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Flow or collective movement is a frequently observed phenomenon for many cellular components including the cytoskeletal proteins actin and myosin. To study protein flow in living cells, we and others have previously used spatiotemporal image correlation spectroscopy (STICS) analysis on fluorescence microscopy image time series. Yet, in cells, multiple protein flows often occur simultaneously on different scales resulting in superimposed fluorescence intensity fluctuations that are challenging to separate using STICS. Here, we exploited the characteristic that distinct protein flows often occur at different spatial scales present in the image series to disentangle superimposed protein flow dynamics. We employed a newly developed and an established spatial filtering algorithm to alternatively accentuate or attenuate local image intensity heterogeneity across different spatial scales. Subsequently, we analysed the spatially filtered time series with STICS, allowing the quantification of two distinct superimposed flows within the image time series. As a proof of principle of our analysis approach, we used simulated fluorescence intensity fluctuations as well as time series of nonmuscle myosin II in endothelial cells and actin-based podosomes in dendritic cells and revealed simultaneously occurring contiguous and noncontiguous flow dynamics in each of these systems. Altogether, this work extends the application of STICS for the quantification of multiple protein flow dynamics in complex biological systems including the actomyosin cytoskeleton.

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The Fallopian tube epithelium harbors the origin cells for the majority of high-grade serous ovarian carcinomas (HGSCs), the most lethal form of gynecologic malignancies. PAX8 belongs to the paired-box gene family of transcription factors and it is a marker of the FTE secretory cell lineage. Its role has been investigated in migration, invasion, proliferation, cell survival, stem cell maintenance, angiogenesis and tumor growth. In this review, we focus on the pro-tumorigenic role of PAX8 in ovarian cancer; in this context, PAX8 possibly continues to exert its transcriptional activity on its physiological targets but may also function on newly available targets after the tumorigenic hits. Acquiring new insights into the different PAX8 mechanism(s) of action in the tumor microenvironment could uncover new viable therapeutic targets and thus improve the current treatment regimen.

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Intercropping of two or more species on the same piece of land can enhance biodiversity and resource use efficiency in agriculture. Traditionally, intercropping systems have been developed and improved by empirical methods within a specific local context. To support the development of promising intercropping systems, the individual species that are part of an intercrop can be subjected to breeding. Breeding for intercropping aims at resource foraging traits of the admixed species to maximize niche complementarity, niche facilitation, and intercrop performance. The breeding process can be facilitated by modeling tools that simulate the outcome of the combination of different species' (or genotypes') traits for growth and yield development, reducing the need of extensive field testing. Here, we revisit the challenges associated with breeding for intercropping, and give an outlook on applying crop growth models to assist breeding for intercropping. We conclude that crop growth models can assist breeding for intercropping, provided that (i) they incorporate the relevant plant features and mechanisms driving interspecific plant-plant interactions; (ii) they are based on model parameters that are closely linked to the traits that breeders would select for; and (iii) model calibration and validation is done with field data measured in intercrops. Minimalist crop growth models are more likely to incorporate the above elements than comprehensive but parameter-intensive crop growth models. Their lower complexity and reduced parameter requirement facilitate the exploration of mechanisms at play and fulfil the model requirements for calibration of the appropriate crop growth models.

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Background: The collagen architecture in high grade serous ovarian cancer (HGSOC) is highly remodeled compared to the normal ovary and the fallopian tubes (FT). We previously used Second Harmonic Generation (SHG) microscopy and machine learning to classify the changes in collagen fiber morphology occurring in serous tubal intraepithelial carcinoma (STIC) lesions that are concurrent with HGSOC. We now extend these studies to examine collagen remodeling in pure p53 signatures, STICs and normal regions in tissues that have no concurrent HGSOC. This is an important distinction as high-grade disease can result in distant collagen changes through a field effect mechanism. Methods: We trained a linear discriminant model based on SHG texture and image features as a classifier to discriminate the tissue groups. We additionally performed mass spectrometry analysis of normal and HGSOC tissues to associate the differential expression of collagen isoforms with collagen fiber morphology alterations. Results: We quantified the differences in the collagen architecture between normal tissue and the precursors with good classification accuracy. Through proteomic analysis, we identified the downregulation of single α-chains including those for Col I and III, where these results are consistent with our previous SHG-based supramolecular analyses. Conclusion: This work provides new insights into ECM remodeling in early ovarian cancer and suggests the combined use of SHG microscopy and mass spectrometry as a new diagnostic/prognostic approach.

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Improved assessment and prediction of soil organic nitrogen (SON) mineralization is essential, as it contributes significantly to the nitrogen (N) nutrition of crops and remains a major economic and environmental challenge. SON mineralization is a function of soil properties, land use and climate, which led us to monitor a network of 137 cultivated fields covering the wide diversity of soils, crop rotations and cropping practices throughout Brittany (France). SON mineralization was quantified by the mineral N balance calculated for a maize crop not fertilized with N; it was determined by measuring soil mineral N (SMN) in the 0-90 cm soil profile in March (Ni) and October (Nf) and N uptake by the maize crop, and predicting nitrate leaching (Nleached) using the STICS model. SMN and plant N uptake were measured in triplicate. To predict Nleached, STICS was initialized at the date of Ni measurement. In addition, the experimental design was based on estimating SON for three consecutive years (2012-2014) to improve the accuracy of measuring mineralization. An indicator of the cropping system (I_Sys) was developed that integrated well the effects of crop rotation and the frequency of manure application; it can be considered a good index of effects of the cropping system on SON mineralization. This dataset may be used for a variety of applications, such as analysing effects of soil properties, cropping history and climatic conditions on SON mineralization, or evaluating the accuracy of soil-plant models (e.g. STICS, CERES).

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Many studies have assessed the potential of agricultural practices to sequester carbon (C). A comprehensive evaluation of impacts of agricultural practices requires not only considering C storage but also direct and indirect emissions of greenhouse gases (GHG) and their side effects (e.g., on the water cycle or agricultural production). We used a high-resolution modeling approach with the Simulateur mulTIdisciplinaire pour les Cultures Standard soil-crop model to quantify soil organic C (SOC) storage potential, GHG balance, biomass production and nitrogen- and water-related impacts for all arable land in France for current cropping systems (baseline scenario) and three mitigation scenarios: (i) spatial and temporal expansion of cover crops, (ii) spatial insertion and temporal extension of temporary grasslands (two sub-scenarios) and (iii) improved recycling of organic resources as fertilizer. In the baseline scenario, SOC decreased slightly over 30 years in crop-only rotations but increased significantly in crop/temporary grassland rotations. Results highlighted a strong trade-off between the storage rate per unit area (kg C ha-1  year-1 ) of mitigation scenarios and the areas to which they could be applied. As a result, while the most promising scenario at the field scale was the insertion of temporary grassland (+466 kg C ha-1  year-1 stored to a depth of 0.3 m compared to the baseline, on 0.68 Mha), at the national scale, it was by far the expansion of cover crops (+131 kg C ha-1  year-1 , on 17.62 Mha). Side effects on crop production, water irrigation and nitrogen emissions varied greatly depending on the scenario and production situation. At the national scale, combining the three mitigation scenarios could mitigate GHG emissions of current cropping systems by 54% (-11.2 from the current 20.5 Mt CO2 e year-1 ), but the remaining emissions would still lie far from the objective of C-neutral agriculture.

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Although organic cropping systems are promoted for their environmental benefits, little is known about their long-term impact on nitrogen (N) fate in the soil-plant-atmosphere system. In this paper, we analyze two long-term experiments: DOK in Switzerland (39-yr) and Foulum organic in Denmark (19-yr). Four treatments were considered in each experiment: two conventional treatments with (CONFYM) or without manure (CONMIN), organic with manure (BIOORG) and unfertilized treatment (NOFERT) at DOK; conventional (CGL-CC+IF) and three organic treatments, one with cover crops only (OGL+CC-M) and two including cover crops and grass-clover with (OGC+CC+M) or without manure (OGC+CC-M), at Foulum. STICS model was used to simulate crop production, N surplus, nitrate leaching, gaseous N losses and changes in soil organic N. It was calibrated in the conventional treatments and tested in organic systems. The crop production, N surplus and soil organic N stocks were satisfactorily predicted. The mean N surplus greatly differed between treatments at DOK, from -58 (NOFERT) to +21 kg N ha-1 yr-1 (CONFYM), but only from -9 (OGL+CC-M) to +21 kg N ha-1 yr-1 (OGC+CC+M) in Foulum. Soil N pools declined continuously in both sites and treatments at a rate varying from -18 to -78 kg N ha-1 yr-1, depending on fertilization and crop rotation. The decline was consistent with the observed N surpluses. Although not all simulations could be tested against field observations and despite of prediction uncertainties, simulations confirm the hypothesis that environmental performances resulting from C and N cycles depend more on specificities of individual than nominal treatments. Significant correlations appeared between long-term N surplus and soil N storage and between total N fertilization and total N gaseous losses. Results showed in both experiments that arable organic systems do not systematically have lower N surplus and N losses than conventional ones, providing opportunity for increasing N use efficiency of these systems.

