191 research outputs found
Targeting sphingosine kinase-1 with the low MW inhibitor SKI-5C suppresses the development of endometriotic lesions in mice
Background and Purpose
Limited evidence suggests that the sphingosine-1-phosphate/sphingosine kinase 1 (S1P/SPHK1) signalling pathway is involved in the pathogenesis of endometriosis. Therefore, we analyzed in this study whether the inhibition of SPHK1 and, consequently, decreased levels of S1P affected the vascularization and growth of endometriotic lesions.
Experimental Approach
Endometriotic lesions were surgically induced in the peritoneal cavity and the dorsal skinfold chamber of female BALB/c mice. The animals received a daily dose of the SPHK1 inhibitor SKI-5C or vehicle (control). Analyses involved the determination of lesion growth, cyst formation, microvessel density and cell proliferation within peritoneal endometriotic lesions by means of high-resolution ultrasound imaging, caliper measurement, histology and immunohistochemistry. In the dorsal skinfold chamber model the development of newly formed microvascular networks and their microhemodynamic parameters within endometriotic lesions were investigated by means of intravital fluorescence microscopy.
Key Results
SKI-5C significantly inhibited the development and vascularization of peritoneal endometriotic lesions, as indicated by a reduced growth and cyst formation, a lower microvessel density and a suppressed cell proliferation, when compared to vehicle-treated controls. Endometriotic lesions in dorsal skinfold chambers of SKI-5C-treated animals exhibited a significantly smaller lesion size, lower functional microvessel density, smaller microvessel diameters and a reduced blood perfusion of the newly developing microvascular networks.
Conclusions and Implications
SPHK1/S1P signalling promotes the establishment and progression of endometriotic lesions. The inhibition of this pathway suppresses the development of endometriotic lesions, suggesting SPHK1 as a potential novel target for future endometriosis therapy
Indole-3-Carbinol Inhibits the Growth of Endometriotic Lesions by Suppression of Microvascular Network Formation
Endometriosis represents an estrogen‑dependent disorder with a complex pathophysiol‑
ogy. Phytochemicals are promising candidates for endometriosis therapy, because they simulta‑
neously target different cellular processes involved in the pathogenesis of endometriosis. Herein,
we analyzed whether indole‑3‑carbinol (I3C) suppresses the development of endometriotic lesions,
which were surgically induced by fixation of uterine tissue samples (diameter: 2 mm) from female
BALB/c donor mice to the peritoneum of recipient animals. The mice received either I3C or ve‑
hicle (control) by peroral administration once per day. Growth, cyst formation, cell proliferation,
microvascularization and protein expression of the lesions were assessed by high‑resolution ultra‑
sound imaging, caliper measurements, histology, immunohistochemistry and Western blotting. I3C
inhibited the vascularization and growth of endometriotic lesions without inducing anti‑angiogenic
and anti‑proliferative side effects on reproductive organs. This was associated with a significantly
reduced number of proliferating stromal and endothelial cells and a lower expression of the pro‑
angiogenic signaling molecules vascular endothelial growth factor receptor‑2 (VEGFR2), phospho‑
inositide 3‑kinase (PI3K) and phosphorylated extracellular signal‑regulated kinase (pERK) within
I3C‑treated lesions when compared to controls. These findings indicate that I3C effectively inhibits
endometriotic lesion formation in mice. Thus, further studies should clarify whether I3C may be
also beneficial for the prevention and therapy of the human disease
The ischemic time window of ectopic endometrial tissue crucially determines its ability to develop into endometriotic lesions
Endometriosis develop from shed endometrial fragments via retrograde menstruation. This afects
the survival, proliferation and vascularization of the tissue and its fnal ability to form endometriotic
lesions. Within this study, uterine tissue samples from donor mice were precultivated for 24 h or
72 h to simulate avascular periods. Their morphology, microvessel density, apoptotic activity and
expression of angiogenesis-related proteins were analyzed in vitro. The formation of endometriotic
lesions in vivo was assessed after transplantation of precultivated uterine tissue samples to the
abdominal wall and dorsal skinfold chambers by means of high-resolution ultrasound, intravital
fuorescence microscopy, histology and immunohistochemistry. In vitro, 72-h-precultivated
uterine tissue samples exhibit extensive areas of tissue necrosis and high numbers of apoptotic
cells as well as a signifcantly reduced cell and microvessel density. These samples failed to develop
into endometriotic lesions. In contrast, the 24-h-precultivated samples showed, that their early
vascularization and growth in vivo was improved when compared to controls. This indicates that
avascular periods have a strong impact on the survival of ectopic endometrial tissue and the chance for
the development of endometriosis
Extended Classical Over-Barrier Model for Collisions of Highly Charged Ions with Conducting and Insulating Surfaces
