Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Bcl-2-regulated cell death signalling in the prevention of autoimmunity

Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention

Spatial and temporal patterns of root distribution in developing stands of four woody crop species grown with drip irrigation and fertilization.

Abstract In forest trees, roots mediate such significant carbon fluxes as primary production and soil C02 efflux. Despite the central role of roots in these critical processes, information on root distribution during stand establishment is limited, yet must be described to accurately predict how various forest types, which are growing with a range of resource limitations, might respond to environmental change. This study reports root length density and biomass development in young stands of eastern cottonwood (Populus deltoidies Bartr.) and American sycamore (Platanus occidentalis L.) that have narrow, high resource site requirements, and compares them with sweetgum (Liquidambar styraczj7ua L.) and loblolly pine (Pinus taeda L.), which have more robust site requirements. Fine roots (5 mm) were sampled to determine spatial distribu-tion in response to fertilizer and irrigation treatments delivered through drip irrigation tubes. Root length density and biomass were predominately controlled by stand development, depth and proximity to drip tubes. After accounting for this spatial and temporal variation, there was a significant increase in RLD with fertilization and irrigation for all genotypes. The response to fertilization was greater than that of irrigation. Both fine and coarse roots responded positively to resources delivered through the drip tube, indicating a wholeroot- system response to resource enrichment and not just a feeder root response. The plastic response to drip tube water and nutrient enrichment demonstmte the capability of root systems to respond to supply heterogeneity by increasing acquisition surface. Fineroot biomass, root density and specific root length were greater for broadleaved species than pine. Roots of all genotypes explored the rooting volume within 2 years, but this occurred faster and to higher root length densities in broadleaved species, indicating they had greater initial opportunity for resource acquisition than pine. Sweetgum's root characteristics and its response to resource availability were similar to the other broadleaved species, despite its hnctional resemblance to pine regarding robust site requirements. It was concluded that genotypes, irrigation arid fertilization significantly influenced tree root system development, which varied spatially in response to resource-supply heterogeneity created by dnp tubes. Knowledge of spatial and temporal patterns of root distribution in these stands will be used to interpret nutrient acquisition and soil respiration measurements

Differentiated Quality-of-Protection Provisioning in Optical/MPLS Networks

This paper investigates the problem of dynamic survivable lightpath provisioning against single node/link failures in optical mesh networks employing wavelengthdivision multiplexing (WDM). We present a new approach to provisioning lightpath requests according to their differentiated quality-of-protection (QoP) requirements. We focus on one of the most important QoP parameters, namely protection-switching time, since lightpath requests may have differentiated protection-switching-time requirements. For example, lightpaths carrying voice traffic may require 50 ms protection while lightpaths carrying data traffic may have a wide range of protection-switching-time requirements. Numerical results show that, compared to shared-path protection, our approach achieves significant performance gain which leads to remarkable reduction in blocking probability. While our focus is on optical WDM network, the basic ideas of our approaches can be applied to multiprotocol label switching (MPLS) networks with appropriate variations, e.g., differentiated bandwidth granularities

Endocrine side-effects of new anticancer therapies: Overall monitoring and conclusions

IF 0.795 (2017)International audienceThe present final consensus statement of the French Society of Endocrinology lays out the assessments that are to be systematically performed before and during anticancer treatment by immunotherapy, tyrosine kinase inhibitors or mTOR inhibitors, even without onset of any endocrinopathy. It also discusses the CTCAE adverse event grading system in oncology and the difficulty of implementing it for endocrine side-effects of these anticancer treatments. Notably, this is why certain treatment steps applied in other side-effects (e.g., high-dose corticosteroids, contraindications to immunotherapy, etc.) need to be discussed before implementation for endocrine side-effects

XIAP discriminates between type I and type II FAS-induced apoptosis

FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions