The protease activities are tightly regulated by inhibitors and dysregulation contribute to pathological processes such as cancer and inflammatory disorders. Tissue factor pathway inhibitor 2 ...(TFPI-2) is a serine proteases inhibitor, that mainly inhibits plasmin. This protease activated matrix metalloproteases (MMPs) and degraded extracellular matrix. Other serine proteases are implicated in these mechanisms like kallikreins (KLKs). In this study, we identified for the first time that TFPI-2 is a potent inhibitor of KLK5 and 12. Computer modeling showed that the first Kunitz domain of TFPI-2 could interact with residues of KLK12 near the catalytic triad. Furthermore, like plasmin, KLK12 was able to activate proMMP-1 and -3, with no effect on proMMP-9. Thus, the inhibition of KLK12 by TFPI-2 greatly reduced the cascade activation of these MMPs and the cleavage of cysteine-rich 61, a matrix signaling protein. Moreover, when TFPI-2 bound to extracellular matrix, its classical localisation, the KLK12 inhibition was retained. Finally, TFPI-2 was downregulated in human non-small-cell lung tumour tissue as compared with non-affected lung tissue. These data suggest that TFPI-2 is a potent inhibitor of KLK12 and could regulate matrix remodeling and cancer progression mediated by KLK12.
The design of hydrophobic surfaces requires a material which has a low solid surface tension and a simple fabrication process for anchoring and controlling the surface morphology. A generic method ...for the spontaneous formation of robust instability patterns is proposed through the hydrosilylation of a fluoroalkene bearing dangling chains, Rf = C6F13(CH2)3–, with a soft polymethylhydrosiloxane (PMHS) spin-coated gel polymer (0.8 μm thick) using Karstedt catalyst. These patterns were easily formed by an irreversible swelling reaction due to the attachment of a layer to various substrates. The buckling instability was created by two different approaches for a gel layer bound to a rigid silicon wafer substrate (A) and to a soft nonswelling silicone elastomer foundation (B). The observations of grafted Rf-PMHS films in the swollen state by microscopy revealed two distinct permanent patterns on various substrates: dotlike of wavelength λ = 0.4–0.7 μm (A) or wrinkle of wavelength λ = 4–7 μm (B). The elastic moduli ratios of film/substrate were determined using PeakForce quantitative nanomechanical mapping. The characteristic wavelengths (λ) of the patterns for systems A and B were quantitatively estimated in relation to the thickness of the top layer. A diversity of wrinkle morphologies can be achieved by grafting different side chains on pristine PMHS films. The water contact angle (WCA) hysteresis of fluorinated chain (R f) was enhanced upon roughening the surfaces, giving highly hydrophobic surface properties for water with static/hysteresis WCAs of 136°/74° in the resulting wrinkle (B) and 119°/41° in the dotlike of lower roughness (A). The hydrophobic properties of grafted films on A with various mixtures of hexyl/fluoroalkyl chains were characterized by static CA: WCA 104–119°, ethylene glycol CA 80–96°, and n-hexadecane CA 17–61°. A very low surface energy of 15 mN/m for Rf-PMHS was found on the smoother dotlike pattern.
Hospitalizations for anaphylaxis have been increasing steadily in many countries, whereas the anaphylaxis mortality rate has remained low and stable over the past 20 years.1-3 A small proportion of ...patients experiencing anaphylactic reactions are hospitalized in an intensive care unit (ICU). In the United States, this proportion was 5% of the patients seen in the emergency department for anaphylaxis.4 In the United Kingdom, 81 pediatric anaphylaxis cases were collected between 2005 and 2009, with a steady yearonyear increase.
