Geometric Approach to Pontryagin's Maximum Principle

Since the second half of the 20th century, Pontryagin's Maximum Principle has been widely discussed and used as a method to solve optimal control problems in medicine, robotics, finance, engineering, astronomy. Here, we focus on the proof and on the understanding of this Principle, using as much geometric ideas and geometric tools as possible. This approach provides a better and clearer understanding of the Principle and, in particular, of the role of the abnormal extremals. These extremals are interesting because they do not depend on the cost function, but only on the control system. Moreover, they were discarded as solutions until the nineties, when examples of strict abnormal optimal curves were found. In order to give a detailed exposition of the proof, the paper is mostly self\textendash{}contained, which forces us to consider different areas in mathematics such as algebra, analysis, geometry.Comment: Final version. Minors changes have been made. 56 page

Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation

Terminally differentiated neutrophils are short-lived but the key effector cells of the innate immune response, and have a prominent role in the pathogenesis and propagation of many inflammatory diseases. Delayed apoptosis, which is responsible for their extended longevity, is critically dependent on a balance of intracellular survival versus pro-apoptotic proteins. Here, we elucidate the mechanism by which the cyclin-dependent kinase (CDK) inhibitor drugs such as R-roscovitine and DRB (5,6-dichloro-1-beta--ribofuranosylbenzimidazole) mediate neutrophil apoptosis. We demonstrate (by a combination of microarray, confocal microscopy, apoptosis assays and western blotting) that the phosphorylation of RNA polymerase II by CDKs 7 and 9 is inhibited by R-roscovitine and that specific effects on neutrophil transcriptional capacity are responsible for neutrophil apoptosis. Finally, we show that specific CDK7 and 9 inhibition with DRB drives resolution of neutrophil-dominant inflammation. Thus, we highlight a novel mechanism that controls both primary human neutrophil transcription and apoptosis that could be targeted by selective CDK inhibitor drugs to resolve established inflammation

Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field

Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

Abstract Background A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. Results We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16− monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers. Conclusions Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability

A randomised controlled phase II trial to examine the feasibility of using hyper-oxygenated fatty acids (HOFA) to prevent facial pressure injuries from medical devices among adults admitted to intensive care-A research protocol.

One in three patients admitted to intensive care will sustain a pressure injury (PI) from a medical device. These injuries are painful and when on the face, head or neck they can result in permanent disfigurement. Preliminary evidence of the efficacy of hyper-oxygenated fatty acids (HOFAs) to prevent facial pressure injuries from medical devices is promising; however, the feasibility of incorporating HOFAs into current standard care to prevent PI from a medical device of the face, head and neck has not been extensively explored. It is intended that the findings from this phase II feasibility study will inform the design of a larger phase III trial, by addressing two primary aims: (1) to assess the feasibility of incorporating HOFAs into standard care to prevent device-related pressure ulcers of the skin associated with the face, head and neck assess the feasibility and (2) efficacy preliminary effectiveness of HOFA. This feasibility study is an investigator-initiated mixed method study incorporating a multi-centre randomised controlled trial of using HOFAs as an adjunct to standard pressure injury prevention and care, compared with standard care alone to prevent facial, head or neck from medical devices among adults admitted to intensive care. The primary outcome of interest is the incidence of facial, head or neck pressure injuries during the first 14 days in intensive care. Secondary outcomes include PI staging, medical device exposure and intensive care and hospital outcomes. The primary analysis will be undertaken using Cox's Proportional Hazards model, and due to the exploratory nature of this phase II trial, efficacy will be based on a one-sided p-value for superiority set at 0.10. Type I and Type II error rates are set at 20%; therefore, a total sample size of 196 study participants is planned. To explore the feasibility of incorporating HOFA into usual care and to design a larger phase III trial, we will aim to interview between 10 and 20 nurses across participating intensive care unit sites. Pressure injuries of the face, head or neck from medical devices, among adults admitted to intensive care, are considered preventable. This phase II study will investigate the feasibility and efficacy of HOFAs as an adjunct to standard care. Importantly, we aim to inform the development of a larger phase III trial

Investigating the health implications of social policy initiatives at the local level: study design and methods

<p>Abstract</p> <p>Background</p> <p>In this paper we present the research design and methods of a study that seeks to capture local level responses to an Australian national social policy initiative, aimed at reducing inequalities in the social determinants of health.</p> <p>Methods/Design</p> <p>The study takes a policy-to-practice approach and combines policy and stakeholder interviewing with a comparative case study analysis of two not-for-profit organisations involved in the delivery of federal government policy.</p> <p>Discussion</p> <p>Before the health impacts of broad-scale policies, such as the one described in this study, can be assessed at the population level, we need to understand the implementation process. This is consistent with current thinking in political science and social policy, which has emphasised the importance of investigating how, and if, policies are translated into operational realities.</p

Gene expression patterns associated with blood-feeding in the malaria mosquito Anopheles gambiae

BACKGROUND: Blood feeding, or hematophagy, is a behavior exhibited by female mosquitoes required both for reproduction and for transmission of pathogens. We determined the expression patterns of 3,068 ESTs, representing ~2,000 unique gene transcripts using cDNA microarrays in adult female Anopheles gambiae at selected times during the first two days following blood ingestion, at 5 and 30 min during a 40 minute blood meal and at 0, 1, 3, 5, 12, 16, 24 and 48 hours after completion of the blood meal and compared their expression to transcript levels in mosquitoes with access only to a sugar solution. RESULTS: In blood-fed mosquitoes, 413 unique transcripts, approximately 25% of the total, were expressed at least two-fold above or below their levels in the sugar-fed mosquitoes, at one or more time points. These differentially expressed gene products were clustered using k-means clustering into Early Genes, Middle Genes, and Late Genes, containing 144, 130, and 139 unique transcripts, respectively. Several genes from each group were analyzed by quantitative real-time PCR in order to validate the microarray results. CONCLUSION: The expression patterns and annotation of the genes in these three groups (Early, Middle, and Late genes) are discussed in the context of female mosquitoes' physiological responses to blood feeding, including blood digestion, peritrophic matrix formation, egg development, and immunity