FLAMINGO – Fulfilling enhanced location accuracy in the mass-market through initial GalileO services

This paper discusses FLAMINGO, an initiative that will provide a high accuracy positioning service to be used by mass market applications. The status and future for the initiative are discussed, the required accuracies and other location parameters are described, and the target applications are identified. Finally, the currently achieved accuracies from today’s Smartphones are assessed and presented. FLAMINGO (Fulfilling enhanced Location Accuracy in the Mass-market through Initial GalileO services), part funded through the European GNSS Agency, is a collaborative venture comprising NSL (as lead organization), Telespazio France, University of Nottingham, Rokubun, Thales Alenia Space France, VVA, BQ, ECLEXYS and Blue Dot Solutions. The initiative is developing the infrastructure, solutions and services to enable the use of accurate and precise GNSS within the mass-market, thereby operating predominantly in an urban environment. Whilst mass-market receivers are yet to achieve accuracies below one metre for standard positioning, the introduction of Android raw GNSS measurements and the Broadcom dual frequency chipset (BCM47755), has presented the devices such an opportunity. FLAMINGO will enable and demonstrate the future of high accuracy positioning and navigation information on mass-market devices such as smartphones and Internet of Things (IoT) devices by producing a service delivering accuracies of 50cm (at 95%) and better, employing multi-constellation, PPP and RTK mechanisms, power consumption optimisation techniques. Whereas the Galileo High Accuracy Service targets 10cm precision within professional markets, FLAMINGO targets 30-50cm precision in the mass-market consumer markets. By targeting accuracies of a few decimetres, a range of improved and new applications in diverse market sectors are introduced. These sectors include, but are not limited to, mapping and GIS, autonomous vehicles, AR environments, mobile-location based gaming and people tracking. To obtain such high accuracies with mass market devices, FLAMINGO must overcome several challenges which are technical, operational and environmental. This includes the hardware capabilities of most mass-market devices, where components such as antennas and processors are prioritised for other purposes. We demonstrate that, despite these challenges, FLAMINGO has the potential to meet the accuracy required. Tests with the current Smartphones that provide access to multi-constellation raw measurements (the dual frequency Xiaomi Mi 8 and single frequency Samsung S8 and Huawei P10) demonstrate significant improvements to the PVT solution when processing using both RTK and PPP techniques

NKCC1 downregulation induces hyperpolarizing shift of GABA responsiveness at near term fetal stages in rat cultured dorsal root ganglion neurons

GABA A receptor-mediated neurotransmission is greatly influenced by cation-chloride cotransporter activity during developmental stages. In embryonic neurons Na–K–2Cl (NKCC1) cotransporters mediate active chloride uptake, thus increasing the intracellular chloride concentration associated with GABA-induced depolarization. At fetal stages near term, oxytocin-induced NKCC1 downregulation has been implicated in the developmental shift from depolarizing to hyperpolarizing GABA action. Mature dorsal root ganglion neurons (DRGN), however, express high NKCC1 levels and maintain high intracellular chloride levels with consequent GABA-induced depolarization.Results: Gramicidin-perforated patch-clamp recordings were used to assess the developmental change in chloride homeostasis in rat cultured small DRGN at the embryonic day 16 (E16) and 19 (E19). The results were compared to data previously obtained in fetal DRGN at E14 and in mature cells. A significant NKCC1 downregulation, leading to reduction in excitatory GABAergic transmission, was observed at E16 and E19.Conclusion: These results indicate that NKCC1 activity transiently decreases in DRGN at fetal stages near term. This developmental shift in GABAergic transmission may contribute to fetal analgesia and neuroprotection at birth

Residual stress measurements in electrolytic copper-nickel compositionally modulated multilayers

Residual stresses in electrolyte copper-nickel compositionally modulated multilayers (CMM) deposited from sulfate plating solutions on low carbon steel substrates have been determined using a low incident beam angle x-ray diffraction technique. The sublayer thickness was Varied from 0.1 to 1.5 mu m, while the total thickness of the compositionally modulated multilayer was kept at 3 mu m. For reference, residual stress measurements were performed on electrolytic nickel deposited from Watts' nickel plating solutions. The evolution of the residual stresses in the compositionally modulated multilayers was measured as a function of the copper and nickel sublayer thicknesses. A general formula to calculate the x-ray information depth in CMMs was derived and used to obtain the residual stress depth profile in electrolytic copper-nickel CMMs.status: publishe

An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids

Saponins are a structurally diverse family of triterpenes that are widely found as main constituents in many traditional plant-based medicines and often have bioactivities of industrial interest. The heterologous production of triterpene saponins in microbes remains challenging and only limited successful pathway engineering endeavors have been reported. To improve the production capacities of a Saccharomyces cerevisiae saponin production platform, we assessed the effects of several hitherto unexplored gene knockout targets on the heterologous production of triterpenoids. Here, we show that the disruption of the phosphatidic acid phosphatase-encoding PAH1 through CRISPR/Cas9 results in a dramatic expansion of the endoplasmic reticulum (ER), which stimulated the production of recombinant triterpene biosynthesis enzymes and ultimately boosted triterpenoid and triterpene saponin accumulation. Compared to the wild-type starter strain, accumulation of the oleanane-type sapogenin beta-amyrin, of its oxidized derivative medicagenic acid, and its glucosylated version medicagenic-28-O-glucoside was respectively increased by eight-, six-and 16-fold in the pah1 strain. A positive effect of pah1 could also be observed for the production of other terpenoids depending on ER-associated enzymes for their biosynthesis, such as the sesquiterpenoid artemisinic acid, which increased by twofold relative to the wild-type strain. Hence, this report demonstrates that pathway engineering in yeast through transforming the subcellular morphology rather than altering metabolic fluxes is a powerful strategy to increase yields of bioactive plant-derived products in heterologous hosts

