A Comparison of Astronaut Near-Earth Object Missions

NASA intends to send astronauts to a near Earth object (NEO) in or around 2025. This is expected to involve a six month mission with a few weeks stay-time at the NEO. Problems with this concept include lack of abort modes, vulnerability to solar flares, and lack of resupply opportunities. Studies by the authors (the Asteroid Mining Group) and a recent workshop at JPL organized by the Keck Institute opens the door to an alternative that addresses these problems and creates additional opportunities. Both groups investigated the feasibility of bringing one of more small NEOs into Earth or Lunar orbit. Particularly for High Earth Orbits (HEO) or High Lunar Orbits (HLO), this appears feasible with near-term technology, especially high-propellant-velocity, low-thrust solar electric propulsion (SEP) inspace vehicles. This paper compares the currently planned mission with an alternative: bringing one or more NEOs into HEO or HLO using SEP and lunar gravity assist. An astronaut mission to the NEO is then similar to a mission to the Moon without a landing. Trip times are measured in days, the NEO can be used for solar flare protection for most of the mission, and resupply within a few days is practical. Furthermore, materials derived from the NEO, e.g., propellant, water, radiation shielding, metals, silicon, and others, are available for projects in cis-lunar space, including satellite refueling, habitats, and space solar power. The alternative mission also develops much of the technology, experience, and infrastructure needed to protect Earth from potentially hazardous NEOs. As an outcome of these studies we are proposing a process whereby early missions can lead to large-scale industrialization of cis-lunar space based on solar energy and asteroidal resources

DNA replication stress restricts ribosomal DNA copy number

Ribosomal RNAs (rRNAs) in budding yeast are encoded by ~100–200 repeats of a 9.1kb sequence arranged in tandem on chromosome XII, the ribosomal DNA (rDNA) locus. Copy number of rDNA repeat units in eukaryotic cells is maintained far in excess of the requirement for ribosome biogenesis. Despite the importance of the repeats for both ribosomal and non-ribosomal functions, it is currently not known how “normal” copy number is determined or maintained. To identify essential genes involved in the maintenance of rDNA copy number, we developed a droplet digital PCR based assay to measure rDNA copy number in yeast and used it to screen a yeast conditional temperature-sensitive mutant collection of essential genes. Our screen revealed that low rDNA copy number is associated with compromised DNA replication. Further, subculturing yeast under two separate conditions of DNA replication stress selected for a contraction of the rDNA array independent of the replication fork blocking protein, Fob1. Interestingly, cells with a contracted array grew better than their counterparts with normal copy number under conditions of DNA replication stress. Our data indicate that DNA replication stresses select for a smaller rDNA array. We speculate that this liberates scarce replication factors for use by the rest of the genome, which in turn helps cells complete DNA replication and continue to propagate. Interestingly, tumors from mini chromosome maintenance 2 (MCM2)-deficient mice also show a loss of rDNA repeats. Our data suggest that a reduction in rDNA copy number may indicate a history of DNA replication stress, and that rDNA array size could serve as a diagnostic marker for replication stress. Taken together, these data begin to suggest the selective pressures that combine to yield a “normal” rDNA copy number

Glycated albumin modulates the contact system with implications for the kallikrein-kinin and intrinsic coagulation systems

Background Human serum albumin (HSA) is the most abundant plasma protein and is sensitive to glycation in vivo. The chronic hyperglycemic conditions in patients with diabetes mellitus (DM) induce a nonenzymatic Maillard reaction that denatures plasma proteins and forms advanced glycation end products (AGEs). HSA-AGE is a prevalent misfolded protein in patients with DM and is associated with factor XII activation and downstream proinflammatory kallikrein-kinin system activity without any associated procoagulant activity of the intrinsic pathway. Objectives This study aimed to determine the relevance of HSA-AGE toward diabetic pathophysiology. Methods The plasma obtained from patients with DM and euglycemic volunteers was probed for activation of FXII, prekallikrein (PK), and cleaved high-molecular-weight kininogen by immunoblotting. Constitutive plasma kallikrein activity was determined via chromogenic assay. Activation and kinetic modulation of FXII, PK, FXI, FIX, and FX via in vitro–generated HSA-AGE were explored using chromogenic assays, plasma-clotting assays, and an in vitro flow model using whole blood. Results Plasma obtained from patients with DM contained increased plasma AGEs, activated FXIIa, and resultant cleaved cleaved high-molecular-weight kininogen. Elevated constitutive plasma kallikrein enzymatic activity was identified, which positively correlated with glycated hemoglobin levels, representing the first evidence of this phenomenon. HSA-AGE, generated in vitro, triggered FXIIa-dependent PK activation but limited the intrinsic coagulation pathway activation by inhibiting FXIa and FIXa-dependent FX activation in plasma. Conclusion These data indicate a proinflammatory role of HSA-AGEs in the pathophysiology of DM via FXII and kallikrein-kinin system activation. A procoagulant effect of FXII activation was lost through the inhibition of FXIa and FIXa dependent FX activation by HSA-AGEs

