The [Het-s] Prion, an Amyloid Fold as a Cell Death Activation Trigger

International audienc

Information Dynamics in Living Systems: Prokaryotes, Eukaryotes, and Cancer

BACKGROUND: Living systems use information and energy to maintain stable entropy while far from thermodynamic equilibrium. The underlying first principles have not been established. FINDINGS: We propose that stable entropy in living systems, in the absence of thermodynamic equilibrium, requires an information extremum (maximum or minimum), which is invariant to first order perturbations. Proliferation and death represent key feedback mechanisms that promote stability even in a non-equilibrium state. A system moves to low or high information depending on its energy status, as the benefit of information in maintaining and increasing order is balanced against its energy cost. Prokaryotes, which lack specialized energy-producing organelles (mitochondria), are energy-limited and constrained to an information minimum. Acquisition of mitochondria is viewed as a critical evolutionary step that, by allowing eukaryotes to achieve a sufficiently high energy state, permitted a phase transition to an information maximum. This state, in contrast to the prokaryote minima, allowed evolution of complex, multicellular organisms. A special case is a malignant cell, which is modeled as a phase transition from a maximum to minimum information state. The minimum leads to a predicted power-law governing the in situ growth that is confirmed by studies measuring growth of small breast cancers. CONCLUSIONS: We find living systems achieve a stable entropic state by maintaining an extreme level of information. The evolutionary divergence of prokaryotes and eukaryotes resulted from acquisition of specialized energy organelles that allowed transition from information minima to maxima, respectively. Carcinogenesis represents a reverse transition: of an information maximum to minimum. The progressive information loss is evident in accumulating mutations, disordered morphology, and functional decline characteristics of human cancers. The findings suggest energy restriction is a critical first step that triggers the genetic mutations that drive somatic evolution of the malignant phenotype

Minimum follow-up time required for the estimation of statistical cure of cancer patients: verification using data from 42 cancer sites in the SEER database

BACKGROUND: The present commonly used five-year survival rates are not adequate to represent the statistical cure. In the present study, we established the minimum number of years required for follow-up to estimate statistical cure rate, by using a lognormal distribution of the survival time of those who died of their cancer. We introduced the term, threshold year, the follow-up time for patients dying from the specific cancer covers most of the survival data, leaving less than 2.25% uncovered. This is close enough to cure from that specific cancer. METHODS: Data from the Surveillance, Epidemiology and End Results (SEER) database were tested if the survival times of cancer patients who died of their disease followed the lognormal distribution using a minimum chi-square method. Patients diagnosed from 1973–1992 in the registries of Connecticut and Detroit were chosen so that a maximum of 27 years was allowed for follow-up to 1999. A total of 49 specific organ sites were tested. The parameters of those lognormal distributions were found for each cancer site. The cancer-specific survival rates at the threshold years were compared with the longest available Kaplan-Meier survival estimates. RESULTS: The characteristics of the cancer-specific survival times of cancer patients who died of their disease from 42 cancer sites out of 49 sites were verified to follow different lognormal distributions. The threshold years validated for statistical cure varied for different cancer sites, from 2.6 years for pancreas cancer to 25.2 years for cancer of salivary gland. At the threshold year, the statistical cure rates estimated for 40 cancer sites were found to match the actuarial long-term survival rates estimated by the Kaplan-Meier method within six percentage points. For two cancer sites: breast and thyroid, the threshold years were so long that the cancer-specific survival rates could yet not be obtained because the SEER data do not provide sufficiently long follow-up. CONCLUSION: The present study suggests a certain threshold year is required to wait before the statistical cure rate can be estimated for each cancer site. For some cancers, such as breast and thyroid, the 5- or 10-year survival rates inadequately reflect statistical cure rates, and highlight the need for long-term follow-up of these patients

Fitness Consequences of Advanced Ancestral Age over Three Generations in Humans

A rapid rise in age at parenthood in contemporary societies has increased interest in reports of higher prevalence of de novo mutations and health problems in individuals with older fathers, but the fitness consequences of such age effects over several generations remain untested. Here, we use extensive pedigree data on seven pre-industrial Finnish populations to show how the ages of ancestors for up to three generations are associated with fitness traits. Individuals whose fathers, grandfathers and great-grandfathers fathered their lineage on average under age 30 were ~13% more likely to survive to adulthood than those whose ancestors fathered their lineage at over 40 years. In addition, females had a lower probability of marriage if their male ancestors were older. These findings are consistent with an increase of the number of accumulated de novo mutations with male age, suggesting that deleterious mutations acquired from recent ancestors may be a substantial burden to fitness in humans. However, possible non-mutational explanations for the observed associations are also discussed

