Tumorigenesis and neurodegeneration: two sides of the same coin?

Dysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxia-telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.     

Racism and Brazilian democracy: two sides of the same coin?

Experiences with racism and age negatively affect how Afro-Brazilians in Salvador and São Paulo rate democracy. Older cohorts are more likely to rate democracy high compared to younger cohorts who rate it as low. Respondents in Salvador tend to rate democracy lower than respondents in São Paulo. Moreover, interviews reveal that as citizens believe they are not accorded full rights, they do not agree that Brazil's political system is fully democratic. Studies examining democracy in Brazil and racial politics throughout the diaspora would benefit from examining racialized experiences of citizens, rather than simply including the demographic variable of race. It is these experiences that affect rating of democracy rather than ascribed notions of race.     

Impact of gut-associated bifidobacteria and their phages on health: two sides of the same coin?

Applied Microbiology and Biotechnology - Bifidobacteria are among the first microbial colonisers of the human infant gut post-partum. Their early appearance and dominance in the human infant gut...     

Viruses and autoimmune disease--two sides of the same coin?

Some viruses have the ability to modulate the development of autoimmune diseases. Virus infections have long been associated with the exacerbation of autoimmune disease, however, there is also evidence that viruses can actually protect against autoimmune disease. Several experimental models have been developed to investigate how some virus infections can prime for and trigger autoimmunity whereas others ameliorate the pathway leading to clinical disease. It is possible that the type I interferons, via interleukin 12, provide the link between viruses and autoimmunity.     

Stability and rigidity/flexibility—Two sides of the same coin?

Protein molecules require both flexibility and rigidity for functioning. The fast and accurate prediction of protein rigidity/flexibility is one of the important problems in protein science. We have determined flexible regions for four homologous pairs from thermophilic and mesophilic organisms by two methods: the fast FoldUnfold which uses amino acid sequence and the time consuming MDFirst which uses three-dimensional structures. We demonstrate that both methods allow determining flexible regions in protein structure. For three of the four thermophile–mesophile pairs of proteins, FoldUnfold predicts practically the same flexible regions which have been found by the MD/First method. As expected, molecular dynamics simulations show that thermophilic proteins are more rigid in comparison to their mesophilic homologues. Analysis of rigid clusters and their decomposition provides new insights into protein stability. It has been found that the local networks of salt bridges and hydrogen bonds in thermophiles render their structure more stable with respect to fluctuations of individual contacts. Such network includes salt bridge triads Agr-Glu-Lys and Arg-Glu-Arg, or salt bridges (such as Arg-Glu) connected with hydrogen bonds. This ionic network connects alpha helices and rigidifies the structure. Mesophiles can be characterized by stand alone salt bridges and hydrogen bonds or small ionic clusters. Such difference in the network of salt bridges results in different flexibility of homologous proteins. Combining both approaches allows characterizing structural features in atomic detail that determine the rigidity/flexibility of a protein structure. This article is a part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.     

Evolutionary and clinical neocentromeres: two faces of the same coin?

It has been hypothesized that human clinical neocentromeres and evolutionary novel centromeres (ENC) represent two faces of the same phenomenon. However, there are only two reports of loci harboring both a novel centromere and a clinical neocentromere. We suggest that only the tip of the iceberg has been scratched because most neocentromerization events have a very low chance of being observed. In support of this view, we report here on a neocentromere at 9q33.1 that emerged in a ring chromosome of about 12 Mb. The ring was produced by a balanced rearrangement that was fortuitously discovered because of its malsegregation in the propositus. Chromatin-immunoprecipitation-on-chip experiments using anti-centromere protein (CENP)-A and anti-CENP-C antibodies strongly indicated that a novel centromeric domain was present in the ring, in a chromosomal domain where an ENC emerged in the ancestor to Old World monkeys.     

Genoprotection and genotoxicity of green tea (Camellia sinensis): Are they two sides of the same redox coin?

