al., 2013). Thus, it is clear that define the mechanisms that orchestrate the choice between repriming and TLS is an important matter for future investigation.
More...

En savoir plus

Show all 1025 documents...