Space station mobile transporter

The first quarter of the next century will see an operational space station that will provide a permanently manned base for satellite servicing, multiple strategic scientific and commercial payload deployment, and Orbital Maneuvering Vehicle/Orbital Transfer Vehicle (OMV/OTV) retrieval replenishment and deployment. The space station, as conceived, is constructed in orbit and will be maintained in orbit. The construction, servicing, maintenance and deployment tasks, when coupled with the size of the station, dictate that some form of transportation and manipulation device be conceived. The Transporter described will work in conjunction with the Orbiter and an Assembly Work Platform (AWP) to construct the Work Station. The Transporter will also work in conjunction with the Mobile Remote Servicer to service and install payloads, retrieve, service and deploy satellites, and service and maintain the station itself. The Transporter involved in station construction when mounted on the AWP and later supporting a maintenance or inspection task with the Mobile Remote Servicer and the Flight Telerobotic Servicer is shown

Targeted Delivery of Epidermal Growth Factor to the Human Placenta to Treat Fetal Growth Restriction

Placental dysfunction is the underlying cause of pregnancy complications such as fetal growth restriction (FGR) and pre-eclampsia. No therapies are available to treat a poorly functioning placenta, primarily due to the risks of adverse side effects in both the mother and the fetus resulting from systemic drug delivery. The use of targeted liposomes to selectively deliver payloads to the placenta has the potential to overcome these issues. In this study, we assessed the safety and efficacy of epidermal growth factor (EGF)-loaded, peptide-decorated liposomes to improve different aspects of placental function, using tissue from healthy control pregnancies at term, and pregnancies complicated by FGR. Phage screening identified a peptide sequence, CGPSARAPC (GPS), which selectively homed to mouse placentas in vivo, and bound to the outer syncytiotrophoblast layer of human placental explants ex vivo. GPS-decorated liposomes were prepared containing PBS or EGF (50–100 ng/mL), and placental explants were cultured with liposomes for up to 48 h. Undecorated and GPS-decorated liposomes containing PBS did not affect the basal rate of amino acid transport, human chorionic gonadotropin (hCG) release or cell turnover in placental explants from healthy controls. GPS-decorated liposomes containing EGF significantly increased amino acid transporter activity in healthy control explants, but not in placental explants from women with FGR. hCG secretion and cell turnover were unaffected by EGF delivery; however, differential activation of downstream protein kinases was observed when EGF was delivered via GPS-decorated vs. undecorated liposomes. These data indicate that targeted liposomes represent a safe and useful tool for the development of new therapies for placental dysfunction, recapitulating the effects of free EGF

The atrial natriuretic peptide (ANP) knockout mouse does not exhibit the phenotypic features of pre-eclampsia or demonstrate fetal growth restriction

The ANP knockout mouse is reported to exhibit pregnancy-associated hypertension, proteinuria and impaired placental trophoblast invasion and spiral artery remodeling, key features of pre-eclampsia (PE). We hypothesized that these mice may provide a relevant model of human PE with associated fetal growth restriction (FGR). Here, we investigated pregnancies of ANP wild type (ANP+/+), heterozygous (ANP+/-) and knockout (ANP−/-) mice. Maternal blood pressure did not differ between genotypes (E12.5, E17.5), and fetal weight (E18.5) was unaffected. Placental weight was greater in ANP−/− versus ANP+/+ mice. Therefore, in our hands, the ANP model does not express phenotypic features of PE with FGR

Tetramethoxystilbene-loaded liposomes restore reactive-oxygen-species-mediated attenuation of dilator responses in rat aortic vessels Ex vivo

The methylated analogue of the polyphenol resveratrol (RV), 2,3',4,5'-tetramethoxystilbene (TMS) displays potent antioxidant properties and is an effective cytochrome P450 (CYP) 1B1 inhibitor. The bioavailability of TMS is low. Therefore, the use of liposomes for the encapsulation of TMS is a promising delivery modality for enhanced uptake into tissues. We examined the effect of delivery of TMS in liposomes on the restoration of vasodilator responses of isolated aortic vessels after acute tension elevation ex vivo. Aortic vessels from young male Wistar rats were isolated, and endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) responses assessed. Acute tension elevation (1 h) significantly reduced ACh dilator responses, which were restored following incubation with superoxide dismutase or apocynin (an NADPH oxidase inhibitor). Incubation with TMS-loaded liposomes (mean diameter 157 ± 6 nm; PDI 0.097) significantly improved the attenuated dilator responses following tension elevation, which was sustained over a longer period (4 h) when compared to TMS solution. Endothelial denudation or co-incubation with L-NNA (Nω-nitro-l-arginine; nitric oxide synthase inhibitor) resulted in loss of dilator function. Our findings suggest that TMS-loaded liposomes can restore attenuated endothelial-dependent dilator responses induced by an oxidative environment by reducing NADPH-oxidase-derived ROS and potentiating the release of the vasodilator nitric oxide. TMS-loaded liposomes may be a promising therapeutic strategy to restore vasodilator function in vascular disease

Internal Mammary Arteries as a Model to Demonstrate Restoration of the Impaired Vasodilation in Hypertension, Using Liposomal Delivery of the CYP1B1 Inhibitor, 2,3′,4,5′-Tetramethoxystilbene

A significant number of patients with severe cardiovascular disease, undergoing coronary artery bypass grafting (CABG), present with hypertension. While internal mammary arteries (IMAs) may be a better alternative to vein grafts, their impaired vasodilator function affects their patency. Our objectives were to (1) determine if inhibition of the cytochrome P450 enzyme CYP1B1, using liposome-encapsulated 2,3′,4,5′-tetramethoxystilbene (TMS), can potentiate vasodilation of IMAs from CABG patients, and (2) assess mechanisms involved using coronary arteries from normal rats, in an ex vivo model of hypertension. PEGylated liposomes were synthesized and loaded with TMS (mean diameter 141 ± 0.9 nm). Liposomal delivery of TMS improved its bioavailability Compared to TMS solution (0.129 ± 0.02 ng/mL vs. 0.086 ± 0.01 ng/mL at 4 h; p < 0.05). TMS-loaded liposomes alleviated attenuated endothelial-dependent acetylcholine (ACh)-induced dilation in diseased IMAs (@ACh 10−4 M: 56.9 ± 5.1%; n = 8 vs. 12.7 ± 7.8%; n = 6; p < 0.01) for TMS-loaded liposomes vs. blank liposomes, respectively. The alleviation in dilation may be due to the potent inhibition of CYP1B1 by TMS, and subsequent reduction in reactive oxygen species (ROS) moieties and stimulation of nitric oxide synthesis. In isolated rat coronary arteries exposed to a hypertensive environment, TMS-loaded liposomes potentiated nitric oxide and endothelium-derived hyperpolarization pathways via AMPK. Our findings are promising for the future development of TMS-loaded liposomes as a promising therapeutic strategy to enhance TMS bioavailability and potentiate vasodilator function in hypertension, with relevance for early and long-term treatment of CABG patients, via the sustained and localized TMS release within IMA

Targeted Delivery of Epidermal Growth Factor to the Human Placenta to Treat Fetal Growth Restriction