We have extended the classical over-barrier model to simulate the
neutralization dynamics of highly charged ions interacting under grazing
incidence with conducting and insulating surfaces. Our calculations are based
on simple model rates for resonant and Auger transitions. We include effects
caused by the dielectric response of the target and, for insulators, localized
surface charges. Characteristic deviations regarding the charge transfer
processes from conducting and insulating targets to the ion are discussed. We
find good agreement with previously published experimental data for the image
energy gain of a variety of highly charged ions impinging on Au, Al, LiF and KI
crystals.Comment: 32 pages http://pikp28.uni-muenster.de/~ducree
Evaluation of Electrochemotherapy with Bleomycin in the Treatment of Colorectal Hepatic Metastases in a Rat Model
Background: The available ablative procedures for the treatment of hepatic cancer have
contraindications due to the heat-sink effect and the risk of thermal injuries. Electrochemotherapy
(ECT) as a nonthermal approach may be utilized for the treatment of tumors adjacent to high-risk
regions. We evaluated the effectiveness of ECT in a rat model. Methods: WAG/Rij rats were
randomized to four groups and underwent ECT, reversible electroporation (rEP), or intravenous
injection of bleomycin (BLM) eight days after subcapsular hepatic tumor implantation. The fourth
group served as Sham. Tumor volume and oxygenation were measured before and five days after
the treatment using ultrasound and photoacoustic imaging; thereafter, liver and tumor tissue were
additionally analysed by histology and immunohistochemistry. Results: The ECT group showed
a stronger reduction in tumor oxygenation compared to the rEP and BLM groups; moreover, ECTtreated tumors exhibited the lowest levels of hemoglobin concentration compared to the other groups.
Histological analyses further revealed a significantly increased tumor necrosis of >85% and a reduced
tumor vascularization in the ECT group compared to the rEP, BLM, and Sham groups. Conclusion:
ECT is an effective approach for the treatment of hepatic tumors with necrosis rates >85% five days
following treatment
Electronic structure and spectroscopy of the quaternary Heusler alloy CoCrFeAl
Quaternary Heusler alloys CoCrFeAl with varying Cr to Fe
ratio were investigated experimentally and theoretically. The electronic
structure and spectroscopic properties were calculated using the full
relativistic Korringa-Kohn-Rostocker method with coherent potential
approximation to account for the random distribution of Cr and Fe atoms as well
as random disorder. Magnetic effects are included by the use of spin dependent
potentials in the local spin density approximation.
Magnetic circular dichroism in X-ray absorption was measured at the
edges of Co, Fe, and Cr of the pure compounds and the alloy in order to
determine element specific magnetic moments. Calculations and measurements show
an increase of the magnetic moments with increasing iron content. Resonant
(560eV - 800eV) soft X-ray as well as high resolution - high energy (keV) hard X-ray photo emission was used to probe the density of the
occupied states in CoCrFeAl.Comment: J.Phys.D_Appl.Phys. accepte
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State of the California current 2013-14: El niño looming
In 2013, the California current was dominated by strong coastal upwelling and high productivity. Indices of total cumulative upwelling for particular coastal locations reached some of the highest values on record. Chlorophyll a levels were high throughout spring and summer. Catches of upwelling-related fish species were also high. After a moderate drop in upwelling during fall 2013, the California current system underwent a major change in phase. Three major basin-scale indicators, the PDO, the NPGO, and the ENSO-MEI, all changed phase at some point during the winter of 2013/14. The PDO changed to positive values, indicative of warmer waters in the North Pacific; the NPGO to negative values, indicative of lower productivity along the coast; and the MEI to positive values, indicative of an oncoming El Niño. Whereas the majority of the California Current system appears to have transitioned to an El Niño state by August 2014, based on decreases in upwelling and chlorophyll a concentration, and increases in SST, there still remained pockets of moderate upwelling, cold water, and high chlorophyll a biomass at various central coast locations, unlike patterns seen during the more major El Niños (e.g., the 97-98 event). Catches of rockfish, market squid, euphausiids, and juvenile sanddab remained high along the central coast, whereas catches of sardine and anchovy were low throughout the CCS. 2014 appears to be heading towards a moderate El Niño state, with some remaining patchy regions of upwellingdriven productivity along the coast. Superimposed on this pattern, three major regions have experienced possibly non-El Niño-related warming since winter: the Bering Sea, the Gulf of Alaska, and offshore of southern California. It is unclear how this warming may interact with the predicted El Niño, but the result will likely be reduced growth or reproduction for many key fisheries species