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LINE-1 (L1) retrotransposons are mobile genetic elements capable of "copy-and-pasting" their own sequences into random genomic loci, and one of the proteins it uses to achieve mobility is LINE-1 open reading frame 1 protein (L1ORF1p). L1ORF1p expression is found across many epithelial cancers, including small cohorts of ovarian and endometrial cancers, and is highly expressed in cancers with mutant p53 expressions. Here we aimed to gain insights into L1ORF1p expression levels within specific histotypes of ovarian cancers: high-grade serous (n = 585), low-grade serous (n = 26), clear cell (n = 132), endometrioid (n = 148), and mucinous (n = 32) ovarian cancers, as well as endometrial cancers (n = 607) using tissue microarray (TMA's). We demonstrated that L1ORF1p expression is associated with advanced stage and serous histotype in gynecological cancers. Like previous studies, we found a higher proportion of L1ORF1p expression in cases with aberrant p53 expression. We evaluated the expression of L1ORF1p in serous tubal intraepithelial carcinomas (STICs) (n = 6) and p53 signature lesions (n = 2) in fallopian tubes. Three STIC cases displayed aberrant p53 overexpression with corresponding L1ORF1p expression in the same tissues, but such correlation was not seen in the two p53 signature lesions, suggesting that L1 protein may be expressed after dysplastic transformation. The remaining three STIC cases have TP53 nonsense mutations with absent p53 expression but a strong and clear L1ORF1p expression within the STIC lesions. While L1ORF1p may not be prognostic in gynecological cancers, it may be useful clinically as a diagnostic IHC marker for p53 null STIC lesions and this warrants further investigation.

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The urethra is a muscular tube that extends from the bladder neck and is composed of an inner layer of smooth muscle referred to as the internal urethral sphincter and an outer layer of striated muscle which forms the external urethral sphincter. The smooth muscle layer can be separated into an inner layer of longitudinally orientated smooth muscle and an outer, relatively thinner, layer of circular muscle. Tonic contraction of both the smooth and striated muscle components of the urethra generates a urethral closure pressure which exceeds intravesical pressure in the bladder to maintain urinary continence. It is likely that contraction of urethral smooth muscle is involved in the long-term maintenance of tone, since it can achieve this at relatively low energy cost, whereas the striated muscle contributes more to the rise in urethral tone that accompanies increases in bladder pressure secondary to coughing or other sudden increases in intra-abdominal pressure. The level of urethral smooth muscle tone is regulated by several autonomic neurotransmitters, including noradrenaline, acetylcholine, ATP and nitric oxide. However, it is also clear that urethral smooth muscle is capable of generating significant tone in the absence of neural input. In this chapter we will discuss the mechanisms responsible for contraction of urethral smooth muscle, with specific focus on the role of ion channels and Ca2+ handling proteins to this process. The mechanisms underlying spontaneous activity in urethral interstitial cells (UICs), putative pacemaker cells of the urethra, will also be examined along with the modulation of these mechanisms by key excitatory and inhibitory neurotransmitters.

