Damage segregation at fissioning may increase growth rates: A superprocess model

A fissioning organism may purge unrepairable damage by bequeathing it preferentially to one of its daughters. Using the mathematical formalism of superprocesses, we propose a flexible class of analytically tractable models that allow quite general effects of damage on death rates and splitting rates and similarly general damage segregation mechanisms. We show that, in a suitable regime, the effects of randomness in damage segregation at fissioning are indistinguishable from those of randomness in the mechanism of damage accumulation during the organism's lifetime. Moreover, the optimal population growth is achieved for a particular finite, non-zero level of combined randomness from these two sources. In particular, when damage accumulates deterministically, optimal population growth is achieved by a moderately unequal division of damage between the daughters. Too little or too much division is sub-optimal. Connections are drawn both to recent experimental results on inheritance of damage in protozoans, to theories of the evolution of aging, and to models of resource division between siblings.Comment: Version 2 had significant conceptual and organizational changes, though only minor changes to the mathematics. Version 3 has minor proofreading corrections, and a few new references. The paper will appear in Theoretical Population Biolog

The regeneration capacity of the flatworm Macrostomum lignano—on repeated regeneration, rejuvenation, and the minimal size needed for regeneration

The lion’s share of studies on regeneration in Plathelminthes (flatworms) has been so far carried out on a derived taxon of rhabditophorans, the freshwater planarians (Tricladida), and has shown this group’s outstanding regeneration capabilities in detail. Sharing a likely totipotent stem cell system, many other flatworm taxa are capable of regeneration as well. In this paper, we present the regeneration capacity of Macrostomum lignano, a representative of the Macrostomorpha, the basal-most taxon of rhabditophoran flatworms and one of the most basal extant bilaterian protostomes. Amputated or incised transversally, obliquely, and longitudinally at various cutting levels, M. lignano is able to regenerate the anterior-most body part (the rostrum) and any part posterior of the pharynx, but cannot regenerate a head. Repeated regeneration was observed for 29 successive amputations over a period of almost 12 months. Besides adults, also first-day hatchlings and older juveniles were shown to regenerate after transversal cutting. The minimum number of cells required for regeneration in adults (with a total of 25,000 cells) is 4,000, including 160 neoblasts. In hatchlings only 1,500 cells, including 50 neoblasts, are needed for regeneration. The life span of untreated M. lignano was determined to be about 10 months

Functional Characterization of the Frost Gene in Drosophila melanogaster: Importance for Recovery from Chill Coma

BACKGROUND: Almost all animals, including insects, need to adapt to temperature fluctuations. The molecular basis of thermal adaptation is not well understood, although a number of candidate genes have been proposed. However, a functional link between candidate genes and thermal tolerance has rarely been established. The gene Frost (Fst) was first discovered when Drosophila flies were exposed to cold stress, but the biological function(s) of Fst has so far not been characterized. Because Fst is up-regulated after a cold stress, we tested whether it was essential for chill-coma recovery. METHODOLOGY/PRINCIPAL FINDINGS: A marked increase in Fst expression was detected (by RT-PCR) during recovery from cold stress, peaking at 42-fold after 2 h. The GAL4/UAS system was used to knock down expression of Fst and recovery ability was assessed in transgenic adults following 12 h of chill coma at 0 degrees C. The ability to recover from cold stress (short-, medium- and long-term) was significantly altered in the transgenic adults that had Fst silenced. These findings show that Fst plays an essential role in the recovery from chill coma in both males and females. CONCLUSIONS/SIGNIFICANCE: The Frost gene is essential for cold tolerance in Drosophila melanogaster and may play an important role in thermal adaptation

The TNF-α antagonist etanerceptreverses age-related decreases in colonic SERT expression and faecal output in mice

Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. A lack of understanding about the causes of this condition has hampered the development of effective treatments. 5-HT is an important pro-kinetic agent in the colon. We examined whether alterations in colonic 5-HT signalling underlie age–related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24- month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg-1). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to “anti-TNFα” drugs as potential treatments for age-related chronic constipation