Simulated vaginal delivery causes transients vaginal smooth muscle hypersensitivity and urethral sphincter dysfunction

BACKGROUND: Although pelvic floor dysfunction (PFD) has a multifactorial etiology, pregnancy and childbirth are considered crucial events predisposing to urinary incontinence as well as pelvic organ prolapse, which are highly prevalent. Rats are the most frequently used animal model and pudendal nerve crush (PNC) and vaginal distension (VD) are often used to mimic vaginal delivery. OBJECTIVE: To document the time course of events after simulated vaginal delivery (SVD) on the urethral sphincter and the vaginal smooth muscle layer. MATERIALS AND METHODS: Virgin female Sprague-Dawley rats were subjected to SVD (PNC + VD) or sham surgery and evaluated at 7, 14, 21, and 42 days after the injury. Urethral function was determined in vivo by microultrasound during cystometry and vaginal smooth muscle layer was harvested for in vitro pharmacologic investigation by isometric tension recording. Furthermore, vaginal and urethral samples were investigated by immunohistochemistry and real-time quantitative polymerase chain reaction. RESULTS: Microultrasound showed no bursting of the urethral sphincter in the SVD group at 7 days with a functional recovery starting at 14 days, and normal bursting at 21 and 42 days. Vaginal smooth muscle showed higher sensitivity to carbachol at 14 and 21 days after injury; however, at 42 days, its sensitivity decreased when compared with sham. CONCLUSION: SVD induces urethral dysfunction and a shift in vaginal smooth muscle contractile responses to carbachol.status: publishe

GlyConnect-Ugi : site-selective, multi-component glycoprotein conjugations through GlycoDelete expressed glycans

Recently, the GlyConnect-oxime (GC) protein conjugation strategy was developed to provide a site-selective glycan-based conjugation strategy as an extension to the in-house developed GlycoDelete (GD) technology. GD gives access to glycoproteins with single GlcNAc, LacNAc, or LacNAc-Sia type glycans on their N-glycosylation sites. We have previously shown that these glycans provide a unique handle for site-selective conjugation as they provide a short, homogeneous and hydrophilic link to the protein backbone. GC focused on the use of chemical and chemo-enzymatic pathways for conjugation of a single molecule of interest via oxime formation or reductive amination. In the current work, we explore multicomponent reactions (MCR), namely Ugi and Passerini reactions, for GlycoDelete glycan directed, site-specific protein conjugation (MC-GC). The use of the Ugi and Passerini multicomponent reactions holds the potential of introducing multiple groups of interest in a single reaction step while creating a hydrophilic peptide-like linker

Physical activity in the androgen receptor knockout mouse: Evidence for reversal of androgen deficiency on cancellous bone

Disruption of the androgen receptor (AR) in male mice reduces cortical bone expansion and muscle mass during puberty and results in high bone turnover-related cancellous osteopenia. We hypothesized that voluntary wheel running during growth is able to rescue the effects of AR disruption on bone. To this end, 5-week-old AR knockout (ARKO) mice were randomized to a running group (cage with running wheel) and a sedentary group (cage without wheel) and followed-up until 16 weeks of age. Voluntary wheel running in ARKO mice did not influence body weight, muscle mass or periosteal bone expansion. Interestingly, Voluntary running significantly reduced bone turnover in ARKO mice and prevented cancellous bone loss due to a preservation of trabecular number. Thus, voluntary running in ARKO mice was able to reduce cancellous bone resorption, suggesting that sustained exercise may potentially compensate the effects of androgen disruption on cancellous bone. (C) 2008 Elsevier Inc. All rights reservedstatus: publishe

Release of urinary extracellular vesicles in prostate cancer is associated with altered urinary N-glycosylation profile

Aim: Nowadays, extracellular vesicles are of great interest in prostate cancer (PCa) research. Asparagine (N)-linked glycosylation could play a significant role in the pathological mechanism of these vesicles. We investigated if prostatic protein N-glycosylation profiles were related to urinary vesicle-associated prostate-specific antigen (PSA) extractability and if this parameter showed diagnostic potential for PCa. Methods: Urinary extracellular vesicles were visualised using transmission electron microscopy. Urinary extracellular vesicles extraction by means of n-butanol allowed determination of urinary vesicle-associated PSA extractability. Diagnostic value was assessed between benign prostate hyperplasia (BPH; n=122) and patients with PCa (n=85). Additionally, correlation with urine N-glycosylation was assessed. Results: Urinary extracellular vesicles with a diameter of approximately 100 nm were more abundantly present in urine of patients with PCa versus patients with BPH resulting in a higher vesicle-associated PSA extraction ratio (p<0.001). Next, vesicle-associated PSA extraction ratio was correlated to biantennary core-fucosylation (p=0.003). Finally, vesicle-associated PSA extraction ratio proved beneficial in PCa diagnosis, next to serum PSA and the urinary glycosylation marker (p=0.021). Conclusions: The urinary vesicle-associated PSA extraction ratio is increased in PCa which is a direct result of the abundant presence of extracellular vesicles in urine of patients with PCa. The urinary vesicle-associated PSA extraction ratio was associated with changes in N-glycoforms and showed diagnostic potential. Further research is warranted to unravel the pathological link between N-glycosylation and extracellular vesicles in cancer, as well as to assess the prognostic value of this biomarker