Functional and Structural Characteristics of Tumor Angiogenesis in Lung Cancers Overexpressing Different VEGF Isoforms Assessed by DCE- and SSCE-MRI

The expressions of different vascular endothelial growth factor (VEGF) isoforms are associated with the degree of tumor invasiveness and the patient's prognosis in human cancers. We hypothesized that different VEGF isoforms can exert different effects on the functional and structural characteristics of tumor angiogenesis. We used dynamic contrast-enhanced MRI (DCE-MRI) and steady-state contrast-enhanced MRI (SSCE-MRI) to evaluate in vivo vascular functions (e.g., perfusion and permeability) and structural characteristics (e.g., vascular size and vessel density) of the tumor angiogenesis induced by different VEGF isoforms (VEGF121, VEGF165, and VEGF189) in a murine xenograft model of human lung cancer. Tumors overexpressing VEGF189 were larger than those overexpressing the other two VEGF isoforms. The Ktrans map obtained from DCE-MRI revealed that the perfusion and permeability functions of tumor microvessels was highest in both the rim and core regions of VEGF189-overexpressing tumors (p<0.001 for both tumor rim and core). The relative vessel density and relative vessel size indexes derived from SSCE-MRI revealed that VEGF189-overexpressing tumors had the smallest (p<0.05) and the most-dense (p<0.01) microvessels, which penetrated deeply from the tumor rim into the core, followed by the VEGF165-overepxressing tumor, whose microvessels were located mainly in the tumor rim. The lowest-density microvessels were found in the VEGF121-overexpressing tumor; these microvessels had a relatively large lumen and were found mainly in the tumor rim. We conclude that among the three VEGF isoforms evaluated, VEGF189 induces the most densely sprouting and smallest tumor microvessels with the highest in vivo perfusion and permeability functions. These characteristics of tumor microvessels may contribute to the reported adverse effects of VEGF189 overexpression on tumor progression, metastasis, and patient survival in several human cancers, including non-small cell lung cancer, and suggest that applying aggressive therapy may be necessary in human cancers in which VEGF189 is overexpressed

Albert Pierrepoint and the cultural persona of the twentieth-century hangman

Albert Pierrepoint was Britain’s most famous 20th-century hangman. This article utilises diverse sources in order to chart his public representation, or cultural persona, as hangman from his rise to prominence in the mid-1940s to his portrayal in the biopic Pierrepoint(2005). It argues that Pierrepoint exercised agency in shaping this persona through publishing his autobiography and engagement with the media, although there were also representations that he did not influence. In particular, it explores three iterations of his cultural persona – the Professional Hangman, the Reformed Hangman and the Haunted Hangman. Each of these built on and reworked historical antecedents and also communicated wider understandings and contested meanings in relation to capital punishment. As a hangman who remained in the public eye after the death penalty in Britain was abolished, Pierrepoint was an important, authentic link to the practice of execution and a symbolic figure in debates over reintroduction. In the 21st century, he was portrayed as a victim of the ‘secondary trauma’ of the death penalty, which resonated with worldwide campaigns for abolition

Expression of FAP-1 by human colon adenocarcinoma: implication for resistance against Fas-mediated apoptosis in cancer

Although colon carcinoma cells express Fas receptors, they are resistant to Fas-mediated apoptosis. Defects within the intracellular Fas signal transduction may be responsible. We investigated whether the Fas-associated phosphatase-1 (FAP-1), an inhibitor of Fas signal transduction, contributed to this resistance in colon carcinomas. In vivo, apoptosis of cancer cells was detected in situ using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling ( TUNEL). FAP-1, FasR, and Fas ligand (FasL) were detected using immunohistochemistry. In vitro, colon carcinoma cells were primarily cultured, and their sensitivity to Fas-mediated apoptosis was evaluated by treatment with agonistic anti-FasR CH11 IgM monoclonal antibody in the presence or absence of synthetic Ac-SLV (serine-leucine-valine) tripeptide. Fas-associated phosphatase-1 expression was detected in 20 out of 28 colon adenocarcinomas. In vivo, a positive correlation between the percentage of apoptotic tumour cells and the number of FasL-positive tumour infiltrating lymphocytes was observed in FAP-1 negative cancers, but not in FAP-1-positive ones. Primarily cultured colon cancer cells, which were refractory to CH-11-induced apoptosis, had higher expression of FAP-1 on protein and mRNA levels than the sensitive group. Resistance to Fas-mediated apoptosis in tumour cells could be abolished by Ac-SLV tripetides. Fas-associated phosphatase-1 expression protects colon cancer cells from Fas-mediated apoptosis, and blockade of FAP-1 and FasR interaction sensitises tumour cells to Fas-dependent apoptosis