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The corpus cavernosum smooth muscle is important for both erection of the penis and for maintaining penile flaccidity. Most of the time, the smooth muscle cells are in a contracted state, which limits filling of the corpus sinuses with blood. Occasionally, however, they relax in a co-ordinated manner, allowing filling to occur. This results in an erection. When contractions of the corpus cavernosum are measured, it can be deduced that the muscle cells work together in a syncytium, for not only do they spontaneously contract in a co-ordinated manner, but they also synchronously relax. It is challenging to understand how they achieve this.In this review we will attempt to explain the activity of the corpus cavernosum, firstly by summarising current knowledge regarding the role of ion channels and how they influence tone, and secondly by presenting data on the intracellular Ca2+ signals that interact with the ion channels. We propose that spontaneous Ca2+ waves act as a primary event, driving transient depolarisation by activating Ca2+-activated Cl- channels. Depolarisation then facilitates Ca2+ influx via L-type voltage-dependent Ca2+ channels. We propose that the spontaneous Ca2+ oscillations depend on Ca2+ release from both ryanodine- and inositol trisphosphate (IP3)-sensitive stores and that modulation by signalling molecules is achieved mainly by interactions with the IP3-sensitive mechanism. This pacemaker mechanism is inhibited by nitric oxide (acting through cyclic GMP) and enhanced by noradrenaline. By understanding these mechanisms better, it might be possible to design new treatments for erectile dysfunction.

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In this study, we analyzed the patterns of relationships between multiple ecosystem services in apple orchards by considering the cascade that links agricultural practices to ecosystem functions and then to ecosystem services. Five major ecosystem services were considered: fruit production, soil nitrogen availability, climate regulation, water cycle maintenance and regulation, including water quality, and pest and disease control. We derived indicators of ecosystem functions and of ecosystem services from model simulations of orchards driven by virtual cropping systems combining various modalities of nitrogen fertilization, irrigation, and pest control. We deciphered the links between practices and ecosystem functions and between those functions and ecosystem services and clustered cropping systems according to their ecosystem service supply. Noticeable synergies were found between yield, fruit mass and sequestrated carbon. The contribution of carbon allocation to fruit in sequestrated carbon was considerable. Nitrogen absorption, impacted by fertilization and irrigation, was a major driver of these relationships. The typology built from these virtual cropping systems clearly followed a gradient of provisioning and regulating ecosystem services. Five cropping systems optimized the compromise between provisioning and regulating services and were essentially characterized by organo-mineral fertilization, comfort irrigation, apple scab-resistant cultivars and exclusion nets against codling moth. Our approach could contribute to the design of cropping systems that would provide an acceptable compromise between multiple ecosystem services in orchards.

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Cover crops provide ecosystem services such as storing atmospheric carbon in soils after incorporation of their residues. Cover crops also influence soil water balance, which can be an issue in temperate climates with dry summers as for example in southern France and Europe. As a consequence, it is necessary to understand cover crops' long-term influence on greenhouse gases (GHG) and water balances to assess their potential to mitigate climate change in arable cropping systems. We used the previously calibrated and validated soil-crop model STICS to simulate scenarios of cover crop introduction to assess their influence on rainfed and irrigated cropping systems and crop rotations distributed among five contrasted sites in southern France from 2007 to 2052. Our results showed that cover crops can improve mean direct GHG balance by 315 kg CO2 e ha-1  year-1 in the long term compared to that of bare soil. This was due mainly to an increase in carbon storage in the soil despite a slight increase in N2 O emissions which can be compensated by adapting fertilization. Cover crops also influence the water balance by reducing mean annual drainage by 20 mm/year but increasing mean annual evapotranspiration by 20 mm/year compared to those of bare soil. Using cover crops to improve the GHG balance may help to mitigate climate change by decreasing CO2 e emitted in cropping systems which can represent a decrease from 4.5% to 9% of annual GHG emissions of the French agriculture and forestry sector. However, if not well managed, they also could create water management issues in watersheds with shallow groundwater. Relationships between cover crop biomass and its influence on several variables such as drainage, carbon sequestration, and GHG emissions could be used to extend our results to other conditions to assess the cover crops' influence in a wider range of areas.