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-17, pub-electronic 2021-10-25Publication status: PublishedFunder: Medical Research Council; Grant(s): MR/P023401/1Funder: European Regional Development Fund; Grant(s): 2014-2020.4.01.15-0012Funder: Estonian Research Council; Grant(s): PRG230Placental dysfunction is the underlying cause of pregnancy complications such as fetal growth restriction (FGR) and pre-eclampsia. No therapies are available to treat a poorly functioning placenta, primarily due to the risks of adverse side effects in both the mother and the fetus resulting from systemic drug delivery. The use of targeted liposomes to selectively deliver payloads to the placenta has the potential to overcome these issues. In this study, we assessed the safety and efficacy of epidermal growth factor (EGF)-loaded, peptide-decorated liposomes to improve different aspects of placental function, using tissue from healthy control pregnancies at term, and pregnancies complicated by FGR. Phage screening identified a peptide sequence, CGPSARAPC (GPS), which selectively homed to mouse placentas in vivo, and bound to the outer syncytiotrophoblast layer of human placental explants ex vivo. GPS-decorated liposomes were prepared containing PBS or EGF (50–100 ng/mL), and placental explants were cultured with liposomes for up to 48 h. Undecorated and GPS-decorated liposomes containing PBS did not affect the basal rate of amino acid transport, human chorionic gonadotropin (hCG) release or cell turnover in placental explants from healthy controls. GPS-decorated liposomes containing EGF significantly increased amino acid transporter activity in healthy control explants, but not in placental explants from women with FGR. hCG secretion and cell turnover were unaffected by EGF delivery; however, differential activation of downstream protein kinases was observed when EGF was delivered via GPS-decorated vs. undecorated liposomes. These data indicate that targeted liposomes represent a safe and useful tool for the development of new therapies for placental dysfunction, recapitulating the effects of free EGF

In vitro assessment of mouse fetal abdominal aortic vascular function

tion (FGR) affects 3–8 % of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assess-ment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evalu-ation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significan

Adaptations in Maternofetal Calcium Transport in Relation to Placental Size and Fetal Sex in Mice

Appropriate placental transport of calcium is essential for normal fetal skeletal mineralization. In fetal growth restriction (FGR), the failure of a fetus to achieve its growth potential, a number of placental nutrient transport systems show reduced activity but, in the case of calcium, placental transport is increased. In a genetic mouse model of FGR this increase, or adaptation, maintains appropriate fetal calcium content, relative to the size of the fetus, despite a small, dysfunctional placenta. It is unknown whether such an adaptation is also apparent in small, but normally functioning placentas. We tested the hypothesis that calcium transfer would be up-regulated in the lightest vs. heaviest placentas in the same C57Bl/6J wild-type (WT) mouse litter. Since lightest placentas are often from females, we also assessed whether fetal sex influenced placental calcium transfer. Placentas and fetuses were collected at embryonic day (E)16.5 and 18.5; the lightest and heaviest placentas, and female and male fetuses, were identified. Unidirectional maternofetal calcium clearance (CaKmf) was assessed following 45Ca administration to the dam and subsequent radiolabel counts within the fetuses. Placental expression of calcium pathway components was measured by Western blot. Data (median) are lightest placenta expressed as percentage of the heaviest within a litter and analyzed by Wilcoxon signed-rank test. In WT mice having normally grown fetuses, CaKmf, per gram placenta near term, in the lightest placentas was increased (126%; P &lt; 0.05) in association with reduced fetal calcium accretion earlier in gestation (92%; P &lt; 0.05), that was subsequently normalized near term. Increased placental expression of calbindin-D9K, an important calcium binding protein, was observed in the lightest placentas near term (122%; P &lt; 0.01). There was no difference in fetal calcium accretion between male and female littermates but a trend toward higher CaKmf in females (P = 0.055). These data suggest a small, normal placenta adapts calcium transfer according to its size, as previously demonstrated in a mouse model of FGR. Fetal sex had limited influence on this adaptive increase. These adaptations are potentially driven by fetal nutrient demand, as evidenced by the normalization of fetal calcium content. Understanding the regulatory mechanisms involved may provide novel avenues for treating placental dysfunction

Crossing mice deficient in eNOS with placental-specific Igf2 knockout mice: A new model of fetal growth restriction

We tested the hypothesis that crossing two mouse models of fetal growth restriction (FGR) of differing phenotype would induce more severe FGR than either model alone. Female endothelial nitric oxide synthase knockout mice (eNOS(−/−)) were mated with placental-specific Igf2 knockout males (P0). Resultant fetuses were no more growth restricted than those with P0 deletion alone. However, P0 deletion attenuated the reduced placental system A amino acid transporter activity previously observed in eNOS(−/−) mice. Manipulating maternal and fetal genotypes provides a means to compare maternal and fetal regulation of fetal growth