Autonomous Changes Research Articles

Usefulness of heart rate recovery parameters to monitor cardiovascular adaptation in elite athletes: The impact of the type of sport.

The purpose of this study is to determine heart rate (HR) recovery after maximal test in elite athletes who compete in high dynamic, high static, and in mixed sport disciplines; to assess differences in HR recovery between these groups of athletes; and to measure the association of HR index (HRI) with heart adaptation variables to determine whether these values were correlated with the type of exercise. One hundred and ninety-four elite athletes were divided into three groups according to the predominant type of exercise performed: endurance (n = 40), strength-sprinter (n = 36), and ball-game players (n = 118). They performed maximal cardiopulmonary exercise testing on a treadmill and were subjected to echocardiography. The rate of decline (HR recovery) was calculated as the difference between maximum and recovery HRs (HRrec1 and HRrec3). The HRI was calculated as HRmax - 1-min post-exercise HR (HRrec1). The most significant correlation of HRI was with posterior wall diameter and left ventricular (LV) mass index (r = 0.43 and r = 0.51; p = 0.012 and p = 0.003, respectively). LV mass index [Beta (B) = 0.354, p = 0.001] was an independent predictor of HRI and HRrec1. HRI may be an effective tool for discrimination of physiological and "gray zone" LV hypertrophy, with area under the curve of 0.545 (95% CI = 0.421-0.669, p = 0.0432). HRI displayed a sensitivity of 50% and specificity of 52.2% at the optimal cut-off value of 23.5. HR recovery pattern, especially HRI, may offer a timely and efficient tool to identify athletes with autonomous nervous system adaptive changes.

Intraocular Pressure as an Indicator of the Level of Induced Anxiety in Basketball.

Our data demonstrate that intraocular pressure (IOP) is sensitive to anxiety manipulation in sport scenarios, specifically in a basketball free throw task. The present outcomes may be of special relevance because of its practical advantages for the objective control of athletes' anxiety levels. Athletes experience high levels of anxiety during sport competition, and IOP has demonstrated to reflect autonomous nervous system changes during mentally demanding situations. We tested whether different levels of induced anxiety during basketball free throw shooting alter IOP. We followed a repeated-measures design to test the effects of anxiety-induced manipulation during basketball free throw shooting on IOP, shooting performance, and perceived anxiety. Eighteen amateur basketball players performed three experimental sessions consisting of 100 free throws each. However, we gave three different instructions to participants regarding the score assigned to each free throw, allowing us to manipulate the level of induced anxiety (low, medium, and high). Confirming a successful anxiety manipulation, basketball players reported more perceived anxiety with higher levels of induced anxiety (P < .001, η = 0.37). Our data show that higher levels of induced anxiety provoke an acute IOP rise (P < .001, η = 0.44), with the low-, medium-, and high-anxiety-induced conditions promoting an average IOP rise of 0.21, 1.63, and 18.46%, respectively. Also, there was a linear IOP rise over time in the high-anxiety-induced condition (r = 0.82). Nevertheless, we found no effect of anxiety-induced manipulation on basketball free throw performance (P = .93). Intraocular pressure is sensitive to anxiety-induced manipulation during basketball free throw shooting, showing an increase in parallel with accumulated anxiety. Based on these findings, IOP may be considered a promising tool for the assessment of the level of anxiety in certain sport situations. Future studies are required to explore the generalizability of these results in other scenarios with different physical and mental demands.

