Light diffraction by sarcomeres produces iridescence in transmission in the transparent ghost catfish.

Despite the elaborate varieties of iridescent colors in biological species, most of them are reflective. Here we show the rainbow-like structural colors found in the ghost catfish (Kryptopterus vitreolus), which exist only in transmission. The fish shows flickering iridescence throughout the transparent body. The iridescence originates from the collective diffraction of light after passing through the periodic band structures of the sarcomeres inside the tightly stacked myofibril sheets, and the muscle fibers thus work as transmission gratings. The length of the sarcomeres varies from ~1 µm from the body neutral plane near the skeleton to ~2 µm next to the skin, and the iridescence of a live fish mainly results from the longer sarcomeres. The length of the sarcomere changes by ~80 nm as it relaxes and contracts, and the fish shows a quickly blinking dynamic diffraction pattern as it swims. While similar diffraction colors are also observed in thin slices of muscles from non-transparent species such as the white crucian carps, a transparent skin is required indeed to have such iridescence in live species. The ghost catfish skin is of a plywood structure of collagen fibrils, which allows more than 90% of the incident light to pass directly into the muscles and the diffracted light to exit the body. Our findings could also potentially explain the iridescence in other transparent aquatic species, including the eel larvae (Leptocephalus) and the icefishes (Salangidae).

In-Plane Topological-Defect-Enriched Graphene as an Efficient Metal-Free Catalyst for pH-Universal H2O2 Electrosynthesis.

Developing efficient metal-free catalysts to directly synthesize hydrogen peroxide (H2O2) through a 2-electron (2e) oxygen reduction reaction (ORR) is crucial for substituting the traditional energy-intensive anthraquinone process. Here, in-plane topological defects enriched graphene with pentagon-S and pyrrolic-N coordination (SNC) is synthesized via the process of hydrothermal and nitridation. In SNC, pentagon-S and pyrrolic-N originating from thiourea precursor are covalently grafted onto the basal plane of the graphene framework, building unsymmetrical dumbbell-like S─C─N motifs, which effectively modulates atomic and electronic structures of graphene. The SNC catalyst delivers ultrahigh H2O2 productivity of 8.1, 7.3, and 3.9 mol gcatalyst -1 h-1 in alkaline, neutral, and acidic electrolytes, respectively, together with long-term operational stability in pH-universal electrolytes, outperforming most reported carbon catalysts. Theoretical calculations further unveil that defective S─C─N motifs efficiently optimize the binding strength to OOH* intermediate and substantially diminish the kinetic barrier for reducing O2 to H2O2, thereby promoting the intrinsic activity of 2e-ORR.

Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia.

BACKGROUND: The adipokine chemerin regulates adipogenesis and the metabolic function of both adipocytes and liver. Chemerin is elevated in preeclamptic women, and overexpression of chemerin in placental trophoblasts induces preeclampsia-like symptoms in mice. Preeclampsia is known to be accompanied by dyslipidemia, albeit via unknown mechanisms. Here, we hypothesized that chemerin might be a contributor to dyslipidemia. METHODS: Serum lipid fractions as well as lipid-related genes and proteins were determined in pregnant mice with chemerin overexpression in placental trophoblasts and chemerin-overexpressing human trophoblasts. In addition, a phospholipidomics analysis was performed in chemerin-overexpressing trophoblasts. RESULTS: Overexpression of chemerin in trophoblasts increased the circulating and placental levels of cholesterol rather than triglycerides. It also increased the serum levels of lysophosphatidic acid, high-density lipoprotein cholesterol (HDL-C), and and low-density lipoprotein cholesterol (LDL-C), and induced placental lipid accumulation. Mechanistically, chemerin upregulated the levels of peroxisome proliferator-activated receptor g, fatty acid-binding protein 4, adiponectin, sterol regulatory element-binding protein 1 and 2, and the ratio of phosphorylated extracellular signal-regulated protein kinase (ERK)1/2 / total ERK1/2 in the placenta of mice and human trophoblasts. Furthermore, chemerin overexpression in human trophoblasts increased the production of lysophospholipids and phospholipids, particularly lysophosphatidylethanolamine. CONCLUSIONS: Overexpression of placental chemerin production disrupts trophoblast lipid metabolism, thereby potentially contributing to dyslipidemia in preeclampsia.

Tuning Binding Strength of Multiple Intermediates towards Efficient pH-universal Electrocatalytic Hydrogen Evolution by Mo8 O26 -NbNx Oy Heterocatalysts.

Developing efficient and robust hydrogen evolution reaction (HER) catalysts for scalable and sustainable hydrogen production through electrochemical water splitting is strategic and challenging. Herein, heterogeneous Mo8 O26 -NbNx Oy supported on N-doped graphene (defined as Mo8 O26 -NbNx Oy /NG) is synthesized by controllable hydrothermal reaction and nitridation process. The O-exposed Mo8 O26 clusters covalently confined on NbNx Oy nanodomains provide a distinctive interface configuration and appropriate electronic structure, where fully exposed multiple active sites give excellent HER performance beyond commercial Pt/C catalyst in pH-universal electrolytes. Theoretical studies reveal that the Mo8 O26 -NbNx Oy interface with electronic reconstruction affords near-optimal hydrogen adsorption energy and enhanced initial H2 O adsorption. Furthermore, the terminal O atoms in Mo8 O26 clusters cooperate with Nb atoms to promote the initial H2 O adsorption, and subsequently reduce the H2 O dissociation energy, accelerating the entire HER kinetics.

Engineering Steam Induced Surface Oxygen Vacancy onto Ni-Fe Bimetallic Nanocomposite for CO2 Electroreduction.

Surface oxygen vacancies (Vo ) regulation is an effective strategy to improve the electrochemical CO2  reduction reaction (CO2 RR) performance by lowering the activation energy barrier of CO2 ; however, the lack of precise control over the local atomic structures severely hinders the large-scale application of Vo -activated electrocatalyst for CO2 RR. Herein, an efficient strategy to facilitate CO2  activation is developed by introducing Vo into transition metal nanoparticles (NPs) with a steam-assisted chemical vapor deposition method. With the steam process, abundant surface Vo are introduced into the assembled Ni-Fe bimetallic NPs composite (H-NiFe/NG), which adjust surface Ni/Fe atoms to low-valent coordinatively unsaturated Ni (+1)/Fe (+2) sites, serving as electron-rich centers to adsorb and activate inert CO2  molecules. The as-prepared H-NiFe/NG composite exhibits excellent catalytic performance with a maximum Faradaic efficiency of 94% at -0.80 V (vs RHE) for CO production with remarkable stability. The density function theory calculations corroborate that the Ni atoms around surface Vo significantly lower the energy barrier for COOH* intermediate formation, which gives a low overpotential for reducing CO2  to CO, exhibiting superior CO2 RR performance. This general synthetic strategy provides a new insight to introduce surface Vo on transition metal for efficient CO2  reduction.

Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms.

Maternal circulating levels of the adipokine chemerin are elevated in preeclampsia, but its origin and contribution to preeclampsia remain unknown. We therefore studied (1) placental chemerin expression and release in human pregnancy, and (2) the consequences of chemerin overexpression via lentivirus-mediated trophoblast-specific gene manipulation in both mice and immortalized human trophoblasts. Placental chemerin expression and release were increased in women with preeclampsia, and their circulating chemerin levels correlated positively with the soluble Fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, a well-known biomarker of preeclampsia severity. Placental trophoblast chemerin overexpression in mice induced a preeclampsia-like syndrome, involving hypertension, proteinuria, and endotheliosis, combined with diminished trophoblast invasion, a disorganized labyrinth layer, and up-regulation of sFlt-1 and the inflammation markers nuclear factor-κB (NFκB), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts up-regulated sFlt-1, reduced vascular endothelial factor-A, and inhibited migration and invasion, as well as tube formation during co-culture with human umbilical vein endothelial cells (HUVECs). The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomenon, although it did not reverse the chemerin-induced down-regulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, up-regulation of placental chemerin synthesis disturbs normal placental development via its CMKLR1 receptor, thereby contributing to fetal growth restriction/resorption and the development of preeclampsia. Chemerin might be a novel biomarker of preeclampsia, and inhibition of the chemerin/CMKLR1 pathway is a promising novel therapeutic strategy to treat preeclampsia.

Placenta-Specific miR-125b Overexpression Leads to Increased Rates of Pregnancy Loss in Mice.

Pregnancy loss (PL) is one of the common complications that women can experience during pregnancy, with an occurrence rate of 1 to 5%. The potential causes of pregnancy loss are unclear, with no effective treatment modalities being available. It has been previously reported that the level of miR-125b was significantly increased in placentas of PL patients. However, the role of miR-125b in the development of PL still remains unknown. In the current study, an miR-125b placenta-specific over-expression model was constructed by lentiviral transfecting zona-free mouse embryos followed by embryo transfer. On gestation day 15, it was observed that the placenta was significantly smaller in the miR-125b placenta-specific overexpression group than the control group. Additionally, the abortion rate of the miR-125b placenta-specific overexpression group was markedly higher than in the control group. The blood vessel diameter was larger in the miR-125b-overexpressing specific placenta. In addition, miR-125b-overexpressing HTR8 and JEG3 cell lines were also generated to analyze the migration and invasion ability of trophoblasts. The results showed that miR-125b overexpression significantly suppressed the migration and invasion ability of HTR8 and JEG3 cells. Overall, our results demonstrated that miR-125b can affect embryo implantation through modulating placenta angiogenesis and trophoblast cell invasion capacity that can lead to PL.

Contribution of placental 11ß-HSD2 to the pathogenesis of preeclampsia.

Preeclampsia, a major human pregnancy-specific disorder, leads to maternal and fetal morbidity and mortality. Here we reported that 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), an enzyme that degrades active glucocorticoids, is one of the key factors that contributes to preeclampsia development. In the pregnant rat model, we firstly confirmed that administration of 11ß-HSD2 inhibitor carbenoxolone (CBX) subcutaneously or by placenta-targeted delivery system could lead to a decrease in placental 11ß-HSD2 expression and activity and an increase in corticosterone level in placenta and maternal circulation. Then, we showed that subcutaneous administration and placenta-targeted delivery of CBX resulted in the hallmark of preeclampsia-like features including hypertension, proteinuria, renal damages as well as elevated circulatory soluble fms-like tyrosine kinase 1 (sFlt1) and increased sFlt1/placental growth factor (PlGF) ratio in pregnant rats. These animals displayed decreased trophoblast invasion in uterus, impaired spiral artery remodeling, and reduced placental blood flow. Preeclampsia-like features could also be induced by administration of dexamethasone in pregnant rats. In the cultured human trophoblast models, we found that cortisol only inhibited migration and invasion of the extravillous trophoblasts with 11ß-HSD2 knockdown, and promoted sFlt1 release in the cultured syncytiotrophoblasts with 11ß-HSD2 knockdown. Furthermore, we elucidated that cortisol stimulated a disintegrin and metalloprotease (ADAM)17 expression in placentas, thereby promoting sFlt1 release in placenta. Collectively, our study provided the evidence that placental 11ß-HSD2 dysfunction plays a key role in the development of preeclampsia and immediately identified innovative target to counteract preeclampsia.

Reduction of pl-CSA through ChSy-2 knockout inhibits tumorigenesis and metastasis of choriocarcinoma in JEG3 cells.