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

Association between actual weight status, perceived weight and depressive, anxious symptoms in Chinese adolescents: a cross-sectional study

<p>Abstract</p> <p>Backgroud</p> <p>The purpose of this study was to describe actual measured weight and perceived weight and to explore associations with depressive, anxiety symptoms in school adolescents in China.</p> <p>Methods</p> <p>A sample of 1144 Chinese adolescents was randomly selected from four schools in Wuhan, China, including 665 boys and 479 girls with ages ranging between 10 and 17 years. Actual measured weight and height and perceived weight status were compared to anxiety and depressive symptoms measured using the revised Self-Rating Anxiety Scale and Children's Depression Inventory. A general linear model was used to compare differences in psychological symptoms among the teenagers with different measured and perceived weights.</p> <p>Results</p> <p>When compared with standardized weight tables (WHO age- and gender-specific body mass index (BMI) cutoffs (2007 reference)), girls were more likely to misperceive themselves as overweight, whereas more boys misclassified their weight status as underweight. The adolescents who perceived themselves as overweight were more likely to experience depressive and anxiety symptoms (except girls) than those who perceived themselves as normal and/or underweight. However, no significant association was found between depressive and anxiety symptoms actual measured weight status.</p> <p>Conclusions</p> <p>Perceived weight status, but not the actual weight status, was associated with psychological symptoms.</p

Body weight dissatisfaction and communication with parents among adolescents in 24 countries: international cross-sectional survey

BACKGROUND: Parents have significant influence on behaviors and perceptions surrounding eating, body image and weight in adolescents. The aim of this study was to examine the prevalence of body weight dissatisfaction, difficulty in communication with the parents and the relationship between communication with parents and adolescents' dissatisfaction with their body weight (dieting or perceived need to diet). METHODS: Survey data were collected from adolescents in 24 countries and regions in Europe, Canada, and the USA who participated in the cross-sectional 2001/2002 Health Behaviour of School-Aged Children (HBSC) study. The association between communication with parents and body weight dissatisfaction was examined using binary logistic regression analysis. RESULTS: Body weight dissatisfaction was highly prevalent and more common among girls than boys, among overweight than non-overweight, and among older adolescents than younger adolescents. Difficulty in talking to father was more common than difficulty in talking to mother in all countries and it was greater among girls than among boys and increased with age. Difficulties in talking to father were associated with weight dissatisfaction among both boys and girls in most countries. Difficulties in talking to mother were rarely associated with body weight dissatisfaction among boys while among girls this association was found in most countries. CONCLUSION: The findings suggest that enhanced parent communication might contribute in most countries to less body dissatisfaction in girls and better communication with the father can help avoiding body weight dissatisfaction in boys. Professionals working with adolescents and their families should help adolescents to have a healthy weight and positive body image and promote effective parent – adolescent communication.peerReviewe

Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila

The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration

Advanced paternal age effects in neurodevelopmental disorders?review of potential underlying mechanisms

Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders

Monitoring the newly qualified nurses in Sweden: the Longitudinal Analysis of Nursing Education (LANE) study

BACKGROUND: The Longitudinal Analysis of Nursing Education (LANE) study was initiated in 2002, with the aim of longitudinally examining a wide variety of individual and work-related variables related to psychological and physical health, as well as rates of employee and occupational turnover, and professional development among nursing students in the process of becoming registered nurses and entering working life. The aim of this paper is to present the LANE study, to estimate representativeness and analyse response rates over time, and also to describe common career pathways and life transitions during the first years of working life. METHODS: Three Swedish national cohorts of nursing students on university degree programmes were recruited to constitute the cohorts. Of 6138 students who were eligible for participation, a total of 4316 consented to participate and responded at baseline (response rate 70%). The cohorts will be followed prospectively for at least three years of their working life. RESULTS: Sociodemographic data in the cohorts were found to be close to population data, as point estimates only differed by 0-3% from population values. Response rates were found to decline somewhat across time, and this decrease was present in all analysed subgroups. During the first year after graduation, nearly all participants had qualified as nurses and had later also held nursing positions. The most common reason for not working was due to maternity leave. About 10% of the cohorts who graduated in 2002 and 2004 intended to leave the profession one year after graduating, and among those who graduated in 2006 the figure was almost twice as high. Intention to leave the profession was more common among young nurses. In the cohort who graduated in 2002, nearly every fifth registered nurse continued to further higher educational training within the health professions. Moreover, in this cohort, about 2% of the participants had left the nursing profession five years after graduating. CONCLUSION: Both high response rates and professional retention imply a potential for a thorough analysis of professional practice and occupational health