Aging and Immortality in a Cell Proliferation Model

We investigate a model of cell division in which the length of telomeres within the cell regulate their proliferative potential. At each cell division the ends of linear chromosomes change and a cell becomes senescent when one or more of its telomeres become shorter than a critical length. In addition to this systematic shortening, exchange of telomere DNA between the two daughter cells can occur at each cell division. We map this telomere dynamics onto a biased branching diffusion process with an absorbing boundary condition whenever any telomere reaches the critical length. As the relative effects of telomere shortening and cell division are varied, there is a phase transition between finite lifetime and infinite proliferation of the cell population. Using simple first-passage ideas, we quantify the nature of this transition.Comment: 6 pages, 1 figure, 2-column revtex4 format; version 2: final published form; contains various improvements in response to referee comment

The Heumann-Hotzel model for aging revisited

Since its proposition in 1995, the Heumann-Hotzel model has remained as an obscure model of biological aging. The main arguments used against it were its apparent inability to describe populations with many age intervals and its failure to prevent a population extinction when only deleterious mutations are present. We find that with a simple and minor change in the model these difficulties can be surmounted. Our numerical simulations show a plethora of interesting features: the catastrophic senescence, the Gompertz law and that postponing the reproduction increases the survival probability, as has already been experimentally confirmed for the Drosophila fly.Comment: 11 pages, 5 figures, to be published in Phys. Rev.

Time evolution of the Partridge-Barton Model

The time evolution of the Partridge-Barton model in the presence of the pleiotropic constraint and deleterious somatic mutations is exactly solved for arbitrary fecundity in the context of a matricial formalism. Analytical expressions for the time dependence of the mean survival probabilities are derived. Using the fact that the asymptotic behavior for large time $t$ is controlled by the largest matrix eigenvalue, we obtain the steady state values for the mean survival probabilities and the Malthusian growth exponent. The mean age of the population exhibits a $t^{-1}$ power law decayment. Some Monte Carlo simulations were also performed and they corroborated our theoretical results.Comment: 10 pages, Latex, 1 postscript figure, published in Phys. Rev. E 61, 5664 (2000

Exact Solution of an Evolutionary Model without Ageing

We introduce an age-structured asexual population model containing all the relevant features of evolutionary ageing theories. Beneficial as well as deleterious mutations, heredity and arbitrary fecundity are present and managed by natural selection. An exact solution without ageing is found. We show that fertility is associated with generalized forms of the Fibonacci sequence, while mutations and natural selection are merged into an integral equation which is solved by Fourier series. Average survival probabilities and Malthusian growth exponents are calculated indicating that the system may exhibit mutational meltdown. The relevance of the model in the context of fissile reproduction groups as many protozoa and coelenterates is discussed.Comment: LaTeX file, 15 pages, 2 ps figures, to appear in Phys. Rev.

Deepening democracy within Ireland's social partnership

Ireland's social partnership process, now under attack from a number of quarters, has repeatedly been charged with being 'undemocratic' in that it undermines the sovereign position of elected political representatives, with key policy formulation and decision-making taking place in fora outside the institutions of representative democracy. These critiques echo those against new forms of networked governance more globally. A key question therefore is how (and if) democracy may be deepened within social partnership or its potential successor(s). This article addresses this question by employing a post-liberal democratic framework to examine social partnership in practice, and by drawing lessons from another partnership process, Malawi's PRSP. Drawing from Malawi's experience, it is argued that democracy can be deepened within social partnership when governance deliberations and negotiations are conducted under conditions of vibrant public debate and genuine perspective-based representation, and when the communicative and discursive norms are widened to allow for such representation

A Gradualist Approach to Criminality: Early British Socialists, Utopia and Crime

The attitudes of early British socialists to criminality are a thoroughly under-researched area of historical scholarship. This paper draws on the utopian ideas of Robert Owen, William Morris, H. G. Wells, Robert Blatchford, Edward Carpenter and Ramsay MacDonald as a vehicle for investigating the attitudes of mainstream fin de siècle British socialists to crime, punishment and penal reform. Placing these figures and their utopias along a spectrum that sees radical ‘Arcadian’ socialists on the far left, ‘technological’ socialists on the far right, and moderate socialists occupying the middle ground, it presents two principal findings. First it demonstrates how crime was predicted by most of the left to decrease to a minimum level under socialism. ‘Arcadians’, ‘technological’ and moderate socialists invoked different methods in this pursuit, but each were in essence grappling with the same broader issue of the relationship of the individual to the state under socialism. Secondly, examining the multifaceted ideological heritage of the British left in relation to their approaches to crime, it is argued that, despite the left’s gradualist philosophy, their own attitudes to criminality actually closely reflected utopian conceptions. Examination of these issues offers an important opportunity to re-evaluate the evolution of British socialist thought

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Longitudinal Multi-Omics Study of a Mother-Infant Dyad from Breastfeeding to Weaning: An Individualized Approach to Understand the Interactions Among Diet, Fecal Metabolome and Microbiota Composition

The development of the human gut microbiota is characterized by a dynamic sequence of events from birth to adulthood, which make the gut microbiota unique for everyone. Its composition and metabolism may play a critical role in the intestinal homeostasis and health. We propose a study on a single mother-infant dyad to follow the dynamics of an infant fecal microbiota and metabolome changes in relation to breast milk composition during the lactation period and evaluate the changes induced by introduction of complementary food during the weaning period. Nuclear Magnetic Resonance (NMR)-based metabolomics was performed on breast milk and, together with 16S RNA targeted-metagenomics analysis, also on infant stool samples of a mother-infant dyad collected over a period running from the exclusive breastfeeding diet to weaning. Breast milk samples and neonatal stool samples were collected from the 4th to the 10th month of life. Both specimens were collected from day 103 to day 175, while from day 219–268 only stool samples were examined. An exploratory and a predictive analysis were carried out by means of Common component and specific weight analysis and multi-block partial least squares discriminant analysis, respectively. Stools collected during breastfeeding and during a mixed fruit/breastfeeding diet were characterized by high levels of fucosyl-oligosaccharides and glycolysis intermediates, including succinate and formate. The transition to a semi-solid food diet was characterized by several changes in fecal parameters: increase in short-chain fatty acids (SCFAs) levels, including acetate, propionate and butyrate, dissapearance of HMOs and the shift in the community composition, mainly occurring within the Firmicutes phylum. The variations in the fecal metabolome reflected the infant’s diet transition, while the composition of the microbiota followed a more complex and still unstable behavior

Immunomodulation of inflammatory leukocyte markers during intravenous immunoglobulin treatment associated with clinical efficacy in chronic inflammatory demyelinating polyradiculoneuropathy

© 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Objective: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy. Methods: Response to IVIg treatment in newly diagnosed IVIg-naïve and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response. Results: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185 + follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16 + myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16 + dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response. Conclusions: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome

Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps

<p>Abstract</p> <p>Background</p> <p>Adjusting medication for uncontrolled asthma involves selecting one of several options from the same or a higher treatment step outlined in asthma guidelines. We examined the relative benefit of introducing budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (Symbicort SMART^®Turbuhaler^®) in patients previously prescribed treatments from Global Initiative for Asthma (GINA) Steps 2, 3 or 4.</p> <p>Methods</p> <p>This is a <it>post hoc </it>analysis of the results of five large clinical trials (>12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined.</p> <p>Results</p> <p>At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) (plus short-acting β₂-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps.</p> <p>Conclusions</p> <p>BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.</p