Background: Placental-like chondroitin sulfate A (pl-CSA) is exclusively expressed in cancerous and placental tissues and is highly correlated with the degree of malignancy. However, the mechanism through which pl-CSA regulates tumorigenesis and metastasis in choriocarcinoma remains unclear. Methods: Stable transfectants of the JEG3 choriocarcinoma cell line, including a negative control (NC) line and a cell line with knockout of the biosynthetic enzyme CS synthase-2 (ChSy-2) (ChSy-2-/-), were obtained using CRISPR/Cas9 systems and identified by immunofluorescence, flow cytometry, western blots and enzyme-linked immunosorbent assays (ELISAs). The proliferation, migration, invasion and colony formation of the cells were determined by a cell counting kit, scratch-wound assays, transwell assays and soft agar colony formation assays in vitro, respectively. The tumorigenesis and metastasis of choriocarcinoma were also investigated through two xenograft models in vivo. Results: The ChSy-2 protein in the ChSy-2-/-group was below the detection threshold, which was accompanied a significant reduction in the pl-CSA level. Reducing pl-CSA through ChSy-2 knockout significantly inhibited cell proliferation, migration, invasion and colony formation in vitro and tumorigenesis and metastasis of choriocarcinoma, with deceases in tumor volume and metastatic foci and a high percent survival compared to the NC in vivo. Conclusion: pl-CSA, as a necessary component of JEG-3 cells, was efficiently reduced through ChSy-2 knockout, which significantly inhibited the tumorigenesis and metastasis of choriocarcinoma. ChSy-2/pl-CSA could be alternative targets for tumor therapy.

R-spondin3 promotes the tumor growth of choriocarcinoma JEG-3 cells.

R-spondin3 (RSPO3), an activator of Wnt/ß-catenin signaling, plays a key role in tumorigenesis of various cancers, but its role in choriocarcinoma remains unknown. To investigate the effect of RSPO3 on the tumor growth of choriocarcinoma JEG-3 cells, the expression of RSPO3 in human term placenta was detected, and a stable RSPO3-overexpressing JEG-3 cell line was established via lentivirus-mediated transduction. The expression of biomarkers involved in tumorigenicity was detected in the RSPO3-overexpressing JEG-3 cells, and cell proliferation, invasion, migration, and apoptosis were investigated. Moreover, soft agar clonogenic assays and xenograft tumorigenicity assays were performed to assess the effect of RSPO3 on tumor growth in vitro and in vivo. The results showed that RSPO3 was widely expressed in human term placenta and overexpression of RSPO3 promoted the proliferation and inhibited the migration, invasion, and apoptosis of the JEG-3 cells. Meanwhile, RSPO3 overexpression promoted tumor growth both in vivo and in vitro. Further investigation showed that the phosphorylation levels of Akt, phosphatidylinositol 3-kinase (PI3K), and ERK as well the expression of ß-catenin and proliferating cell nuclear antigen (PCNA) were increased in the RSPO3-overexpressing JEG-3 cells and tumor xenograft. Taken together, these data indicate that RSPO3 promotes the tumor growth of choriocarcinoma via Akt/PI3K/ERK signaling, which supports RSPO3 as an oncogenic driver promoting the progression of choriocarcinoma.

Elevated cell-free fetal DNA contributes to placental inflammation and antiangiogenesis via AIM2 and IFI16 during pre-eclampsia.

Accumulated evidence has shown that pre-eclampsia (PE) is related to both maternal and utero-placental antiangiogenesis and inflammation. Remarkably, an elevated cell-free fetal DNA (cffDNA) level has been found in maternal circulation; however, it remains unclear whether this DNA can induce activation of cytosolic DNA sensor signaling pathways and lead to the development of PE. In this study, we found that trophoblast cells constitutively expressed the cytosolic DNA sensors, absent in melanoma 2 (AIM2) and interferon-inducible protein 16 (IFI16). The cffDNA and pro-inflammatory and antiangiogenic factors were present at higher concentrations in PE compared with the control group and correlated with the severity of PE. DNA stimulation significantly increased the AIM2 and IFI16 levels, consistent with the elevated AIM2 and IFI16 expression in women with PE, and elicited increased production of AIM2-mediated interleukin IL-8 (IL-8), IL-6 and CC chemokine ligand 2 (CCL2) and IFI16-mediated sEndoglin, sFlt-1 and CXCL10. Furthermore, enhancement of the inflammatory response was found to be induced by DNA exposure, but DNA exposure did not induce PE-like symptoms in pregnant mice. It is possible that elevated cffDNA could reflect the degree of placental damage and trigger cytosolic DNA sensor activation, which disrupts the immunity balance and, consequently, contributes to inflammatory and antiangiogenic responses. In conclusion, the results of this study suggest that circulating cffDNA levels are increased in preeclamptic women and act through AIM2 and IFI16 activation to promote the production of pro-inflammatory and antiangiogenic factors, which correlate with the severity of the disease, and may offer insights into the etiology and pathogenesis of PE.