Towards a more complete quantification of the global carbon cycle

Abstract. The main components of global carbon budget calculations are the emissions from burning fossil fuels, cement production, and net land-use change, partly balanced by ocean CO2 uptake and CO2 increase in the atmosphere. The difference between these terms is referred to as the residual sink, assumed to correspond to increasing carbon storage in the terrestrial biosphere through physiological plant responses to changing conditions (ΔBphys). It is often used to constrain carbon exchange in global earth-system models. More broadly, it guides expectations of autonomous changes in global carbon stocks in response to climatic changes, including increasing CO2, that may add to, or subtract from, anthropogenic CO2 emissions. However, a budget with only these terms omits some important additional fluxes that are needed to correctly infer ΔBphys. They are cement carbonation and fluxes into increasing pools of plastic, bitumen, harvested-wood products, and landfill deposition after disposal of these products, and carbon fluxes to the oceans via wind erosion and non-CO2 fluxes of the intermediate breakdown products of methane and other volatile organic compounds. While the global budget includes river transport of dissolved inorganic carbon, it omits river transport of dissolved and particulate organic carbon, and the deposition of carbon in inland water bodies. Each one of these terms is relatively small, but together they can constitute important additional fluxes that would significantly reduce the size of the inferred ΔBphys. We estimate here that inclusion of these fluxes would reduce ΔBphys from the currently reported 3.6 GtC yr−1 down to about 2.1 GtC yr−1 (excluding losses from land-use change). The implicit reduction in the size of ΔBphys has important implications for the inferred magnitude of current-day biospheric net carbon uptake and the consequent potential of future biospheric feedbacks to amplify or negate net anthropogenic CO2 emissions.

Rationalizing Systems Analysis for the Evaluation of Adaptation Strategies in Complex Human‐Water Systems

AbstractWater resources management is a nontrivial process requiring a holistic understanding of the factors driving the dynamics of human‐water systems. Policy‐induced or autonomous behavioral changes in human systems may affect water and land management, which may affect water systems and feedback to human systems, further impacting water and land management. Currently, hydro‐economic models lack the ability to describe such dynamics either because they do not account for the multifactor/multioutput nature of these systems and/or are not designed to operate at a river basin scale. This paper presents a flexible and replicable methodological framework for integrating a microeconomic multifactor/multioutput Positive Multi‐Attribute Utility Programming (PMAUP) model with an eco‐hydrologic model, the Soil and Water Assessment Tool (SWAT). The connection between the models occurs in a sequential modular approach through a common spatial unit, the “hydrologic‐economic representative units” (HERUs), derived from the boundaries of decision‐making entities and hydrologic responsive units. The resulting SWAT‐PMAUP model aims to provide the means for exploring the dynamics between the behavior of socio‐economic agents and their connection with the water system through water and land management. The integrated model is illustrated by simulating the impacts of irrigation restriction policies on the Río Mundo subbasin in south‐eastern Spain. The results suggest that agents' adaptation strategies in response to the irrigation restrictions have broad economic impacts and subsequent consequences on surface and groundwater hydrology. We suggest that the integrated modeling framework can be a valuable tool to support decision‐making in water resources management across a wide range of scales.

Impact of aging on bone, marrow and their interactions.

Hematopoiesis in land dwelling vertebrates and marine mammals occurs within the bone marrow, continually providing mature progeny over the course of an organism's lifetime. This conserved dependency highlights the critical relationship between these two organs, yet the skeletal and hematopoietic systems are often thought of as separate. In fact, data are beginning to show that skeletal disease pathogenesis influences hematopoiesis and viceversa, offering novel opportunities to approach disease affecting bone and blood. With a growing global population of aged individuals, interest has focused on cell autonomous changes in hematopoietic and skeletal systems that result in dysfunction. The purpose of this review is to summarize the literature on aging effects in both fields, and provide critical examples of organ cross-talk in the aging process.

Preparation of Molecular Stimuli-Responsive Gel Valves That Regulate Microchannels Autonomously