Acquisition of data on animal movement when developing management strategies is a common challenge in species conservation, especially when dealing with a critically endangered species as the ...hawksbill turtle Eretmochelys imbricata. To reach the objective of the 2008 national action plan for Martinique Island (French West Indies), the present paper examines horizontal and vertical movements in juveniles (n = 3) and adults life stages (11 females and 2 males) of 16 hawksbill turtles. Our results reveal the strong site fidelity of individuals to their foraging grounds (mean male foraging home range: 89.3 ± 20.2 km2, mean female foraging home range: 336 ± 284.7 km2, mean juvenile foraging home range: 157.3 ± 71.2 km2) and to the females' inter-nesting areas (mean home range: 284.2 ± 523.7 km2). A spatial foraging overlap occurred between juveniles and males as they shared 41% of their 95% kernel foraging habitat. The turtles performed mainly long and shallow dives within the first 20 m deep around Martinique Island, occupying shallow waters close to shore. The migratory routes of the adult females revealed regional connectivity between the Caribbean islands, crossing 31 exclusive economic zones and international waters, and featuring distinct foraging grounds. This finding reinforces the significance of a cooperative network at the Caribbean scale to ensure the efficient conservation of this critically endangered species.
Successful bioinspired design depends on practitioners' access to biological data in a relevant form. Although multiple open-access biodiversity databases exist, their presentation is often adapted ...to life scientists, rather than bioinspired designers. In this paper, we present a new tool, "Bioinspire-Explore", for navigating biodiversity data in order to uncover biological systems of interest for a range of sectors. Bioinspire-Explore allows users to search for inspiring biological models via taxa (species, genera, etc.) as an entry point. It provides information on a taxon's position in the "tree of life", its distribution and climatic niche, as well as its appearance. Bioinspire-Explore also shows users connections in the bioinspiration literature between their taxon of interest and associated biological processes, habitats, and physical measurements by way of their semantic proximity. We believe Bioinspire-Explore has the potential to become an indispensable resource for both biologists and bioinspired designers in different fields.
During pregnancy, exposure to environmental contaminants can lead to adverse effects on fetal growth and development, especially by targeting the placenta. Di(2-ethylhexyl)phthalate (DEHP), the most ...abundant chemical used in plastic materials, is known to induce toxicity on animals reproductive system and is suspected to give rise to similar effect in humans. Toxicity of DEHP is due to its main metabolite, MEHP, which is also known to disturb lipid synthesis in several organs. Moreover, mono-(2-ethylhexyl)phtalate (MEHP) is a high affinity ligand of the peroxisome proliferator-activated receptor PPARγ which is essential for placental development and lipid metabolism. In order to investigate possible lipid disruptions induced by MEHP, in the JEG-3 human trophoblast cell line, a differential lipidomic analysis was carried out by UPLC-MS on both exposed and control cells. Our results showed that MEHP induced an important change of JEG-3 cells lipidome, especially in glycerolipids and glycerophospholipids, with a marked accumulation of triacylglycerols. For the first time, our results highlighted adverse effects of MEHP on human placental cells lipidome and thus, its potential effect on placental physiology.
•Cell viability and PPARγ activation were assessed after MEHP incubation of JEG-3 cells.•A lipidomic analysis of JEG-3 cell pellets was conducted in mass spectrometry.•MEHP incubation led to significant modifications in the lipidome of JEG-3 cells.
Phthalates are environmental contaminants commonly used as plasticizers in polyvinyl chloride (PVC) products. In the literature, phthalate exposure has been associated with preterm birth, low birth ...weight, and pregnancy loss, but information on possible mechanisms linking maternal phthalate exposure and placental development is limited. One hypothesis is the involvement of the peroxisome proliferator-activated receptor-γ (PPARγ), which belongs to the superfamily of nuclear receptors that regulate, in a ligand-dependent manner, the transcription of target genes. Studies of PPARγ-deficient mice have demonstrated its essential role in lipid metabolism and placental development. In the human placenta, PPARγ is expressed in the villous cytotrophoblast (VCT) and is activated during its differentiation into syncytiotrophoblast (ST). The goal of this study was to investigate the action of mono-2-ethylhexylphthalate (MEHP) on PPARγ activity during in vitro differentiation of VCTs into ST, the essential tissue of the human placenta providing hormonal and exchange functions between maternal and fetal blood.