Genuine Active Species Generated from Fe3 N Nanotube by Synergistic CoNi Doping for Boosted Oxygen Evolution Catalysis.

The surface reconstruction of oxygen evolution reaction (OER) catalysts has been proven favorable for enhancing its catalytic activity. However, what is the active site and how to promote the active species generation remain unclear and are still under debate. Here, the in situ synthesis of CoNi incorporated Fe3 N nanotubes (CoNi-Fe3 N) on the iron foil through the anodization/electrodeposition/nitridation process for use of boosted OER catalysis is reported. The synergistic CoNi doping induces the lattice expansion and up shifts the d-band center of Fe3 N, which enhances the adsorption of hydroxyl groups from electrolyte during the OER catalysis, facilitating the generation of active CoNi-FeOOH on the Fe3 N nanotube surface. As a result of this OER-conditioned surface reconstruction, the optimized catalyst requires an overpotential of only 285 mV at a current density of 10 mA cm-2 with a Tafel slope of 34 mV dec-1 , outperforming commercial RuO2 catalysts. Density functional theory (DFT) calculations further reveal that the Ni site in CoNi-FeOOH modulates the adsorption of OER intermediates and delivers a lower overpotential than those from Fe and Co sites, serving as the optimal active site for excellent OER performance.

Screening and surveillance of multiple solid tumours using plasma placental-like chondroitin sulfate A (pl-CSA).

Rationale: Placental-like chondroitin sulfate A (pl-CSA) is known to be exclusively synthesized in multiple cancer tissues and associated with disease severity. Here, we aimed to assess whether pl-CSA is released into bio-fluids and can serve as a cancer biomarker. Methods: A novel ELISA was developed to analyse pl-CSA content in bio-fluids using pl-CSA binding protein and an anti-pl-CSA antibody. Immunohistochemical staining of tissue chips was used as the gold standard control. Results: The developed ELISA method was specific and sensitive (1.22 µg/ml). The pl-CSA content was significantly higher in lysates and supernatants of cancer cell lines than in those of normal cell lines, in plasma from mouse cancer models than in that from control mice, and in plasma from patients with oesophageal, cervical, ovarian, or lung cancer than in that from healthy controls. Similar to the tissue chip analysis, which showed a significant difference in pl-CSA positivity between cancer tissues and normal adjacent tissues, the plasma pl-CSA analysis had 100% sensitivity and specificity for differentiating oesophageal and lung cancer patients from healthy controls. Importantly, in oesophageal and lung cancer patients, the pl-CSA content was significantly higher in late-stage disease than in early-stage disease, and it dramatically decreased after surgical resection of the tumour. Conclusion: These data indicate a direct link between plasma pl-CSA content and tumour presence, indicating that plasma pl-CSA may be a non-invasive biomarker with clinical applicability for the screening and surveillance of patients with multiple types of solid tumours.

ELABELA, as a potential diagnostic biomarker of preeclampsia, regulates abnormally shallow placentation via APJ.

Preeclampsia (PE) is a major cause of maternal mortality and morbidity worldwide. Although there has been great progress in the understanding of PE, the exact cause for the disease development is still unclear. Recently, studies showed that genetic deletion of ELABELA (ELA, also known as APELA) could induce PE-like symptoms in mice. However, the role of ELA in the disease development of PE remains elusive. Our objective was to measure the changes of ELA levels in maternal serum, urine, and placenta from preeclamptic pregnant women and healthy pregnant women and evaluate the correlation between ELA levels and the occurrence of PE. Additionally, we investigated the effect of ELA on the migration and proliferation of human trophoblast cells. ELA levels are significantly decreased in late-onset PE pregnancies compared with normal pregnancies. The mRNA and protein expressions of ELA and the apelin receptor (APLNR or APJ) in late-onset PE placental tissues are also decreased. Furthermore, our in vitro study showed that the addition of ELA significantly increased the invasion ability and proliferation of trophoblast cells, which were inhibited by the APJ-specific antagonist ML221. Our study identified ELA as significantly decreased in late-onset PE; therefore, it might play an important role in the pathogenesis of late-onset PE.