Diagnosis sensors using micro-total analysis systems (m-TAS) have been developed for detecting target biomolecules such as proteins and saccharides because they are signal biomolecules for monitoring body conditions and diseases. Valve systems that regulate the flow of a sample solution in the microchannels are the most important elements in fabricating m-TAS as diagnostic chips. Standard m-TAS uses electromechanical elements fabricated by MEMS technologies. As such electromechanical elements are based on complicated systems, advantages of m-TAS such as simplicity and miniaturization are lost. We have prepared biomolecularly stimuli-responsive hydrogels using biomolecular complexes as dynamic crosslinks that reversibly form or dissociate according to changes in an external environment. For example, biomolecularly stimuli-responsive hydrogels with antigen-antibody complexes or glycopolymer-lectin complexes swelled gradually in response to the concentration of a target biomolecule such as an antigen and glucose. Biomolecularly stimuli-responsive hydrogels that exhibited unique shrinkage in the presence of a target biomolecule were strategically designed by molecular imprinting. Their biomolecularly stimuli-responsive swelling and shrinkage were based on drastic changes in the crosslinking density of the hydrogel networks, induced by the dissociation and formation of biomolecular complexes as dynamic crosslinks in the presence of a target biomolecule. In this study, three types of micron-sized molecular stimuli-responsive hydrogels, bisphenol A (BPA)-, glucose- and concanavalin A (ConA)-responsive micro-hydrogels, were prepared by photopolymerization in a microchannel. We investigated the flow rate of the microchannels with their responsive micro-hydrogels in the absence and presence of the target molecule. ConA-responsive micro-hydrogels were prepared by molecular imprinting as follows. First, glycosyloxyethyl methacrylate as a ligand monomer and ConA as a molecular template were mixed for forming a molecular complex. Acrylamide as a main monomer, N, N’-methylenbisacrylamide as a crosslinker, and 2, 2'-azobis(2-methylpropionamidine) dihydrochloride as a photoinitiator were dissolved in a phosphate buffer solution. The solution was exposed to UV light focused using an inverted fluorescence microscope to polymerize the monomers. A ConA-imprinted micro-hydrogel was prepared near the branch point of the Y-shaped microchannel. To evaluated the ConA-imprinted micro-hydrogel as a self-regulated valve for a microchannel flow control system, the flow rates of the channels were measured while a buffer solution without and with target ConA was pumped into the Y-shape microchannel. After flowing a buffer solution with ConA, the ConA-imprinted micro-hydrogel in the channel shrank in response to ConA, followed by an increase in the flow rate. These results suggest that the ConA-imprinted micro-hydrogel is useful as a self-regulated micro-hydrogel valve for fabricating smart microchannels which can autonomously change the flow rate in response to the target ConA. ConA-responsive micro-hydrogels leads to the fabrication of smart microchannels in which micro-hydrogel valves can open and close autonomously and sensitively. In addition, BPA-responsive and glucose-responsive micro-hyrogels were prepared in a microchannel by photopolymerization using an inverted fluorescence microscope. This paper also demonstrates the autonomous changes in the flow rate in the microchannel with their micro-hydrogels as molecularly stimuli-responsive valves.

PO-403 The tumour suppressor P53 as a guardian of immune tolerance and suppression

IntroductionPancreatic cancer is one of the poorest understood cancers with a<5% chance of survival after 5 years of diagnosis. Cell autonomous changes in signalling pathways that promote cancer cell proliferation, growth and survival are being successfully targeted by novel cancer therapies that show efficacy, yet generally fail to provide a durable clinical response. The complexity of the tumour/stromal interaction is key to understanding how cancer cells survive and the interplay between cancer cells and the immune system provides another level of complexity. Cancer cells have escaped immunological checkpoints either through promoting immunosuppressing lineages or supressing anti-tumorigenic mechanisms. Genetically engineered mouse models (GEMM) can recapitulate some aspects of human cancers and allow for the study of tumor-stromal interactions in vivo. A model of pancreatic ductal adenocarcinoma (PDAC) was generated using a Cre-recombinase system with the following combinations KRasG12D;p53+/+ or KRasG12D;p53f/f. Using a technique of tumour rejection, we demonstrate a role for p53 in PDAC cells in modulating the immune response.Material and methodsIn vivo studies were done using PDAC cell lines derived from GEMMs with ectopic expression of iRFP. FVB or CD1nu/nu mice were injected subcutaneously with PDAC lines and subcutaneous growth was measured using the Licor Pearl Imager. Immunophenotyping was performed using flow cytometry (i.e. intracellular cytokine staining and surface staining) and acquired on the BD Symphony Fortessa. In vitro studies were conducted on the PDAC cell lines, bone marrow derived macrophages (BMDM) and primary T cells.Results and discussionsGenetic ablation of p53 in PDAC cells provided immunological advantage and delayed tumour rejection. Immunophenotyping results demonstrated a suppression of Th1-like responses in vivo as well as changes in myeloid populations. In vitro studies provided evidence of alterations in macrophage priming and consequential changes in T cell polarisation. Recent studies have demonstrated roles for oncogenes, such as c-Myc and KRas in influencing anti-tumourgenic responses, which supports our data of p53-dependent changes.ConclusionOver the last 50 years immunoediting of the tumour has been shown to be a powerful mechanism of a tumour selection. Loss and mutation of p53 occurs quite frequently in human cancers and understanding the underlying immunological mechanisms of escape in the context of p53 is crucial in developing immunotherapies.

Abstract SY37-03: Mitochondrial genetic contributions to metastatic efficiency

Abstract Complex phenotypes, like tumorigenicity or metastasis, require coordinated expression of multiple genes. Additionally, the contributions of some of those genes can be affected by polymorphisms in the protein coding or regulatory sequences (PMID: 22257951). The pathobiology of metastasis remains poorly understood because both intrinsic (i.e., genetic) and extrinsic (i.e., tumor-microenvironment interactions) are involved. A growing body of data indicates demonstrate that there are underlying genetic components that govern the processes involved in cancer spread and colonization. To assess the contributions of mitochondrial genetics in metastasis, we created Mitochondrial Nuclear Exchange (MNX) mice by transferring an oocyte nucleus from strainx into an enucleated oocyte from strainy, and showed that mammary tumor formation and metastasis are regulated by inherited mitochondrial polymorphisms in an oncogenic driver-dependent manner (PMID: 26471915; PMID: 29070615). Since stromal compartments also possess changed mitochondria in the MNX mice, we hypothesized that mitochondrial polymorphisms in non-cancer cell compartments could exert effects on tumor formation and/or metastasis in addition to genetic (cell autonomous) changes. Syngeneic tumor cells were injected into MNX mice with the same nuclear, and therefore same MHC, background. Experimental metastasis was compared between wild-type and MNX mice (i.e., with same or different mtDNA backgrounds, respectively). E0771 mammary carcinoma and B16-F10 melanoma cells (both syngeneic to C57BL/6J), formed significantly (P&amp;lt;0.01) more lung metastases in C57BL/6J-mtMNX(C3H/HeN). K1735-M2 melanoma cells (syngeneic to C3H/HeN) formed significantly (P&amp;lt;0.05) fewer lung metastases in C3H/HeNmtMNXC57BL/6J. These results have been replicated ≥3 times using &amp;gt;10 mice per experiment. C57BL/6J mitochondria confer resistance to metastasis in both cell autonomous and non-cell autonomous experiments. Basal metabolic and ROS differences comparing mouse embryonic fibroblasts isolated from wild-type and MNX mice are among mechanisms being explored. Differential gene expression occurred in tissues isolated from wild-type and MNX mice (PMID: 28663334). Additionally, altered immune and microbiota profiles have been observed. Together, our findings highlight striking influences that mitochondrial haplotypes can exert on tumorigenicity and metastasis via both intrinsic and extrinsic mechanisms. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res. and CA168524. Citation Format: Danny R. Welch. Mitochondrial genetic contributions to metastatic efficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY37-03.

Distribution Matters: The Reverse Robin-Hood Macroeconomic Effects

This paper examines income distribution’s impact on aggregate demand. Income distribution is introduced by replacing consumption as a function of aggregate income with consumption as the sum of two consumptions: a high income group’s and low income group’s. Notably the high income group’s MPC is assumed to be less than the lower income group’s. Analysis reveals two key results. As the high income group’s proportion of income rises: (1) aggregate demand falls and (2) autonomous spending changes cause smaller aggregate demand shifts. A reduced multiplier is the key. Empirical work supports the assumption that the high income group’s MPC is less than the low income group’s.

Key determinants of citrus fruit quality: Metabolites and main changes during maturation

Abstract Citrus is one of the main fruit crops in the world and widely recognized by their organoleptic, nutritional and health-related properties of both fresh fruit and juice. The genetic diversity among the genus and the autonomous and independent changes in peel and pulp, make the definition of standard maturity indexes of fruit quality difficult. Commercial maturity indexes in the citrus industry are usually based on peel coloration, percentage of juice, soluble solids/acidity ratio but their relevance may differ among varieties and the specific requirements of the markets. There is also a marked influence of environmental and agronomic conditions such as light and temperature, rootstock selection and plant nutrition, among others. Besides commercial requirements, a more comprehensive definition of fruit quality should also consider organoleptic and nutritional properties that are determined by a complex interaction among a number of bioactive components. Citrus fruit are an excellent source of many phytochemical, including ascorbic acid, carotenoids (antioxidant and pro-vitamin A), polyphenols, flavonoids, limonoids, terpenoids, etc., which greatly contribute to the health-related benefits of these fruits. Criteria and definition of the main maturity indexes for citrus fruit worldwide are described, as well as changes during fruit maturation in key components affecting organoleptic and nutritional properties. Moreover, the involvement of hormonal and nutritional signals and their interaction in the regulation of external and internal maturation of citrus fruit, as well as the influence of environmental and agronomic factors are also critically revised and discussed.

Aspects of the Belousov-Zhabotinsky Reaction inside a Self-Oscillating Polymer Brush.

We have developed a novel polymer brush surface exhibiting autonomous swelling-deswelling changes driven by the Belousov-Zhabotinsky (BZ) reaction, that is, the self-oscillating polymer brush. In this system, the ruthenium tris(2,2'-bipyridine) [Ru(bpy)3] catalyst-conjugated polymer chains are densely packed on the solid substrate. It is expected that the BZ reaction in the polymer brush would be influenced by the immobilization effect of the catalyst. To clarify the effect of the immobilization of the catalyst on the self-oscillating polymer brush, the self-oscillating behavior of the polymer brush was investigated by comparing it with that of other self-oscillating polymer materials, the free polymer, and the gel particle under various initial substrate concentrations. The initial substrate dependency of the oscillating period for the polymer brush was found to be different from those for the free polymer and the gel particle. Furthermore, the oscillatory waveform was analyzed on the basis of the Field-Körös-Noyes model. These investigations revealed that the dense immobilization of the self-oscillating polymer on the surface restricted accessibility for the Ru(bpy)3 moiety. These findings would be helpful in understanding the reaction-diffusion mechanism in the polymer brush, which is a novel reaction medium for the BZ reaction.

Global mapping of transcription factor motifs in human aging.

Biological aging is a complex process dependent on the interplay of cell autonomous and tissue contextual changes which occur in response to cumulative molecular stress and manifest through adaptive transcriptional reprogramming. Here we describe a transcription factor (TF) meta-analysis of gene expression datasets accrued from 18 tissue sites collected at different biological ages and from 7 different in-vitro aging models. In-vitro aging platforms included replicative senescence and an energy restriction model in quiescence (ERiQ), in which ATP was transiently reduced. TF motifs in promoter regions of trimmed sets of target genes were scanned using JASPAR and TRANSFAC. TF signatures established a global mapping of agglomerating motifs with distinct clusters when ranked hierarchically. Remarkably, the ERiQ profile was shared with the majority of in-vivo aged tissues. Fitting motifs in a minimalistic protein-protein network allowed to probe for connectivity to distinct stress sensors. The DNA damage sensors ATM and ATR linked to the subnetwork associated with senescence. By contrast, the energy sensors PTEN and AMPK connected to the nodes in the ERiQ subnetwork. These data suggest that metabolic dysfunction may be linked to transcriptional patterns characteristic of many aged tissues and distinct from cumulative DNA damage associated with senescence.