Lifespan extension without fertility reduction following dietary addition of the autophagy activator Torin1 in Drosophila melanogaster

Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan. Ideally, such manipulations should be specific and minimise off-target effects, and it is important to discover additional methods for ‘clean’ lifespan manipulation. Here we report an initial study into the effect of up-regulating autophagy on lifespan and fertility in Drosophila melanogaster by dietary addition of Torin1. Activation of autophagy using this selective TOR inhibitor was associated with significantly increased lifespan in both sexes. Torin1 induced a dose-dependent increase in lifespan in once-mated females. There was no evidence of a trade-off between longevity and fecundity or fertility. Torin1-fed females exhibited significantly elevated fecundity, but also elevated egg infertility, resulting in no net change in overall fertility. This supports the idea that lifespan can be extended without trade-offs in fertility and suggest that Torin1 may be a useful tool with which to pursue anti-ageing research

Dietary Restriction Depends on Nutrient Composition to Extend Chronological Lifespan in Budding Yeast Saccharomyces cerevisiae

10.1371/journal.pone.0064448PLoS ONE85

Nos embates com a morte, os médicos não estão sozinhos

Diferentes pesquisas já identificaram dificuldades, entre médicos, de lidar com o morrer humano, mas tais dificuldades estariam associadas a formas mais amplas e coletivas de lidar com o tema. O presente estudo buscou explorar tal perspectiva investigando grupos fora do âmbito dos profissionais da saúde. Dois grupos, cariocas e mineiros, foram entrevistados sobre suas visões e atitudes em relação ao tema morte. Todos na faixa etária 50-60 anos, com nível superior de escolaridade e padrão socioeconômico e cultural semelhantes e sem atuação em áreas relacionadas à saúde. A pesquisa foi de natureza exploratória e a metodologia de análise foi a do discurso do sujeito coletivo - (DSC) que se baseia na teoria da representação social. Os resultados sugeriram diferenças locais e de gênero. Os mineiros incluíram laços familiares e de amizade como elementos da qualidade de vida. Entre as mulheres (cariocas e mineiras) houve referências frequentes a elementos familiares como pai, mãe, avó e tia. No conjunto, cariocas e mineiros expressaram um padrão geral: preferem não pensar na morte, escolhem pensar na qualidade de vida para envelhecer bem. Ainda que o falar sobre a velhice traga relevantes reflexões, a dificuldade do falar sobre a morte revelou-se também nesse deslocamento. Se os médicos se veem hoje tateando caminhos para lidar com os limites da biomedicina, também os investigados encontram-se envolvidos com o uso de tais recursos no enfrentamento da morte. Uns e outros estão às voltas com as angústias que o tema favorece.Different works have identified doctors' difficulty in dealing with human death, but such difficulties would be associated with broader and more collective forms of handling this theme. This research aimed at exploring this perspective and investigated professionals who were not in the health area. Two groups, from the Brazilian States of Rio de Janeiro and Minas Gerais, were interviewed on their views and attitudes concerning the theme. All the interviewees were aged between 50 and 60 years, had similar socioeconomic, cultural and educational background (university degree) and none of them had worked in the health field. The research had an exploratory nature and used the Collective Subject Discourse - CSD, which is based on the theory of social representation, for the methodological analysis. The results indicated both local and gender differences. The group from Minas Gerais included family and friendship ties as elements of quality of life. Among women (from both States) there were frequent references to family elements such as father, mother, grandmother and aunt. On the whole, both groups expressed a general pattern: they prefer not to think about death, and they would rather think about quality of life in order to age well. Even though talking about aging brings in relevant reflections, the difficulty in talking about death was also revealed in this displacement. Both doctors and the investigated professionals are facing the anguish that is favored by the theme

A Functional Misexpression Screen Uncovers a Role for Enabled in Progressive Neurodegeneration

Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings