Abstract There is a rapid growth of national space launch ambitions and capabilities, e.g. delivering satellites into low-earth and sun-synchronous orbits. With vertical and horizontal delivery methods, and numerous locations under consideration in several continents, the industry has faced early challenges, such as failed launches and licencing timescales. This paper explores the increasing intersection between aviation and air traffic management (ATM) with higher airspace operations (HAOs). It introduces the background and principles of space launches, before addressing the particular impacts on aviation and ATM. The strategic challenges of planning launch windows to align both with orbiting asset congestion and ATM demands, plus promulgating such information to airspace users, is discussed. In the tactical phase, the consequences of impacts on airspace users (such as the re-routing of flights) and on air navigation service providers (such as the demands of coordinating airspace closures in the context of considerable re-entry/splashdown uncertainty) are discussed. A key contribution we make in this paper is the first aircraft-specific, fuel and operating cost analysis of HAO impacts, and the first such European cost assessment, with basic impact geometries. We also propose improved aircraft-specific impact models, which include passenger-centric costs.
Christelle Gross, G. Le-Bel, Pascale Desjardins
et al.
In order to reduce the need for donor corneas, understanding of corneal wound healing and development of an entirely tissue-engineered human cornea (hTECs) is of prime importance. In this study, we exploited the hTEC to determine how deep wound healing affects the transcriptional pattern of corneal epithelial cells through microarray analyses. We demonstrated that the gene encoding clusterin (CLU) has its expression dramatically repressed during closure of hTEC wounds. Western blot analyses confirmed a strong reduction in the expression of the clusterin isoforms after corneal damage and suggest that repression of CLU gene expression might be a prerequisite to hTEC wound closure. Transfection with segments from the human CLU gene promoter revealed the presence of three regulatory regions: a basal promoter and two more distal negative regulatory regions. The basal promoter bears DNA binding sites for very potent transcription factors (TFs): Activator Protein-1 (AP-1) and Specificity protein-1 and 3 (Sp1/Sp3). By exploiting electrophoretic mobility shift assays (EMSA), we demonstrated that AP-1 and Sp1/Sp3 have their DNA binding site overlapping with one another in the basal promoter of the CLU gene in hCECs. Interestingly, expression of both these TFs is reduced (at the protein level) during hTEC wound healing, thereby contributing to the extinction of CLU gene expression during that process. The results of this study contribute to a better understanding of the molecular mechanisms accounting for the repression of CLU gene expression during corneal wound healing.
This research aims to look at the importance of a Sharia Institution in orienting its institutions on an orientation based on benefit. This research is based on the lack of attention of some Sharia Institutions on the principle of the basic purpose of Sharia that is to be able to achieve benefit. In this study will be seen the influence of benefit on satisfaction and loyalty to the Sharia Institution in. This research will use structural equation model method as data processing technique. Data is collected using quiestionaire distributed to sharia institutions customers. This research found that orientation in maslahah is a very important factor in building loyalty to Sharia Institutions. In addition, the orientation on the maslahah needs to be improved as a means in improving customer satisfaction. The results of this study are expected to be the basis for sharia institutions to focus more on the orientation of maslahah for their institutions in accordance with the basic principles of Sharia itself
It is well documented that human hepatic clearance based on in vitro metabolism or transporter assays systematically resulted in underprediction; therefore, large empirical scalars are often needed in either static or physiologically based pharmacokinetic (PBPK) models to accurately predict human pharmacokinetics (PK). In our current investigation, we assessed hepatic uptake in hepatocyte suspension in Krebs-Henseleit buffer in the presence and absence of serum. The results showed that the unbound intrinsic active clearance (CLu,int,active) values obtained by normalizing the unbound fraction in the buffer containing 10% serum were generally higher than the CLu,int,active obtained directly from protein free buffer, suggesting “protein-facilitated” uptake. The differences of CLu,int,active in the buffer with and without protein ranged from 1- to 925-fold and negatively correlated to the unbound serum binding of organic anion transporting polypeptide substrates. When using the uptake values obtained from buffer containing serum versus serum-free buffer, the median of scaling factors (SFs) for CLu,int,active reduced from 24.2–4.6 to 22.7–7.1 for human and monkey, respectively, demonstrating the improvement of in vitro to in vivo extrapolation in a PBPK model. Furthermore, values of CLu,int,active were significantly higher in monkey hepatocytes than that in human, and the species differences appeared to be compound dependent. Scaling up in vitro uptake values derived in assays containing species-specific serum can compensate for the species-specific variabilities when using cynomolgus monkey as a probe animal model. Incorporating SFs calibrated in monkey and together with scaled in vitro data can be a reliable approach for the prospective human PK prediction in early drug discovery. SIGNIFICANCE STATEMENT We investigated the protein effect on hepatic uptake in human and monkey hepatocytes and improved the in vitro to in vivo extrapolation using parameters obtained from the incubation in the present of serum protein. In addition, significantly higher active uptake clearances were observed in monkey hepatocytes than in human, and the species differences appeared to be compound dependent. The physiologically based pharmacokinetic model that incorporates scaling factors calibrated in monkey and together with scaled in vitro human data can be a reliable approach for the prospective human pharmacokinetics prediction.
Late-onset Alzheimer’s disease (LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older. LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decl ine, increased neuronal death and brain atrophy, and significant cognitive impairment. Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials. These failures underscore the significance of identifying the LOAD risk mechanisms that would allow early intervention in the preclinical stage of LOAD. Genome-wide association studies have identified more than a dozen genetic risk variants that are associated with the development of LOAD. Clusterin (CLU), also known as apolipoprotein J (APOJ), has been established as the third most prominent genetic risk factor for LOAD after apolipoprotein E (APOE) and bridging integrator 1 (BIN1) (Harold et al., 2009; Lambert et al., 2009). A number of single nucleotide polymorphisms (SNPs) within the CLU locus, with the majority being intronic, have been linked to significantly altered LOAD risk, independent of APOE status (Figure 1A; (Medical Genetics and Human Variation, 2019)); however, it is unclear how these SNPs affect CLU mRNA, protein isoform expression and function.
GSK3527497, a pre-clinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdu and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdu and present results that suggests that molecular shape-dependent binding to tissue components govern Vdu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a pre-clinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.
K. Bettens, Steven Vermeulen, Caroline Van Cauwenberghe
et al.
BackgroundThe clusterin (CLU) gene has been identified as an important risk locus for Alzheimer’s disease (AD). Although the actual risk–increasing polymorphisms at this locus remain to be identified, we previously observed an increased frequency of rare non-synonymous mutations and small insertion-deletions of CLU in AD patients, which specifically clustered in the β-chain domain of CLU. Nonetheless the pathogenic nature of these variants remained unclear.Here we report a novel non-synonymous CLU mutation (p.I360N) in a Belgian Alzheimer patient and have explored the pathogenic nature of this and 10 additional CLU mutations on protein localization and secretion in vitro using immunocytochemistry, immunodetection and ELISAs.ResultsThree patient-specific CLU mutations in the β-chain (p.I303NfsX13, p.R338W and p.I360N) caused an alteration of the subcellular CLU localization and diminished CLU transport through the secretory pathway, indicative of possible degradation mechanisms. For these mutations, significantly reduced CLU intensity was observed in the Golgi while almost all CLU protein was exclusively present in the endoplasmic reticulum. This was further confirmed by diminished CLU secretion in HEK293T and HEK293 FLp-In cell lines.ConclusionsOur data lend further support to the contribution of rare coding CLU mutations in the pathogenesis of neurodegenerative diseases. Functional analyses suggest reduced secretion of the CLU protein as the mode of action for three of the examined CLU mutations. One of those is a frameshift mutation leading to a loss of secreted protein, and the other two mutations are amino acid substitutions in the disulfide bridge region, possibly interfering with heterodimerization of the α- and β-chain of CLU.
L. Elias-Sonnenschein, S. Helisalmi, T. Natunen
et al.
Objectives To understand the relation between risk genes for Alzheimer’s disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aβ1–42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Methods We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland. Results APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aβ1–42 (corrected p0.05). Conclusions We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aβ1–42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ1–42.
AbstractThis study addresses the characteristics of the nightside magnetospheric current system using the analogy of an electric circuit. The modeled circuit consists of the generator (V: solar wind), inductor (L: tail lobes), capacitor (C: plasma sheet convection), and resistor (R: particle energization). The electric circuit has three time constants: τCR(=CR), , and τL/R(=L/R). Here τCR is of the order of the ion gyroperiod in the plasma sheet, τLC is a global timescale (2πτLC is several tens of minutes), and τL/R is even longer (several hours). Despite uncertainty in the estimate of each circuit element, τCR ≪ τLC ≪ τL/R holds generally for the magnetosphere, which characterizes the electric circuit as overdamped. The following implications are obtained: (1) During the substorm growth phase the cross‐tail current increases continuously even if interplanetary magnetic field (IMF) BZ does not change after southward turning; (2) the magnetotail current weakens following northward turnings if the change of IMF BZ is comparable to the preceding southward IMF BZ; otherwise it may strengthen continuously if more gradually; (3) during the early main phase of magnetospheric storms the enhancement of the lobe magnetic energy is far more prominent than the enhancements of the kinematic and kinetic energies of the plasma sheet plasma; (4) The efficiency of the solar wind‐magnetosphere coupling changes on a timescale of several hours (τL/R) through the change of the tail flaring, and so does the cross polar‐cap potential; and (5) the magnetospheric current system does not resonate to an oscillatory external driver, and therefore, the periodicity of some magnetotail phenomena reflects that of their triggers.
Abstract. The characteristics of stably stratified canopy flows in complex terrain are investigated by employing the Renormalized Group (RNG) k-ε turbulence model. In this two-dimensional simulation, we imposed persistent constant heat flux at ground surface and linearly increasing cooling rate in the upper canopy layer, vertically varying dissipative force from canopy drag elements, buoyancy forcing induced from thermal stratification and the hill terrain. These strong boundary effects keep nonlinearity in the two-dimensional Navier–Stokes equations high enough to generate turbulent behavior. The fundamental characteristics of nighttime canopy flow over complex terrain measured by a few multi-tower advection experiments can be produced by this numerical simulation, such as: (1) unstable layer in the canopy, (2) super-stable layer associated with flow decoupling in deep canopy and near the top of canopy, (3) upward momentum transfer in canopy, and (4) large buoyancy suppression and weak shear production in strong stability.