Childcare Practitioners’ Experiences with an Evaluation Approach Based on Appreciative Inquiry (AI) for Autonomous Changes

Childcare Practitioners’ Experiences with an Evaluation Approach Based on Appreciative Inquiry (AI) for Autonomous Changes

An autonomous shading system based on coupled wood bilayer elements

Climate Adaptive Building Shells can help to reach the aimed and required global reduction of energy consumption in the building sector. By being implemented as, e.g., façade shading systems, their adaptability to environmental changes can improve energy efficiency and indoor comfort of buildings. Autonomous, humidity-driven wood bilayers are proposed as an alternative to motor-driven façade shading elements. Due the hygro-responsiveness of the wood material, the changes of relative humidity during day and night as well as the drying effect of direct solar radiation can be utilized for inducing cyclic programmed shape changes of wood bilayers for aperture opening and closing of such adaptive façade shading systems. The kinetics of such autonomous shape changes of wood bilayers have been analyzed at small scale, but the application-relevant upscaling remains a challenge. So far, the proposed solutions do not allow maintaining a sufficiently high rate of shape change and the required mechanical stability of the wood bilayers at the same time. Here, we present the coupling of two wood bilayers as one possible solution for the implementation as shading elements. By coupling, the rate of aperture opening and closing can be amplified without increasing the (limited) rate of shape change of the single wood bilayers. The coupling and the resulting combination of shape change and rotation are characterized for five different typologies of lever arm configuration. Based on first studies with bilayer strips, an upscaling in width is conducted and its implementation for a humidity-driven shading system is presented by means of a demonstrator.

Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog

A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Both loss-of-function and gain-of-function mechanisms have been proposed to underlie this disease, but the pathogenic pathways are not fully understood. To better understand the involvement of different cell types in the pathogenesis of ALS, we systematically analyzed the distribution of promoter activity of the mouse ortholog of C9orf72 in the central nervous system. We demonstrate that C9orf72 promoter activity is widespread in both excitatory and inhibitory neurons as well as in oligodendrocytes and oligodendrocyte precursor cells. In contrast, few microglia and astrocytes exhibit detectable C9orf72 promoter activity. Although at a gross level, the distribution of C9orf72 promoter activity largely follows overall cellular density, we found that it is selectively enriched in subsets of neurons and glial cells that degenerate in ALS. Specifically, we show that C9orf72 promoter activity is enriched in corticospinal and spinal motor neurons as well as in oligodendrocytes in brain regions that are affected in ALS. These results suggest that cell autonomous changes in both neurons and glia may contribute to C9orf72-mediated disease, as has been shown for mutations in superoxide dismutase-1 (SOD1).

Inhibition of NAMPT decreases cell growth and enhances susceptibility to oxidative stress.

Nicotinamide adenine dinucleotide (NAD) is an essential molecule for living organisms and plays a vital role in aging and age-associated diseases. In eukaryotic cells, cellular NAD is mainly generated by the scavenge pathway in which nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the formation of nicotinamide mononucleotide. Inhibition of NAMPT is a therapeutic strategy for cancer treatment. To explore the effects of NAMPT inhibition on cellular processes, cells were treated with 10nM FK866, an NAMPT inhibitor, resulting in a decrease in the cellular NAD level, a lower growth rate, and enhanced susceptivity to oxidative stress as compared to the untreated cells. Quantitative proteomics revealed that 325proteins were downregulated in the FK866-treated cells, and were involved in diverse cellular processes including nucleobase-containing compound metabolic process, protein metabolic process, antioxidant and DNA repair processes. Downregulation of 4 selected proteins was confirmed by western blotting and quantitative PCR. Downregulation of antioxidant proteins GRX1 and catalase, and DNA-repair proteins PCNA and PARP1 contributed to the enhanced susceptibility of FK866-treated cells to oxidative stress. FK866 treatment also caused mitochondrial dysfunction through downregulation of mitochondrial ribosomal proteins. Taken together, these results demonstrate that FK866 treatment efficiently decreases the cellular NAD level and induces autonomous changes in proteostasis, leading to cell growth inhibition and increased susceptibility to oxidative stress.

