New approaches to genetic therapies for cystic fibrosis

Gene therapy offers great promise for cystic fibrosis which has never been quite fulfilled due to the challenges of delivering sufficient amounts of the CFTR gene and expression persistence for a sufficient period of time in the lungs to have any effect. Initial trials explored both viral and non-viral vectors but failed to achieve a significant breakthrough. However, in recent years, new opportunities have emerged that exploit our increased knowledge and understanding of the biology of CF and the airway epithelium. New technologies include new viral and non-viral vector approaches to delivery, but also alternative nucleic acid technologies including oligonucleotides and siRNA approaches for gene silencing and gene splicing, described in this review, as presented at the 2019 annual European CF Society Basic Science meeting (Dubrovnik, Croatia). We also briefly discuss other emerging technologies including mRNA and CRISPR gene editing that are advancing rapidly. The future prospects for genetic therapies for CF are now diverse and more promising probably than any time since the discovery of the CF gene

Biotic and abiotic retention, recycling and remineralization of metals in the ocean

Trace metals shape both the biogeochemical functioning and biological structure of oceanic provinces. Trace metal biogeochemistry has primarily focused on modes of external supply of metals from aeolian, hydrothermal, sedimentary and other sources. However, metals also undergo internal transformations such as abiotic and biotic retention, recycling and remineralization. The role of these internal transformations in metal biogeochemical cycling is now coming into focus. First, the retention of metals by biota in the surface ocean for days, weeks or months depends on taxon-specific metal requirements of phytoplankton, and on their ultimate fate: that is, viral lysis, senescence, grazing and/or export to depth. Rapid recycling of metals in the surface ocean can extend seasonal productivity by maintaining higher levels of metal bioavailability compared to the influence of external metal input alone. As metal-containing organic particles are exported from the surface ocean, different metals exhibit distinct patterns of remineralization with depth. These patterns are mediated by a wide range of physicochemical and microbial processes such as the ability of particles to sorb metals, and are influenced by the mineral and organic characteristics of sinking particles. We conclude that internal metal transformations play an essential role in controlling metal bioavailability, phytoplankton distributions and the subsurface resupply of metals

The incidence of myocardial injury following post-operative Goal Directed Therapy.

BACKGROUND: Studies suggest that Goal Directed Therapy (GDT) results in improved outcome following major surgery. However, there is concern that pre-emptive use of inotropic therapy may lead to an increased incidence of myocardial ischaemia and infarction. METHODS: Post hoc analysis of data collected prospectively during a randomised controlled trial of the effects of post-operative GDT in high-risk general surgical patients. Serum troponin T concentrations were measured at baseline and on day 1 and day 2 following surgery. Continuous ECG monitoring was performed during the eight hour intervention period. Patients were followed up for predefined cardiac complications. A univariate analysis was performed to identify any associations between potential risk factors for myocardial injury and elevated troponin T concentrations. RESULTS: GDT was associated with fewer complications, and a reduced duration of hospital stay. Troponin T concentrations above 0.01 microg l-1 were identified in eight patients in the GDT group and six in the control group. Values increased above 0.05 microg l-1 in four patients in the GDT group and two patients in the control group. There were no overall differences in the incidence of elevated troponin T concentrations. The incidence of cardiovascular complications was also similar. None of the patients, in whom troponin T concentrations were elevated, developed ECG changes indicating myocardial ischaemia during the intervention period. The only factor to be associated with elevated troponin T concentrations following surgery was end-stage renal failure. CONCLUSION: The use of post-operative GDT does not result in an increased incidence of myocardial injury

Second law, entropy production, and reversibility in thermodynamics of information

We present a pedagogical review of the fundamental concepts in thermodynamics of information, by focusing on the second law of thermodynamics and the entropy production. Especially, we discuss the relationship among thermodynamic reversibility, logical reversibility, and heat emission in the context of the Landauer principle and clarify that these three concepts are fundamentally distinct to each other. We also discuss thermodynamics of measurement and feedback control by Maxwell's demon. We clarify that the demon and the second law are indeed consistent in the measurement and the feedback processes individually, by including the mutual information to the entropy production.Comment: 43 pages, 10 figures. As a chapter of: G. Snider et al. (eds.), "Energy Limits in Computation: A Review of Landauer's Principle, Theory and Experiments

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Single nucleotide polymorphisms and breast cancer: not yet a success story

Numerous studies have examined low penetrance susceptibility polymorphisms in candidate genes, with some reporting significant findings. However, for the most part these associations could not be replicated in subsequent studies, suggesting that the original observations were due to chance. The failure to identify meaningful common genetic variation in relation to breast cancer should give us pause for thought and make us reconsider our current research strategies. The most recent directions of pooling samples to increase statistical power and pursuing whole genome screens may overcome some obstacles while also creating new challenges. Future studies should perhaps also consider alternative designs such as using surrogate (preferably continuous) markers of breast cancer, focusing on high-risk populations, and defining pathologically distinct outcomes