In-Vivo Visualization of Tumor Microvessel Density and Response to Anti-Angiogenic Treatment by High Resolution MRI in Mice

Purpose: Inhibition of angiogenesis has shown clinical success in patients with cancer. Thus, imaging approaches that allow for the identification of angiogenic tumors and the detection of response to anti-angiogenic treatment are of high clinical relevance. Experimental Design: We established an in vivo magnetic resonance imaging (MRI) approach that allows us to simultaneously image tumor microvessel density and tumor vessel size in a NSCLC model in mice. Results: Using microvessel density imaging we demonstrated an increase in microvessel density within 8 days after tumor implantation, while tumor vessel size decreased indicating a switch from macro- to microvessels during tumor growth. Moreover, we could monitor in vivo inhibition of angiogenesis induced by the angiogenesis inhibitor PTK787, resulting in a decrease of microvessel density and a slight increase in tumor vessel size. Conclusions: We present an in vivo imaging approach that allows us to monitor both tumor microvessel density and tumor vessel size in the tumor. Moreover, this approach enables us to assess, early-on, treatment effects on tumor microvessel density as well as on tumor vessel size. Thus, this imaging-based strategy of validating anti-angiogenic treatment effects ha

Classification of Camellia (Theaceae) Species Using Leaf Architecture Variations and Pattern Recognition Techniques

Leaf characters have been successfully utilized to classify Camellia (Theaceae) species; however, leaf characters combined with supervised pattern recognition techniques have not been previously explored. We present results of using leaf morphological and venation characters of 93 species from five sections of genus Camellia to assess the effectiveness of several supervised pattern recognition techniques for classifications and compare their accuracy. Clustering approach, Learning Vector Quantization neural network (LVQ-ANN), Dynamic Architecture for Artificial Neural Networks (DAN2), and C-support vector machines (SVM) are used to discriminate 93 species from five sections of genus Camellia (11 in sect. Furfuracea, 16 in sect. Paracamellia, 12 in sect. Tuberculata, 34 in sect. Camellia, and 20 in sect. Theopsis). DAN2 and SVM show excellent classification results for genus Camellia with DAN2's accuracy of 97.92% and 91.11% for training and testing data sets respectively. The RBF-SVM results of 97.92% and 97.78% for training and testing offer the best classification accuracy. A hierarchical dendrogram based on leaf architecture data has confirmed the morphological classification of the five sections as previously proposed. The overall results suggest that leaf architecture-based data analysis using supervised pattern recognition techniques, especially DAN2 and SVM discrimination methods, is excellent for identification of Camellia species

Nicotinic acetylcholine receptors modulate osteoclastogenesis

Background: Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis. Methods: The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis. Oscillations in the intracellular calcium concentration were detected by measuring the Fura-2 fluorescence intensity. Results: We could demonstrate the presence of several nAChR subunits in bone marrow-derived macrophages stimulated with RANKL and M-CSF, and showed that they are capable of producing acetylcholine. nAChR ligands reduced the number of osteoclasts as well as the number of tartrate-resistant acidic phosphatase-positive mononuclear cells in a dose-dependent manner. In vitro RANKL-mediated osteoclastogenesis was reduced in mice lacking α7 homomeric nAChR or β2-containing heteromeric nAChRs, while bone histomorphometry revealed increased bone volume as well as impaired osteoclastogenesis in male mice lacking the α7 nAChR. nAChR ligands inhibited RANKL-induced calcium oscillation, a well-established phenomenon of osteoclastogenesis. This inhibitory effect on Ca2+ oscillation subsequently led to the inhibition of RANKL-induced NFATc1 and c-fos expression after long-term treatment with nicotine. Conclusions: We have shown that the activity of nAChRs conveys a marked effect on osteoclastogenesis in mice. Agonists of these receptors inhibited calcium oscillations in osteoclasts and blocked the RANKL-induced activation of c-fos and NFATc1. RANKL-mediated in-vitro osteoclastogenesis was reduced in α7 knockout mice, which was paralleled by increased tibial bone volume in male mice in vivo. © 2016 Mandl et al