What patients really think about asthma guidelines: barriers to guideline implementation from the patients\u2019 perspective

BackgroundTreatment of asthma does not always comply with asthma guidelines (AG). This may be rooted in direct or indirect resistance on the doctors’ and/or patients’ side or be caused by the healthcare system. To assess whether patients’ concepts and attitudes are really an implementation barrier for AG, we analysed the patients’ perspective of a “good asthma therapy” and contrasted their wishes with current recommendations.MethodsUsing a qualitative exploratory design, topic centred focus group (FG) discussions were performed until theoretical saturation was reached. Inclusion criteria were an asthma diagnosis and age above 18. FG sessions were recorded audio-visually and analysed via a mapping technique and content analysis performed according to Mayring (supported by MAXQDA®). Participants’ speech times and the proportion of time devoted to different themes were calculated using the Videograph System® and related to the content analysis.ResultsThirteen men and 24 women aged between 20 and 77 from rural and urban areas attended five FG. Some patients had been recently diagnosed with asthma, others years previously or in childhood. The following topics were addressed: (a) concern about or rejection of therapy components, particularly corticosteroids, which sometimes resulted in autonomous uncommunicated medication changes, (b) lack of time or money for optimal treatment, (c) insufficient involvement in therapy choices and (d) a desire for greater empowerment, (e) suboptimal communication between healthcare professionals and (f) difficulties with recommendations conflicting with daily life. Primarily, (g) participants wanted more time with doctors to discuss difficulties and (h) all aspects of living with an impairing condition.ConclusionsWe identified some important patient driven barriers to implementing AG recommendations. In order to advance AG implementation and improve asthma treatment, the patients’ perspective needs to be considered before drafting new versions of AG. These issues should be addressed at the planning stage.Trial registrationDRKS00000562 (German Clinical Trials Registry).

Abstract B15: Defining functional PDAC-suppressive mechanisms of the acinar differentiation factor PTF1A

Abstract The primary goal of this study is to define the cell-intrinsic and cell-extrinsic mechanisms that lead to PDAC initiation in the absence of the acinar differentiation determinant PTF1A. PDAC development is a dynamic process that involves both alterations within the pancreatic epithelium and crosstalk with immune cells. Our lab and others have demonstrated that PanINs and PDAC arise through KRASG12D-mediated dedifferentiation and transformation of mature acinar cells, despite the cancer’s duct-like phenotype. Acinar-to-PanIN transformation, while typically inefficient, is greatly accelerated by caerulein-induced pancreatitis, highlighting the synergy between cell-intrinsic alterations, such as KRAS mutation, and cell-extrinsic influences, including inflammation. Recently, we identified another cell-intrinsic change that greatly hastens PanIN development: loss of acinar cell identity, via downregulation or deletion of the master acinar transcription factor, PTF1A. Since loss of differentiation has consequences both within the acinar cell and on the surrounding microenvironment, we want to understand what cell-autonomous and non-cell autonomous changes drive PDAC initiation following Ptf1a deletion. In this study we address two major questions: first, does SOX9 mediate acinar-to-ductal reprogramming (ADR) within acinar cells following Ptf1a deletion? And second, does Ptf1a deletion alter immune cell infiltration to influence tumorigenesis? Deletion of Ptf1a alone causes ADR and robust upregulation of the lineage-restricted ductal transcription factor SOX9. As previous studies have shown a requirement for the Sox9 gene in PanIN formation, we hypothesized that SOX9 is required to reprogram acinar cells to a tumor-susceptible state upon loss of PTF1A. In order to test this hypothesis, we have generated inducible, acinar specific, Ptf1a/Sox9 double knock-out mice. We are currently using these mice to determine the regulatory relationship between these key transcription factors in ADR and PanIN development, and we will present our preliminary findings at this meeting. Our recently published work additionally suggests that deletion of Ptf1a leads to numerous changes outside of the acinar cells themselves, including upregulation of fibro-inflammatory pathways associated with PDAC. These data suggest that acinar-intrinsic changes influence the stromal microenvironment, and lead us to hypothesize that acinar cell differentiation is a critical determinant of how Kras-mutant cells activate and respond to the immune system during tumor initiation. To begin to test this hypothesis, we characterized the immune cell infiltrate in pancreata from KrasG12D mice in which tumor initiation was stimulated either by caerulein-induced pancreatitis (KRAS/caerulein mice) or Ptf1a deletion (KRAS/cKO mice). While pancreata of both groups had abundant macrophage infiltration, we found that T-cell infiltration was more pronounced in KRAS/cKO mice than KRAS/caerulein mice. These data suggest that dedifferentiation has a non-cell-autonomous effect on the response of the immune system to Kras-mutant precancerous cells. We next wanted to test whether dedifferentiation changed the response of the precancerous microenvironment to anti-inflammatory agents such as dexamethasone (DEX), which has been previously shown to inhibit PanIN formation. Consistent with previous results, we found that DEX alleviated PanIN formation and preserved histologically normal acinar tissue in KRAS/caerulein mice, which retain wild-type PTF1A. Paradoxically, however, DEX treatment enhanced PanIN formation in KRAS/cKO mice, indicating that PTF1A-mediated differentiation pathways are required for the anti-tumor effects of this commonly-used drug. In ongoing studies, we will use these genetic and pharmacological tools to determine what inflammatory cells and signals are required for ADR and subsequent PanIN initiation. Citation Format: Nathan M. Krah, Shuba M. Narayanan, Deanne E. Yugawa, L Charles Murtaugh.{Authors}. Defining functional PDAC-suppressive mechanisms of the acinar differentiation factor PTF1A. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B15.