The process evaluation of it\u27s your move!, an Australian adolescent community-based obesity prevention project

BackgroundEvidence on interventions for preventing unhealthy weight gain in adolescents is urgently needed. The aim of this paper is to describe the process evaluation for a three-year (2005-2008) project conducted in five secondary schools in the East Geelong/Bellarine region of Victoria, Australia. The project, \u27It\u27s Your Move!\u27 aimed to reduce unhealthy weight gain by promoting healthy eating patterns, regular physical activity, healthy body weight, and body size perception amongst youth; and improve the capacity of families, schools, and community organisations to sustain the promotion of healthy eating and physical activity in the region.MethodsThe project was supported by Deakin University (training and evaluation), a Reference Committee (strategic direction, budgetary approval and monitoring) and a Project Management Committee (project delivery). A workshop of students, teachers and other stakeholders formulated a 10-point action plan, which was then translated into strategies and initiatives specific to each school by the School Project Officers (staff members released from teaching duties one day per week) and trained Student Ambassadors. Baseline surveys informed intervention development. Process data were collected on all intervention activities and these were collated and enumerated, where possible, into a set of mutually exclusive tables to demonstrate the types of strategies and the dose, frequency and reach of intervention activities.ResultsThe action plan included three guiding objectives, four on nutrition, two on physical activity and one on body image. The process evaluation data showed that a mix of intervention strategies were implemented, including social marketing, one-off events, lunch time and curriculum programs, improvements in infrastructure, and healthy school food policies. The majority of the interventions were implemented in schools and focused on capacity building and healthy eating strategies as physical activity practices were seen by the teachers as already meeting students\u27 needs.ConclusionsWhile substantial health-promoting activities were conducted (especially related to healthy eating), there remain further opportunities for secondary schools to use a whole-of-school approach through the school curriculum, environment, policies and ethos to improve healthy eating, physical activity and healthy body perceptions in youth. To achieve this, significant, sustained leadership will be required within the education sector generally and within schools specifically.<br /

Single nucleotide polymorphisms and breast cancer: not yet a success story

Numerous studies have examined low penetrance susceptibility polymorphisms in candidate genes, with some reporting significant findings. However, for the most part these associations could not be replicated in subsequent studies, suggesting that the original observations were due to chance. The failure to identify meaningful common genetic variation in relation to breast cancer should give us pause for thought and make us reconsider our current research strategies. The most recent directions of pooling samples to increase statistical power and pursuing whole genome screens may overcome some obstacles while also creating new challenges. Future studies should perhaps also consider alternative designs such as using surrogate (preferably continuous) markers of breast cancer, focusing on high-risk populations, and defining pathologically distinct outcomes

The Evolution of Facultative Conformity Based on Similarity

Conformist social learning can have a pronounced impact on the cultural evolution of human societies, and it can shape both the genetic and cultural evolution of human social behavior more broadly. Conformist social learning is beneficial when the social learner and the demonstrators from whom she learns are similar in the sense that the same behavior is optimal for both. Otherwise, the social learner's optimum is likely to be rare among demonstrators, and conformity is costly. The trade-off between these two situations has figured prominently in the longstanding debate about the evolution of conformity, but the importance of the trade-off can depend critically on the flexibility of one's social learning strategy. We developed a gene-culture coevolutionary model that allows cognition to encode and process information about the similarity between naive learners and experienced demonstrators. Facultative social learning strategies that condition on perceived similarity evolve under certain circumstances. When this happens, facultative adjustments are often asymmetric. Asymmetric adjustments mean that the tendency to follow the majority when learners perceive demonstrators as similar is stronger than the tendency to follow the minority when learners perceive demonstrators as different. In an associated incentivized experiment, we found that social learners adjusted how they used social information based on perceived similarity, but adjustments were symmetric. The symmetry of adjustments completely eliminated the commonly assumed trade-off between cases in which learners and demonstrators share an optimum versus cases in which they do not. In a second experiment that maximized the potential for social learners to follow their preferred strategies, a few social learners exhibited an inclination to follow the majority. Most, however, did not respond systematically to social information. Additionally, in the complete absence of information about their similarity to demonstrators, social learners were unwilling to make assumptions about whether they shared an optimum with demonstrators. Instead, social learners simply ignored social information even though this was the only information available. Our results suggest that social cognition equips people to use conformity in a discriminating fashion that moderates the evolutionary trade-offs that would occur if conformist social learning was rigidly applied