BeO6 Trigonal Prism with Ultralong Be-O Bonds Observed in a Deep Ultraviolet Optical Crystal Li13BeBe6B9O27.

Beryllium (Be) has high ionization energy (9.32 eV) with the greatest degree of covalency in the group IIA elements, and BeO4 tetrahedra (and BeO3 triangles) with covalent character are generally presented in beryllates. An unprecedented BeO6 trigonal prism with ultralong Be-O bonds as well as a BeO4 common tetrahedron is discovered in a new deep ultraviolet crystal Li13BeBe6B9O27 (LBeBBO) with a ∞2[Be6B9O33] double-layer framework. The BeO6 unit and its bond character are verified by an isostructural crystal Li13(Mg0.45Be0.55)Be6B9O27, while the orbital theory and charge density difference further clarify the ionic character of the BeO6 unit. Phonon dispersion confirms the structural stability of LBeBBO.

Surface-Functionalized Nanoparticles as Efficient Tools in Targeted Therapy of Pregnancy Complications.

Minimizing exposure of the fetus to medication and reducing adverse off-target effects in the mother are the primary challenges in developing novel drugs to treat pregnancy complications. Nanomedicine has introduced opportunities for the development of novel platforms enabling targeted delivery of drugs in pregnancy. This review sets out to discuss the advances and potential of surface-functionalized nanoparticles in the targeted therapy of pregnancy complications. We first describe the human placental anatomy, which is fundamental for developing placenta-targeted therapy, and then we review current knowledge of nanoparticle transplacental transport mechanisms. Meanwhile, recent surface-functionalized nanoparticles for targeting the uterus and placenta are examined. Indeed, surface-functionalized nanoparticles could help prevent transplacental passage and promote placental-specific drug delivery, thereby enhancing efficacy and improving safety. We have achieved promising results in targeting the placenta via placental chondroitin sulfate A (plCSA), which is exclusively expressed in the placenta, using plCSA binding peptide (plCSA-BP)-decorated nanoparticles. Others have also focused on using placenta- and uterus-enriched molecules as targets to deliver therapeutics via surface-functionalized nanoparticles. Additionally, we propose that placenta-specific exosomes and surface-modified exosomes might be potential tools in the targeted therapy of pregnancy complications. Altogether, surface-functionalized nanoparticles have great potential value as clinical tools in the targeted therapy of pregnancy complications.

Targeted Delivery Prodigiosin to Choriocarcinoma by Peptide-Guided Dendrigraft Poly-l-lysines Nanoparticles.

The available and effective therapeutic means to treat choriocarcinoma is seriously lacking, mainly due to the toxic effects caused by chemotherapy and radiotherapy. Accordingly, we developed a method for targeting delivery of chemotherapeutical drugs only to cancer cells, not normal cells, in vivo, by using a synthetic placental chondroitin sulfate (CSA)-binding peptide (plCSA-BP) derived from malarial protein VAR2CSA. A 28 amino acids placental CSA-binding peptide (plCSA-BP) from the VAR2CSA was synthesized as a guiding peptide for tumor-targeting delivery, dendrigraft poly-L-lysines (DGL) was modified with plCSA-BP and served as a novel targeted delivery carrier. Choriocarcinoma was selected to test the effect of targeted delivery carrier, and prodigiosin isolated from Serratia marcescens subsp. lawsoniana was selected as a chemotherapeutical drug and encapsulated in the DGL modified by the plCSA-BP nanoparticles (DGL/CSA-PNPs). DGL/CSA-PNPs had a sustained slow-release feature at pH 7.4, which could specifically bind to the JEG3 cells and exhibited better anticancer activity than that of the controls. The DGL/CSA-PNPs induced the apoptosis of JEG3 cells through caspase-3 and the P53 signaling pathway. DGL/CSA-PNPs can be used as an excellent targeted delivery carrier for anticancer drugs, and the prodigiosin could be an alternative chemotherapeutical drug for choriocarcinoma.