Seizures Start without Common Signatures of Critical Transition.

Complex dynamical systems may exhibit sudden autonomous changes from one state to another. Such changes that occur rapidly in comparison to the regular dynamics have been termed critical transitions. Examples of such phenomena can be found in many complex systems: changes in climate and ocean circulation, changes in wildlife populations, financial crashes, as well as in medical conditions like asthma attacks and depression. It has been recognized that critical transitions, even if they arise in completely different contexts and situations, share several common attributes and also generic early-warning signals that indicate that a critical transition is approaching. In the present study, we review briefly the general characteristics that have been observed in systems prior to critical transitions and apply these general indicators to nearly 300 epileptic seizures collected from human subjects using invasive EEG. Only in about 8% of the patients was evidence of critical transitions found. In the remaining majority of cases no early warning signals that behaved consistently prior to seizures were observed. These results do not rule out the possibility of critical transitions to seizure but point to limited relevance of their early warning signals in the context of human epilepsy observed using intracranial EEG recordings.

Observations and analytical modeling of freshwater and rainwater lenses in coastal dune systems

Observations are reported on (i) groundwater recharge rates under various types of vegetation as measured with megalysimeters in the dunes, (ii) freshwater lenses along the Dutch North Sea coast in the early 1900s, and (iii) rainwater lenses that develop on top of laterally migrating, artificially recharged riverwater. Subsequently analytical methods are presented to estimate annual natural groundwater recharge as function of rainfall and vegetation, and to calculate the size, shape and transition zone of freshwater lenses on saline groundwater and rainwater lenses on infiltrated riverwater. An empirical correction factor, based on the hydraulic resistance of an aquitard within the freshwater lens, is proposed to account for the frequently observed reduction of the Ghyben-Herzberg ratio of 40. This factor raises the groundwater table, reduces the depth of the fresh/salt interface and increases the lens formation time. The suite of methods offers a tool box for knowledge based water management of dune systems, by rapidly predicting: (i) more or less autonomous changes due to sealevel rise, climate change and vegetation development; and (ii) the potential (side) effects of interventions. Knowing what happened or will happen to the fresh water lens or a rainwater lens is important, because changes impact on important natural habitat parameters such as salinity, depth to groundwater table, decalcification rate (and thus on pH, Ca/Al, PO4, NH4) and nutrient availability, and on drinking water supply. The analytical models are applied to predict effects of sealevel rise, coastal progradation, vegetation changes, and increased temperature of coastal air and river water to be infiltrated.