La médiation et le règlement des conflits dans les services essentiels au Québec

Le régime québécois de maintien des services essentiels accorde une place prépondérante à la responsabilité des parties. Il est basé d'abord et avant tout sur une recherche de consensus autant dans la détermination et le maintien des services essentiels que dans le règlement des conflits qui peuvent affecter le service au public. L'auteure présente d'abord le mandat et le cadre légal de l'exercice des pouvoirs du Conseil des services essentiels du Québec. Elle explique ensuite comment s'exerce la médiation et, finalement, examine comment la question de la détermination des services essentiels, selon une approche consensuelle, est traitée par d'autres juridictions canadiennes.The right of public service employees and public servants to strike was recognized by the Quebec legislature in the mid-1960s. The need was soon felt to establish mechanisms for determining essential services during strikes, in particular because of the socio-political environment, numerous illegal strikes and the centralization of both administration and collective bargaining in the health-care System.After unsuccessful several attempts, in 1982 the government adopted the current legislation and created the Conseil des services essentiels (Quebec Essential Services Council), the first permanent body responsible for ensuring the maintenance of essential services during strikes in the public services, and as of 1985, in the public sector, more precisely for establishments in the health care and social services sectors. Although the creation of the council and the mechanisms put in place to ensure the maintenance of essential services were greeted with scepticism, everyone concerned would now agree that the evidence is conclusse.One of the most important factors contributing to this success is the consensual approach taken to determine essential services. In fact, the law requires that the parties negotiate essential services on the basis of a list which the union must file with the council and the employer. The approach favoured by the legislature rests on making the parties more responsible, implying profound changes in the mentaliry of the employers and unions concerned. It should be emphasized that the legislature chose a narrow definition of what constitutes an essential service, both by limiting the sectors of activity subject to this obligation and by adopting the protection of health and public safety during a strike as the criterion to evaluate the sufficiency of services.Within the context of the council's activities, mediation is viewed as the effort of a neutral person to help the parties conclude their own agreement on the services that will be provided to the public during a strike. Mediation is conducted under the Essential Services Council, a decision-making tribunal which is empowered to decide whether the services determined to be essential are in fact sufficient. The law requires the parties to negotiate essential services to be provided, thus recognizing the importance of the responsibiliry of the parties in this area because of their knowledge of the establishment in question. It also recognizes that essential services are more likely to be provided without interruption if they have been determined by the parties themselves.The principal functions of the mediators include information, education and awareness. Their efforts are aimed at creating a link between the parties on a question that should ideally remain irrelevant unless a collective agreement is not reached. Through this process, employers and unions must contribute to the protection of public health and safety.Mediators are assigned permanently to enterprises and establishments on a regional basis or on the basis of a specialization. They establish contacts with the parties, draw up a profile of services and establish the first contacts aimed at demonstrating their neutrality and their avallability. When the negotiation of services itself begins, the mediator must ensure that the parties attack all the issues that must be discussed. Agreements, or by default, lists, are submitted to the council for evaluation of their adequacy at a public hearing. If problems of interpretation or application of the essential services list arise during a strike, the mediators intervene with a view to determining the true nature of the conflict, defuse it and help the parties to find solutions so that provision of essential services will not be disrupted. In the absence of an agreement between the parties, the Essential Services Council may intervene, again in the form of a public hearing, and, in the absence of negotiated solutions at this stage, the council can use its powers of redress. By virtue of these powers, the council may issue orders ensuring the provision of essential services. More broadly, the council may also use its powers of redress if a private conflict in a public service or in the public sector deprives, or is likely to deprive the public of a service to which they have a right. As soon as such conflicts are brought to the attention of the council, the mediator is the first to intervene and his or her primary objective is to have the service restored as quickly as possible. The council also sees itself as an active participant in labour relations in the public services and the public sector that corne under its jurisdiction. Indeed, to ensure that essential services are provided to the public, it does not suffice to simply use the powers of redress to stop the outward manifestations of conflict and to ignore its root causes. From this point of view, the mediator works with the parties to find permanent solutions to the problem that brought about the council's intervention. By putting such stress on the search for consensus between the parties, and by entrusting an independent and neutral third party to solve disputes, the Quebec legislature sought to dejudiciarize this sector of labour relations. The entire legislation and its application are in keeping with the search for a fair balance between the right to strike, a result of the freedom of association recognized in democracies, and the public's right to services despite industrial conflict

Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents

Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma. We used a homogenous proximity assay to screen for compounds that disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of DNA-binding chemotherapeutic agents were found to non-specifically disrupt protein binding to DNA. In contrast, actinomycin D was found to preferentially disrupt EWS-FLI1 binding by comparison to p53 binding to their respective cognate DNA targets in vitro. In cell-based assays, low concentrations of actinomycin D preferentially blocked EWS-FLI1 binding to chromatin, and disrupted EWS-FLI1-mediated gene expression. Higher concentrations of actinomycin D globally repressed transcription. These results demonstrate that actinomycin D preferentially disrupts EWS-FLI1 binding to DNA at selected concentrations. Although the window between this preferential effect and global suppression is too narrow to exploit in a therapeutic manner, these results suggest that base-preferences may be exploited to find DNA-binding compounds that preferentially disrupt subclasses of transcription factors

The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells

The transcription factor BATF is required for interleukin 17 (IL-17)-producing helper T cell (TH17) and follicular helper T cell (TFH) differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved

Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair

BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

SummaryMYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.PaperFlic

Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells

Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic β cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In β cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in β cells to affect insulin secretion

Inactivation of a Single Copy of Crebbp Selectively Alters Pre-mRNA Processing in Mouse Hematopoietic Stem Cells

Global expression analysis of fetal liver hematopoietic stem cells (FL HSCs) revealed the presence of unspliced pre-mRNA for a number of genes in normal FL HSCs. In a subset of these genes, Crebbp+/− FL HSCs had less unprocessed pre-mRNA without a corresponding reduction in total mRNA levels. Among the genes thus identified were the key regulators of HSC function Itga4, Msi2 and Tcf4. A similar but much weaker effect was apparent in Ep300+/− FL HSCs, indicating that, in this context as in others, the two paralogs are not interchangeable. As a group, the down-regulated intronic probe sets could discriminate adult HSCs from more mature cell types, suggesting that the underlying mechanism is regulated with differentiation stage and is active in both fetal and adult hematopoiesis. Consistent with increased myelopoiesis in Crebbp hemizygous mice, targeted reduction of CREBBP abundance by shRNA in the multipotent EML cell line triggered spontaneous myeloid differentiation in the absence of the normally required inductive signals. In addition, differences in protein levels between phenotypically distinct EML subpopulations were better predicted by taking into account not only the total mRNA signal but also the amount of unspliced message present. CREBBP thus appears to selectively influence the timing and degree of pre-mRNA processing of genes essential for HSC regulation and thereby has the potential to alter subsequent cell fate decisions in HSCs

Mediator Kinase Inhibition Further Activates Super-Enhancer Associated Genes in AML

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors (TFs), and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling TFs and oncogenes 1, 2. BRD4 and CDK7 are positive regulators of SE-mediated transcription3,4,5. In contrast, negative regulators of SE-associated genes have not been well described. Here we report that Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We determined that the natural product cortistatin A (CA) selectively inhibited Mediator kinases, had antileukaemic activity in vitro and in vivo, and disproportionately induced upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the TFs CEBPA, IRF8, IRF1 and ETV6 6, 7, 8. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has antileukaemic activity. Individually increasing or decreasing expression of these TFs suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types and can be pharmacologically targeted as a therapeutic approach to AML