Synthesis of the Fully Protected Phosphoramidite of the Benzene-DNA Adduct,N 2-(4-Hydroxyphenyl)-2′-Deoxyguanosine and Incorporation of the Later into DNA Oligomers

N²- (4-Hydroxyphenyl)-2 ′-deoxyguanosine-5 ′-O-DMT-3 ′-phosphoramidite has been synthesized and used to incorporate the N²-(4-hydroxyphenyl)-2 ′-dG (N²-4-HOPh-dG) into DNA, using solid-state synthesis technology. The key step to obtaining the xenonucleoside is a palladium (Xantphos-chelated) catalyzed N²-arylation (Buchwald-Hartwig reaction) of a fully protected 2 ′-deoxyguanosine derivative by 4-isobutyryloxybromobenzene. The reaction proceeded in good yield and the adduct was converted to the required 5 ′-O-DMT-3 ′-O-phosphoramidite by standard methods. The latter was used to synthesize oligodeoxynucleotides in which the N²-4-HOPh-dG adduct was incorporated site-specifically. The oligomers were purified by reverse-phase HPLC. Enzymatic hydrolysis and HPLC analysis confirmed the presence of this adduct in the oligomers.     

Causation and the Origin of Life. Metabolism or Replication First?

The conceptual gulf that separates the 'metabolism first' and 'replication first' mechanisms for the emergence of life continues to cloud the origin of life debate. In the present paper we analyze this aspect of the origin of life problem and offer arguments in favor of the 'replication first' school. Utilizing Wicken's two-tier approach to causation we argue that a causal connection between replication and metabolism can only be demonstrated if replication would have preceded metabolism. In conjunction with existing empirical evidence and theoretical reasoning, our analysis concludes that there is no substantive evidence for a 'metabolism first' mechanism for life's emergence, while a coherent case can be made for the 'replication first' group of mechanisms. The analysis reaffirms our conviction that life is an extreme expression of kinetic control, and that the emergence of metabolic pathways can be understood by considering life as a manifestation of 'replicative chemistry'.     

Changes in the aquatic flora along a stretch of the river Umeälven,N. Sweden,following hydro-electric exploitation

An attempt to use floristic analysis to monitor the vegetational changes along a stretch of the river Umeälven, N. Sweden, following hydro-electric works is described. The aquatic flora list includes 45 phanerogamic taxa, of which 39 were present in 1977. Changes in such ecological factors as e.g. frost action, silting, water flow and water-level amplitude were noted. So far, these have only affected the abundance and vertical distributions of some species; few have disappeared or immigrated. The method used is consifered to be insufficiently precise for establishing whether or not vegetational changes have occurred in such habitats.     

Mitochondrial Ageing and the Beneficial Role of α-Lipoic Acid

Oxidative damage has been implicated to be a major causative factor in the decline in physiological functions that occur during the ageing process. Mitochondria are known to be a rich source for the production of free radicals and, consequently, mitochondrial components are susceptible to lipid peroxidation (LPO) that decreases respiratory activity. In the present investigation, we have evaluated mitochondrial LPO, 8-oxo-dG, oxidized glutathione, reduced glutathione, ATP, lipoic acid, TCA cycle enzymes and electron transport chain (ETC) complex activities in the brain of young versus aged rats. In aged rats, the contents of LPO, oxidized glutathione and 8-oxo-dG were high whereas reduced glutathione, ATP, lipoic acid, TCA cycle enzymes and ETC complex activities were found to be low. Lipoic acid administration to aged rats reduced the levels of mitochondrial LPO, 8-oxo-dG and oxidized glutathione and enhanced reduced glutathione, ATP, lipoic acid and ETC complex activities. In young rats lipoic acid administration showed only minimal lowering the levels of LPO, 8-oxo-dG and oxidized glutathione and slight increase in the levels of reduced glutathione, ATP, lipoic acid, TCA cycle enzymes and ETC complex activities. These findings suggest that the dithiol, lipoic acid, provides protection against age-related oxidative damage in the mitochondria of aged rats.     

Rapamycin and Ageing: When,for How Long,and How Much?

正The mechanistic target of rapamycin(mTOR)is a nutrient and growth factor responsive kinase that modulates lifespan in species from yeast to mice(Johnson et al.,2013b).mTOR exists in two complexes within cells,mTOR complexⅠ(mTORC1)and mTOR complex 2(mTORC2)(Laplante and Sabatini,2012).Abundant evidence suggests that mTORC1is the primary mTOR complex involved in regulating longevity:mutations that reduce the     

Bioethics,Disability, and the Good Life: Remembering Christopher Newell, 1964–2008

The untimely passing of Reverend Canon Dr Christopher Newell, AM, came as a shock to many in the bioethics world. As well as an obituary, this article notes a number of important themes in his work, and provides a select bibliography. Christopher's major contribution to this field is that he was one of a handful of scholars who made disability not only an acceptable area of bioethics—indeed a vital, central, fertile area of enquiry. Crucially Christopher emphasised that where we do ethics is actually in everyday life—while we mourn his passing, his rich work and example will continue to inspire bioethical inquiry.     

Ageing and the regulation of protein synthesis: a balancing act?

Ageing in diverse species ranging from yeast to humans is associated with extensive changes in both general and specific protein synthesis. Accumulating evidence now indicates that these alterations are not simply a corollary of the ageing process but, rather, they have a causative role in senescent decline. Indeed, interfering with mRNA translation significantly influences longevity. Interestingly, the mechanisms that control mRNA translation interface with intricate, conserved signalling pathways and specific conditions that regulate ageing, such as the insulin-insulin growth factor 1 signalling pathway and caloric restriction. This emerging relationship reveals that protein synthesis is a novel determinant of ageing in diverse organisms such as yeast, worms, flies and mice and can thus be considered as a universal component of the ageing process.     

The Tipping of the Big Stone—And Life itself. Obesity,Moral Work and Responsive Selves Over Time

Why is “everything I know is the right thing to do a million miles removed from what I do in reality?” This question posed by Rita, my main interlocutor and friend in a fieldwork that started in 2001–2003 and was taken up again in 2014–2015, opens up an exploration of moral work and moral selves in the context of the obesity epidemic and weight loss processes. I address these questions through the notion of “moral laboratories” taking up Mattingly’s argument that moral cultivation over time cannot be disconnected from a notion of self. Mattingly has consistently argued for a biographical and narrative self, which is processual and created in community. Along these lines, and by recourse to the German philosopher Bernhard Waldenfels’ phenomenology, I will propose the notion of a responsive self. The responsive self highlights the eventness of ongoing experimentation against the odds and captures equally pathic and agentive dimensions of a self that both persists and is transformed over time.