Abstract

Objectives

Regular intake of green tea associates with lower DNA damage and increased resistance of DNA to oxidant challenge. However, in vitro pro-oxidant effects of green tea have been reported. Both effects could be mediated by hydrogen peroxide (H₂O₂) which is generated by autoxidation of tea catechins. In large amounts, H₂O₂ is genotoxic, but low concentrations could activate the redox-sensitive antioxidant response element (ARE) via the Keap-1/Nrf2 redox switch, inducing genoprotective adaptations. Our objective was to test this hypothesis.

Methods

Peripheral lymphocytes from healthy volunteers were incubated for 30 minutes at 37°C in freshly prepared tea solutions (0.005, 0.01, 0.05%w/v (7, 14, 71 µmol/l total catechins) in phosphate buffered saline (PBS), with PBS as control) in the presence and absence of catalase (CAT). H₂O₂ in tea was measured colorimetrically. Oxidation-induced DNA lesions were measured by the Fpg-assisted comet assay.

Results

H₂O₂ concentrations in 0.005, 0.01, and 0.05% green tea after 30 minutes at 37°C were, respectively, ～3, ～7, and ～52 µmol/l. Cells incubated in 0.005 and 0.01% tea showed less (P < 0.001) DNA damage compared to control cells. Cells treated with 0.05% green tea showed ～50% (P < 0.001) more DNA damage. The presence of CAT prevented this damage, but did not remove the genoprotective effects of low-dose tea. No significant changes in expression of ARE-associated genes (HMOX1, NRF2, KEAP1, BACH1, and hOGG1) were seen in cells treated with tea or tea + CAT.

Conclusion

Genoprotection by low-dose green tea could be due to direct antioxidant protection by green tea polyphenols, or to H₂O₂-independent signalling pathways.     

Leptin in energy balance and reward: two faces of the same coin?

Leptin receptors are expressed on mesolimbic dopamine neurons, yet little is known about the functional significance of this anatomical relationship. In this issue of Neuron, Hommel et al. reveal a novel site for leptin's regulation of feeding. In turn, Fulton et al. propose a novel role for leptin in regulating non-feeding-related motivated behaviors.     

Explaining forest productivity using tree functional traits and phylogenetic information: two sides of the same coin over evolutionary scale?

Given evidences that diverse ecosystems provide more services than depauperate ones, much attention has now turned toward finding meaningful and operational diversity indices. We ask two questions: (1) Does phylogenetic diversity contain additional information not explained by functional traits? And (2) What are the strength and nature of the correlation between phylogeny and functional traits according to the evolutionary scale considered? We used data from permanent forest plots of northeastern Canada for which these links have been demonstrated and important functional traits identified. We show that the nature of the relationship between traits and phylogeny varies dramatically among traits, but also according to the evolutionary distance considered. The demonstration that different characters show phylogenetic autocorrelation at different evolutionary depths suggests that phylogenetic content of traits may be too crude to determine whether phylogenies contain relevant information. However, our study provides support for the use of phylogenies to assess ecosystem functioning when key functional traits are unavailable. We also highlight a potentially important contribution of phylogenetics for conservation and the study of the impact of biodiversity loss on ecosystem functioning and the provision of services, given the accumulating evidence that mechanisms promoting diversity effects shift over time to involve different traits.     

Patient and public involvement: Two sides of the same coin or different coins altogether?

Patient and public involvement (PPI) has gained widespread support in health research and health policy circles, but there is little consensus on the precise meaning or justifications of PPI. We argue that an important step towards clarifying the meaning and justification for PPI is to split apart the familiar acronym and draw a distinction between patient and public involvement. Specifically, we argue that patient involvement should refer to the practice of involving individuals in health research or policy on the basis of their experience with a particular condition, while public involvement should refer to the practice of involving individuals in health policy or research based on their status as members of a relevant population. Analyzing cases from the UK, Australia, and the USA, we show how our proposed distinction can deliver much needed clarity to conversations on PPI, while guiding the development and evaluation of future PPI‐based policies.     

Invasion success and threat status: two sides of a different coin?

The characteristics possessed by invasive species have been suggested to be the reverse of those possessed by species threatened with extinction, such that relationships of species’ traits to invasion success should be opposite in sign to relationships of the same traits to extinction threat. A recent study (Jeschke, J. M. and Strayer, D. L. 2008. Are threat status and invasion success two sides of the same coin? – Ecography 31: 124–130) found no evidence for this “two‐sides‐of‐the‐same‐coin” hypothesis but compared characteristics of species in each taxon that were invasive to a control group consisting of all other species. A different view of the “two‐sides‐of‐the‐same‐coin” hypothesis may be obtained if the characters of invasive species are compared to those of a control group consisting of species that have not invaded despite actually being introduced. Here, we show that changing the control group for comparison with invasive species does not change the lack of support for the “two‐sides‐of‐the‐same‐coin” hypothesis but does change views about which specific traits are consistent with the hypothesis.     

Melanocyte-specific immune response in melanoma and vitiligo: two faces of the same coin?

The appearance of depigmentation during the course of malignant melanoma has been considered a good prognostic sign. Is it only a side-effect, informative of the immune system's response to the treatment, or does it act as a necessary amplifier of these clinically important anti-tumor responses? The current review will attempt to tackle this question by reviewing the current literature, as well as by posing some novel hypotheses. Understanding the nature of humoral and cellular immune responses directed against normal melanocytes and their malignant counterparts may lead to the design of improved therapeutic strategies relevant to both vitiligo and melanoma.     

Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin?

Autophagy is a homeostatic cellular process required for the recycling of proteins and damaged organelles, and in most scenarios is believed to promote cell survival. However, there is accumulating evidence that under certain pathological situations, autophagy can also trigger and mediate programmed cell death (type II death). Despite the well-established pathophysiological role of apoptosis (type I cell death) in post-ischemic neuron death, there is now increasing interest whether alternative types of programmed cell death might be involved in regulation of neuronal death after both global and focal cerebral ischemia. Initial studies demonstrating the involvement of lysosomal proteases of the cathepsin family in neuron death after global ischemia already had suggested that this type of cell death may occur in an autophagy-dependent manner. Recently it was also shown that focal ischemia is associated with potently enhanced expression of the autophagy regulator Beclin 1 and subcellular redistribution of the autophagic marker LC3 to vacuolic structures in ischemic neurons. Increasing evidence suggests that the effects of autophagy are highly contextual. An insufficient autophagic response might render cells more susceptible to stress conditions whereas on the other hand prolonged overactivation of autophagy can lead to a complete self digestion of the cell. The extent of autophagy may represent a master switch between cell survival and cell death, and it will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death program and thus contribute to cell death after cerebral ischemia. A profound understanding of the biological effects and the mechanisms underlying ischemia-induced autophagy in neurons might be helpful in seeking effective new treatments for cerebral ischemia.     

Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin?

Autophagy is a homeostatic cellular process required for the recycling of proteins and damaged organelles, and in most scenarios is believed to promote cell survival. However, there is accumulating evidence that under certain pathological situations, autophagy can also trigger and mediate programmed cell death (type II death). Despite the well-established pathophysiological role of apoptosis (type I cell death) in post-ischemic neuron death, there is now increasing interest whether alternative types of programmed cell death might be involved in regulation of neuronal death after both global and focal cerebral ischemia. Initial studies demonstrating the involvement of lysosomal proteases of the cathepsin family in neuron death after global ischemia already had suggested that this type of cell death may occur in an autophagy-dependent manner. Recently it was also shown that focal ischemia is associated with potently enhanced expression of the autophagy regulator Beclin 1 and subcellular redistribution of the autophagic marker LC3 to vacuolic structures in ischemic neurons. Increasing evidence suggests that the effects of autophagy are highly contextual. An insufficient autophagic response might render cells more susceptible to stress conditions whereas on the other hand prolonged overactivation of autophagy can lead to a complete self digestion of the cell. The extent of autophagy may represent a master switch between cell survival and cell death, and it will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death program and thus contribute to cell death after cerebral ischemia. A profound understanding of the biological effects and the mechanisms underlying ischemia-induced autophagy in neurons might be helpful in seeking effective new treatments for cerebral ischemia.