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OBJECTIVE: Many high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications. METHODS: We distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (χ2) tests for categorical variables. Free text comments were qualitatively reviewed. RESULTS: Survey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p < 0.05). In specimens from surgery for benign indications in which initial microscopic sections showed an unanticipated suspicious finding, 75.9% of laboratories reported using SEE-Fim to process the remainder of the specimen (94.8% academic versus 76.4% non-academic, p < 0.01), and 84.6% submitted the entire fimbriae. CONCLUSIONS: Changes in the theories of pathogenesis of high-grade serous carcinoma have led to implementation of pathology specimen processing protocols that include detailed analysis of the fallopian tubes. These results have implications for interpreting trends in cancer incidence data and considering the feasibility of developing a bank of gynecologic tissues containing STIC or early cancer precursors.

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The EU directive has addressed ambitious targets concerning the quality of water bodies. Predicting water quality as affected by land use and management requires using dynamic agro-hydrogeological models. In this study, an agronomic model (STICS) and a hydrogeological model (MODCOU) have been associated in order to simulate nitrogen fluxes in the Seine-Normandie Basin, which is affected by nitrate pollution of groundwater due to intensive farming systems. This modeling platform was used to predict and understand the spatial and temporal evolution of water quality over the 1971-2013 period. A quality assurance protocol (Refsgaard et al. Environ Model Softw 20: 1201-1215, 2005) was used to qualify the reliability of STICS outputs. Four iterative runs of the model were carried out with improved parameterization of soils and crop management without any change in the model. Improving model inputs changed much more the spatial distribution of simulated N losses than their mean values. STICS slightly underestimated the crop yields compared to the observed values at the administrative district scale. The platform also slightly underestimated the nitrate concentration at the outlet level with a mean difference ranging from -1.4 to -9.2 mg NO3 L-1 according to the aquifer during the last decade. This outcome should help the stakeholders in decision-making to prevent nitrate pollution and provide new specifications for STICS development.

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The current challenge in sustainable agriculture is to introduce new cropping systems to reduce pesticides use in order to reduce ground and surface water contamination. However, it is difficult to carry out in situ experiments to assess the environmental impacts of pesticide use for all possible combinations of climate, crop, and soils; therefore, in silico tools are necessary. The objective of this work was to assess pesticides leaching in cropping systems coupling the performances of a crop model (STICS) and of a pesticide fate model (MACRO). STICS-MACRO has the advantage of being able to simulate pesticides fate in complex cropping systems and to consider some agricultural practices such as fertilization, mulch, or crop residues management, which cannot be accounted for with MACRO. The performance of STICS-MACRO was tested, without calibration, from measurements done in two French experimental sites with contrasted soil and climate properties. The prediction of water percolation and pesticides concentrations with STICS-MACRO was satisfactory, but it varied with the pedoclimatic context. The performance of STICS-MACRO was shown to be similar or better than that of MACRO. The improvement of the simulation of crop growth allowed better estimate of crop transpiration therefore of water balance. It also allowed better estimate of pesticide interception by the crop which was found to be crucial for the prediction of pesticides concentrations in water. STICS-MACRO is a new promising tool to improve the assessment of the environmental risks of pesticides used in cropping systems.

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STICS-MACRO is a process-based model simulating the fate of pesticides in the soil-plant system as a function of agricultural practices and pedoclimatic conditions. The objective of this work was to evaluate the influence of crop management practices on water and pesticide flows in contrasted environmental conditions. We used the Morris screening sensitivity analysis method to identify the most influential cropping practices. Crop residues management and tillage practices were shown to have strong effects on water percolation and pesticide leaching. In particular, the amount of organic residues added to soil was found to be the most influential input. The presence of a mulch could increase soil water content so water percolation and pesticide leaching. Conventional tillage was also found to decrease pesticide leaching, compared to no-till, which is consistent with many field observations. The effects of the soil, crop and climate conditions tested in this work were less important than those of cropping practices. STICS-MACRO allows an ex ante evaluation of cropping systems and agricultural practices, and of the related pesticides environmental impacts.