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State of the California current 2012-13: No such thing as an “average” year
This report reviews the state of the California Current System (CCS) between winter 2012 and spring 2013, and includes observations from Washington State to Baja California. During 2012, large-scale climate modes indicated the CCS remained in a cool, productive phase present since 2007. The upwelling season was delayed north of 42°N, but regions to the south, especially 33° to 36°N, experienced average to above average upwelling that persisted throughout the summer. Contrary to the indication of high production suggested by the climate indices, chlorophyll observed from surveys and remote sensing was below average along much of the coast. As well, some members of the forage assemblages along the coast experienced low abundances in 2012 surveys. Specifically, the concentrations of all lifestages observed directly or from egg densities of Pacific sardine, Sardinops sagax, and northern anchovy, Engraulis mordax, were less than previous years’ survey estimates. However, 2013 surveys and observations indicate an increase in abundance of northern anchovy. During winter 2011/2012, the increased presence of northern copepod species off northern California was consistent with stronger southward transport. Krill and small-fraction zooplankton abundances, where examined, were generally above average. North of 42°N, salps returned to typical abundances in 2012 after greater observed concentrations in 2010 and 2011. In contrast, salp abundance off central and southern California increased after a period of southward transport during winter 2011/2012. Reproductive success of piscivorous Brandt’s cormorant, Phalacrocorax penicillatus, was reduced while planktivorous Cassin’s auklet, Ptychoramphus aleuticus was elevated. Differences between the productivity of these two seabirds may be related to the available forage assemblage observed in the surveys. California sea lion pups from San Miguel Island were undernourished resulting in a pup mortality event perhaps in response to changes in forage availability. Limited biological data were available for spring 2013, but strong winter upwelling coastwide indicated an early spring transition, with the strong upwelling persisting into early summer
Effect of transport-induced charge inhomogeneity on point-contact Andreev reflection spectra at ferromagnet-superconductor interfaces
We investigate the transport properties of a ferromagnet-superconductor
interface within the framework of a modified three-dimensional
Blonder-Tinkham-Klapwijk formalism. In particular, we propose that charge
inhomogeneity forms via two unique transport mechanisms, namely, evanescent
Andreev reflection and evanescent quasiparticle transmission. Furthermore, we
take into account the influence of charge inhomogeneity on the interfacial
barrier potential and calculate the conductance as a function of bias voltage.
Point-contact Andreev reflection (PCAR) spectra often show dip structures,
large zero-bias conductance enhancement, and additional zero-bias conductance
peak. Our results indicate that transport-induced charge inhomogeneity could be
a source of all these anomalous characteristics of the PCAR spectra.Comment: 9 pages, 6 figure
Identifying Farming Strategies Associated With Achieving Global Agricultural Sustainability
Sustainable agroecosystems provide adequate food while supporting environmental and human wellbeing and are a key part of the United Nations Sustainable Development Goals (SDGs). Some strategies to promote sustainability include reducing inputs, substituting conventional crops with genetically modified (GM) alternatives, and using organic production. Here, we leveraged global databases covering 121 countries to determine which farming strategies—the amount of inputs per area (fertilizers, pesticides, and irrigation), GM crops, and percent agriculture in organic production—are most correlated with 12 sustainability metrics recognized by the United Nations Food and Agriculture Organization. Using quantile regression, we found that countries with higher Human Development Indices (HDI) (including education, income, and lifespan), higher-income equality, lower food insecurity, and higher cereal yields had the most organic production and inputs. However, input-intensive strategies were associated with greater agricultural greenhouse gas emissions. In contrast, countries with more GM crops were last on track to meeting the SDG of reduced inequalities. Using a longitudinal analysis spanning 2004–2018, we found that countries were generally decreasing inputs and increasing their share of agriculture in organic production. Also, in disentangling correlation vs. causation, we hypothesize that a country's development is more likely to drive changes in agricultural strategies than vice versa. Altogether, our correlative analyses suggest that countries with greater progress toward the SDGs of no poverty, zero hunger, good health and wellbeing, quality education, decent work, economic growth, and reduced inequalities had the highest production of organic agriculture and, to a lesser extent, intensive use of inputs
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