Several techniques such as immunofluorescence, PPARγ activity / hCGβ assays, western blotting, and lipidomics analyses were combined to characterize the impacts of physiologically relevant concentrations of MEHP (0.1, 1, and 10μM) on freshly isolated VCTs from human term placenta.
0.1 μM and 1 μM MEHP significantly decreased PPARγ activity and cell fusion index compared to controls, while, surprisingly, 10 μM had the opposite effect. MEHP exposure inhibited hCG secretion regardless of the concentration used and significantly altered lipid composition.
this study suggests that MEHP: (i) disrupts trophoblast differentiation, (ii) alters the production of the essential pregnancy hormone (hCG), and (iii) that these effects are in part mediated by the nuclear receptor PPARγ. Thus, phthalates act as endocrine disruptors in the human placenta.
Phthalates are environmental contaminants commonly used as plasticizers in polyvinyl chloride (PVC) products. In the literature, phthalate exposure has been associated with preterm birth, low birth ...weight, and pregnancy loss, but information on possible mechanisms linking maternal phthalate exposure and placental development is limited. One hypothesis is the involvement of the peroxisome proliferator-activated receptor-γ (PPARγ), which belongs to the superfamily of nuclear receptors that regulate, in a ligand-dependent manner, the transcription of target genes. Studies of PPARγ-deficient mice have demonstrated its essential role in lipid metabolism and placental development. In the human placenta, PPARγ is expressed in the villous cytotrophoblast (VCT) and is activated during its differentiation into syncytiotrophoblast (ST). The goal of this study was to investigate the action of mono-2-ethylhexylphthalate (MEHP) on PPARγ activity during in vitro differentiation of VCTs into ST, the essential tissue of the human placenta providing hormonal and exchange functions between maternal and fetal blood.
Several techniques such as immunofluorescence, PPARγ activity / hCGβ assays, western blotting, and lipidomics analyses were combined to characterize the impacts of physiologically relevant concentrations of MEHP (0.1, 1, and 10μM) on freshly isolated VCTs from human term placenta.
0.1 μM and 1 μM MEHP significantly decreased PPARγ activity and cell fusion index compared to controls, while, surprisingly, 10 μM had the opposite effect. MEHP exposure inhibited hCG secretion regardless of the concentration used and significantly altered lipid composition.
This study suggests that MEHP: (i) disrupts trophoblast differentiation, (ii) alters the production of the essential pregnancy hormone (hCG), and (iii) that these effects are in part mediated by the nuclear receptor PPARγ. Thus, phthalates act as endocrine disruptors in the human placenta.
Caspase-8 is involved in death receptor-mediated apoptosis in type II cells, the proapoptotic programme of which is triggered by truncated Bid. Indeed, caspase-8 and Bid are the known intermediates ...of this signalling pathway. Cardiolipin has been shown to provide an anchor and an essential activating platform for caspase-8 at the mitochondrial membrane surface. Destabilisation of this platform alters receptor-mediated apoptosis in diseases such as Barth Syndrome, which is characterised by the presence of immature cardiolipin which does not allow caspase-8 binding. We used a simplified in vitro system that mimics contact sites and/or cardiolipin-enriched microdomains at the outer mitochondrial surface in which the platform consisting of caspase-8, Bid and cardiolipin was reconstituted in giant unilamellar vesicles. We analysed these vesicles by flow cytometry and confirm previous results that demonstrate the requirement for intact mature cardiolipin for caspase-8 activation and Bid binding and cleavage. We also used confocal microscopy to visualise the rupture of the vesicles and their revesiculation at smaller sizes due to alteration of the curvature following caspase-8 and Bid binding. Biophysical approaches, including Laurdan fluorescence and rupture/tension measurements, were used to determine the ability of these three components (cardiolipin, caspase-8 and Bid) to fulfil the minimal requirements for the formation and function of the platform at the mitochondrial membrane. Our results shed light on the active functional role of cardiolipin, bridging the gap between death receptors and mitochondria.
PDF