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Viticulture is a key socio-economic sector in Europe. Owing to the strong sensitivity of grapevines to atmospheric factors, climate change may represent an important challenge for this sector. This study analyses viticultural suitability, yield, phenology, and water and nitrogen stress indices in Europe, for present climates (1980-2005) and future (2041-2070) climate change scenarios (RCP4.5 and 8.5). The STICS crop model is coupled with climate, soil and terrain databases, also taking into account CO2 physiological effects, and simulations are validated against observational data sets. A clear agreement between simulated and observed phenology, leaf area index, yield and water and nitrogen stress indices, including the spatial differences throughout Europe, is shown. The projected changes highlight an extension of the climatic suitability for grapevines up to 55°N, which may represent the emergence of new winemaking regions. Despite strong regional heterogeneity, mean phenological timings (budburst, flowering, veraison and harvest) are projected to undergo significant advancements (e.g. budburst/harvest can be >1 month earlier), with implications also in the corresponding phenophase intervals. Enhanced dryness throughout Europe is also projected, with severe water stress over several regions in southern regions (e.g. southern Iberia and Italy), locally reducing yield and leaf area. Increased atmospheric CO2 partially offsets dryness effects, promoting yield and leaf area index increases in central/northern Europe. Future biomass changes may lead to modifications in nitrogen demands, with higher stress in northern/central Europe and weaker stress in southern Europe. These findings are critical decision support systems for stakeholders from the European winemaking sector.

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The study of cell-nanoparticle interactions is an important aspect for understanding drug delivery using nanocarriers. In this regard, advances in fluorescence based microscopy are useful for the investigation of temporal and spatial behavior of nanoparticles (NPs) within the intracellular environment. In this work, we focus on the delivery of the naturally-occurring hydrophobic photosensitizer Hypericin in human lung carcinoma A549 cells by using biodegradable poly L-lactic acid NPs. For the first time, Hypericin containing NPs are prepared by combining the miniemulsion technique with the solvent evaporation method. This approach yields an efficient loading of the NPs with Hypericin and allows for additional cargo molecules. To monitor the release of Hypercin from the NPs, an additional fluorescent lipophilic dye Coumarin-6 is incorporated in the NPs. Temporal and spatiotemporal image correlation spectroscopy is used to determine the fate of the NPs carrying the potential cargo. Both directed and non-directed motions are detected. By using image cross-correlation spectroscopy and specific fluorescent labeling of endosomes, lysosomes and mitochondria, the dynamics of the cargo loaded NPs in association with the organelles is studied.

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PVP-Hypericin (PVP: polyvinylpyrrolidone) is a potent anti-cancer photosensitizer for photodynamic diagnosis (PDD) and therapy (PDT). However, cellular targets and mechanisms involved in the cancer-selectivity of the photosensitizer are not yet fully understood. This paper gives new insights into the differential transport and localization of PVP-Hypericin in cancer and normal cells which are essential to unravel the mechanisms of action and cancer-selectivity. Temporal (TICS) and spatiotemporal (STICS) image correlation spectroscopy are used for the assessment of PVP-Hypericin diffusion and/or velocity in the case of concerted flow in human cervical epithelial HeLa and human lung carcinoma A549 cells, as well as in human primary dendritic cells (DC) and human peripheral blood mononuclear cells (PBMC). Spatiotemporal image cross-correlation spectroscopy (STICCS) based on organelle specific fluorescent labeling is employed to study the accumulation of the photosensitizer in nucleus, mitochondria, early-endosomes and lysosomes of the cells and to assess the dynamics of co-migrating molecules. Whereas STICS and TICS did not show a remarkable difference between the dynamics of PVP-Hypericin in HeLa, A549 and DC cells, a significantly different diffusion rate of the photosensitizer was measured in PBMC. STICCS detected a stationary accumulation of PVP-Hypericin within the nucleus, mitochondria, early endosomes and lysosomes of HeLa and A549 cells. However, significant flow due to the directed motion of the organelles was detected. In contrast, no accumulation in the nucleus and mitochondria of DC and PBMC could be monitored.

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In 2008, the National Heart, Lung, and Blood Institute announced its intent to support a new asthma network known as AsthmaNet. This clinical trials consortium, now in its fifth year, has been charged with developing and executing clinical trials to address the most important asthma management questions and identify new treatment approaches in pediatric and adult patients. This review will discuss the organization of AsthmaNet and the scientific context in which the network was developed and began its work, report the results of an internal priority-setting exercise designed to guide the network's scientific strategy, and highlight the portfolio of clinical trials, proof-of-concept studies, and mechanistic studies planned for the 7-year period of the network to update the global asthma community regarding the progress and processes of the network.

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