VEGF-A regulates sFlt-1 production in trophoblasts through both Flt-1 and KDR receptors.

Studies have shown that sFlt-1 overproduction stimulated by excess VEGF of deciduous origin in trophoblasts can cause preeclampsia. However, the mechanism underlying how VEGF regulates sFtl-1 expression in trophoblasts remains unknown. To address this issue, JEG3 and HTR-8/SV neo (HTR8) trophoblast cell lines were used to investigate the signaling pathways involved in the regulation of sFlt-1 production via VEGF overexpression in vitro. JEG3 (VEGF-GFP-JEG3, V-J) and HTR8 (VEGF-GFP-HTR8, V-H) cells overexpressing VEGF165 were established by infecting the JEG3 and HTR8 cell lines with lentivirus expressing VEGF165. Both the mRNA and protein levels of VEGF and sFlt-1 were dramatically up-regulated in the V-J and V-H cells compared to the JEG3 and HTR8 cells, and they were significantly decreased after treatment with an Flt-1 receptor inhibitor (MK-2461), a KDR receptor inhibitor (XL-184), or an Flt-1 and KDR receptor inhibitor (ABT-869). The mRNA levels of sFlt-1, Flt-1, and KDR were increased in V-H cells after treatment, and the VEGF-A mRNA levels were also elevated. The migration and invasion abilities of JEG3 and HTR8 cells were decreased after VEGF overexpression, and this reduction could be reversed with VEGF receptor inhibitor treatment. In addition, after the different treatments, the cell migration rates of V-J cells were significantly increased compared with the control treatment. Taken together, these results indicate that sFlt-1 up-regulation by VEGF may be mediated by the VEGF/Flt-1 and/or VEGF/KDR signaling pathways. However, elucidating which pathway plays this key role requires further investigation.

Alterted SLIT2/ROBO1 signalling is linked to impaired placentation of missed and threatened miscarriage in early pregnancy.

AIMS: Two-thirds of early pregnancy failures present with reduced trophoblast invasion, and SLIT2/ROBO1 signalling is considered to play an important role in trophoblast function during pregnancy. We investigated SLIT2/ROBO1 signalling associated with missed and threatened miscarriage during early gestation. METHODS AND RESULTS: Human placenta samples were collected from women with missed miscarriage (n = 25), threatened miscarriage (n = 22) and termination of pregnancy controls (n = 32). Corresponding decreases in beta human chorionic gonadotrophin (ß-hCG) levels and shallow trophoblast invasion were observed in patients with missed and threatened miscarriage, immunohistological staining revealed abnormal Slit2 and Robo1, as well as E-cadherin and activating protein-2 alpha (AP-2α) expression in villi and extravillous trophoblasts, and the expression of these proteins were confirmed in villi and decidua of miscarriage material by Western blotting. Using HTR8/SVneo cells, blocking SLIT2/ROBO1 signalling promoted cell migration, proliferation and suppressed differentiation. Moreover, blocking SLIT2/ROBO1 signalling in HTR8/SVneo cells altered trophoblast differentiation-related and angiogenesis-related gene mRNA expression, which also occurred in the tissues of missed and threatened miscarriage. CONCLUSIONS: SLIT2/ROBO1 signalling may regulate trophoblast differentiation and invasion causing restricting ß-hCG production, shallow trophoblast invasion and inhibiting placental angiogenesis in missed and threatened miscarriage during the first trimester.

Growth and Transfer of Seamless 3D Graphene-Nanotube Hybrids.

Seamlessly connected graphene and carbon nanotube hybrids (GCNTs) have great potential as carbon platform structures in electronics due to their high conductivity and high surface area. Here, we introduce a facile method for making patterned GCNTs and their intact transfer onto other substrates. The mechanism for selective growth of vertically aligned CNTs (VA-CNTs) on the patterned graphene is discussed. The complete transfer of the GCNT pattern onto other substrates is possible because of the mechanical strength of the GCNT hybrids. Electrical conductivity measurements of the transferred GCNT structures show Ohmic contact through the VA-CNTs to graphene--evidence of its integrity after the transfer process.