Death receptors, such as Fas/CD95 and TRAIL receptors, engage the extrinsic pathway for caspase activation, but also couple to the intrinsic mitochondrial route. In so-called Type II cells, death ...receptors require the mitochondrial pathway for apoptotic execution, whereas in Type I cells they reportedly do not. For established tumor cell lines, the Type I/Type II distinction is based on short-term apoptosis assays. We report here that the mitochondrial pathway is essential for apoptotic execution of Type I tumor cells by death receptors, when long-term clonogenicity is taken into account. A blockade of the mitochondrial pathway in Type I tumor cells - by RNA interference for Bid or Bcl-2 overexpression - reduced effector caspase activity and mediated significant clonogenic resistance to TRAIL. Downstream from the mitochondria, Caspase-9 did not contribute to clonogenic death of TRAIL-treated Type I cells. Rather, the release of Smac/DIABLO and the inhibition of XIAP activity proved to be crucial for full effector caspase activity and clonogenic execution. Thus, in Type I cells the intrinsic pathway downstream from death receptors is not redundant, but limits clonogenicity by virtue of Smac/DIABLO release and XIAP inhibition. This finding is relevant for cancer therapy using death receptor agonists.
In many tumor cell types, ionizing radiation (IR) or DNA-damaging anticancer drugs enhance sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, which is ...of great clinical interest. We have investigated the molecular mechanism underlying the response to combined modality treatment in p53-mutant Jurkat T leukemic cells overexpressing Bcl-2. These cells are largely resistant to individual treatment with TRAIL or IR, but sensitive to combined treatment, in vitro as well as in vivo. We demonstrate that IR and DNA-damaging anticancer drugs enable TRAIL receptor-2 and CD95/Fas to bypass the mitochondrial pathway for effector caspase activation. This was validated by RNA interference for Bax and Bak and by overexpression of dominant-negative Caspase-9. Improved effector caspase activation was neither caused by altered expression of proapoptotic components nor by impaired activity of inhibitor of apoptosis proteins or nuclear factor-kappaB signaling. Rather, we found that pretreatment of cells with IR caused quantitative and qualitative changes in death receptor signaling. It strongly improved the capacity of ligand-bound receptors to recruit FADD and activate Caspase-8 and -10 in the death-inducing signaling complex, while c-FLIP(L) levels were unaffected.
Cardiomyocytes are a stable cell population with only limited potential for renewal after injury. Tissue regeneration may be due to infiltration of stem cells, which differentiate into ...cardiomyocytes. We have analysed the influx of stem cells in the heart of patients who received either a gender-mismatched BMT (male donor to female recipient) or a gender-mismatched cardiac transplant (HTX; female donor to male recipient). The proportion of infiltrating cells was determined by Y-chromosome in situ hybridization combined with immunohistochemical cell characterization. In BM transplanted patients and in cardiac allotransplant recipients, cardiomyocytes of apparent BM origin were detected. The proportions were similar in both groups and amounted up to 1% of all cardiomyocytes. The number of stem cell-derived cardiomyocytes did not alter significantly in time, but were relatively high in cases where large numbers of BM-derived Y-chromosome-positive infiltrating inflammatory cells were present. The number of Y-chromosome-positive endothelial cells was small and present only in small blood vessels. The number of BM-derived cardiomyocytes in both BMT and HTX is not significantly different between the two types of transplantation and is at most 1%.
The mechanical degradation of electrodes caused by lithiation and delithiation is one of the main factors responsible for the short cycle life of lithium-based batteries employing high capacity ...electrodes. In this report, we introduced a simple patterning approach to improve the cycling stability of silicon electrode, which is considered as the next generation negative electrode due to its high Coulombic capacity and low cost, but is limited by the mechanical degradation associated with large volume variations during cycling. The pattern design is based on the observation of a critical size for the crack gap in continuous films. An improvement in cycle life was noted when the pattern size was below the critical (7–10
μm) size, in which case the Si electrode patches adhered well to the Cu substrate after many cycles. By taking the plastic deformation in both Si thin film and substrate into consideration, the calculated crack spacing is consistent with experimental observations. Theoretical considerations gave a feasible explanation for the failure of Si pattern above the critical size. These results suggest a new approach to extend the cycle life of Si-based electrode materials using size to control and relax the stress due to lithiation and delithiation.
ABSTRACT
This article critically evaluates existing causal explanations for the persistence of informality in artisanal and small‐scale mining (ASM). These explanations share a legalistic focus on ...entry barriers and political impediments that prevent or discourage the formalization of poverty‐driven ASM operators: however, they fail to fully explain cases such as that of the Philippines, where ASM is characterized by differentiation between a poverty‐driven workforce and a dominant stratum of ASM entrepreneurs. Even where limited formalization frameworks provide ASM with a degree of legal recognition, this recognition is usually restricted to these more powerful ASM interests, while excluding the workforce at large. This article therefore proposes an integrative approach to analysing informality in ASM, which complements the existing legalistic focus on entry barriers with a structuralist concern over the exploitation of informal labour. Seen from this perspective, the massive expansion of ASM in the Philippines can be seen as the product of a transition away from capital‐intensive large‐scale mining to a flexible regime of accumulation built around the exploitation of informal ASM labour. This observation highlights the need to pay more critical attention to the economic logic and the vested interests underlying the (selective) persistence of informality in the workforce.
Not much is known about lay public perceptions of non-native species and their underlying values. Public awareness and engagement, however, are important aspects in invasive species management. In ...this study, we examined the relations between the lay public’s visions of nature, their knowledge about non-native species, and their perceptions of non-native species and invasive species management with a survey administered in the Netherlands. Within this framework, we identified three measures for perception of non-native species: perceived risk, control and engagement. In general, respondents scored moderate values for perceived risk and personal engagement. However, in case of potential ecological or human health risks, control measures were supported. Respondents’ images of the human–nature relationship proved to be relevant in engagement in problems caused by invasive species and in recognizing the need for control, while images of nature appeared to be most important in perceiving risks to the environment. We also found that eradication of non-native species was predominantly opposed for species with a high cuddliness factor such as mammals and bird species. We conclude that lay public perceptions of non-native species have to be put in a wider context of visions of nature, and we discuss the implications for public support for invasive species management.
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