The hypersonic, speed regime from Mach 5 that has become one of the new areas of competition between the great powers in the world, has not yet finished running ink.
Whether the hypersonic drone developed by the 611 Chengdu Institute of the AVIC aircraft manufacturer, the hypersonic glider "DF-17" of the CASC group, or the specific test benches "Ling Yun" of the National University of Defense Technology and MF-1 from the China Aerodynamics Research and Development Center , not to mention the recent " CAI Institute " Waverider "Xing Kong 2" trial and many parallel fundamental research at Chinese universities. more well known, there are not any projects that are lacking in this field in China.
While all major Chinese institutions have started physical testing of their equipment one after the other, the Chinese Academy of Sciences (CAS), one of the country's largest basic research entities, seems to be relatively silent on the subject so far. But things have started to change recently.
According to a television report from the national military channel CCTV-7, which airs on Friday, September 21, the Institute of Mechanics (IMECH ), a subsidiary of CAS, has successfully completed a trial release of three small-scale prototypes from a balloon at the Jiuquan Space Center the same day.
We learn then that the three gears, named respectively D18-1S, D-182S and D-183S, of different aerodynamic configuration, separated from their carrier one after the other and each recorded its own descent in free fall then the acceleration, the crossing of the sound wall, the aerodynamic rebound, the deployment of parachute and finally the recovery on the ground.
"After the dropping, the basket is separated from the balloon and returned to the ground with a parachute, the balloon exploded at a certain altitude," says the report, "This is the first time in China that a test of dropping large envelope gear from a balloon is made.
Although it is not specified, but it is thought that the word "big envelope" (宽 域) here would mean the speed envelope. The 36-second report also did not indicate which organization designed and conducted these tests, nor did it detail the associated technical data.
So what do we know about these machines named D18-1S, D18-2S and D18-3S?
First, it can be noted that of the three reduced-scale machines in question, two appear to be constructed of conventional aluminum alloy, hence their pale green color due to the anti-corrosion layer, although the extrados of their wing would be covered with unidentified dark matter.
These two "green" aircraft have both opted for a delta wing with an integrated fuselage. The first is equipped with a double vertical drift and a wing in double delta rather high, while the one hung in the middle under the nacelle of the balloon is in mono-drift with a wing delta rather median which seems to be in dihedral slightly negative.
What seems most astonishing is the third gear, in black livery entirely, which has a rather unusual aerodynamic configuration. Indeed, the fuselage, conical Spitzer ball shape, is fixed under a bearing surface (?) Which looks like a flat arrow of elongated square base.
And it is precisely this last device atypical that makes it possible to make the link with the Institute IMECH of the Chinese Academy of Sciences, in particular with their last publication at the beginning of the year concerning a new configuration in "I" for the hypersonic diet (" Hypersonic I-shaped aerodynamic configurations ").
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The main objective of this research is to try to reconcile two contradictory parameter groups for the design of a hypersonic engine - on the one hand the finesse to ensure the range and the lift for the best cruising conditions in the high altitude, and the usable volume of the other.
To obtain a high finesse, the general idea nowadays is to make a machine rather flat and with a rather high angle of arrow, but such a configuration naturally has a surface-volume ratio (SA: V) not very exploitable. The work carried out by IMECH for 10 years on the subject, more specifically via its national laboratory LHD ( State Key Laboratory of High Temperature Gas Dynamics ), are trying to remedy this problem.
Our research on this work by IMECH LHD shows that the concept of this "I" configuration, or rather called by their researchers the concept of "High Pressure Capturing Wing" (HCW), appeared not in 2018, but rather between 2012 and 2013, and this in the form of scientific publications.
The idea is to "capture" the inflow that is compressed by the front of the craft, by a rather thin surface placed just above it to create a zone of overpressure under this same surface. All this allows to generate new lift for the whole without the cell of the machine must be designed according to the usual constraints which makes it can voluminous.
In older IMECH academic papers, the word "lift compensator" was often used before "HCW" was chosen to describe the concept. The Institute's studies show that with a suitable SA: V given at 0.175, a hypersonic machine with such a configuration can reach a fineness of 4.5, with an improved lift coefficient of the order of 60%. in optimal conditions compared to more "classic" configurations such as the Waverider.
The hypersonic glider HTV-2, for example, obtained an average fineness of 2.6 during its tests, while the program was between 3.4 and 4.
We learn, by going deeper into this research of the Chinese Academy of Sciences, that the original idea of this wing used to generate more lift and thus improve the smoothness of a hypersonic machine seems to come from the work of an LHD aerodynamic researcher on a hypersonic missile with deployable arch wing.
CUI Kai (崔 凯), specialized in aerodynamic design and optimization, studied in 2008 the possibility of improving the finesse of a hypersonic missile, flying at Mach 6 and at an angle of incidence of 6 °, at using two wings taking the same shape as the missile cell and deployable on demand.
Two years later, a patent entitled "High-Speed Lift Compensation Machine" was filed by CUI and three of its colleagues. The invention relates to a machine with an arched wing fixed above the fuselage.
And the work has continued until this year, if we believe the documents published by the same team of researchers since 2012. For example, we know that scientists in question have studied the possibility of integrating this concept of HCW to a Waverider configuration, still for hypersonic flights, in 2013.
In October 2014, two new patents were filed, one pertaining to a "High Speed Flying Gear with a Folding High Wing (HCW)", and the other around a "Height Adjustment Device". high wing (HCW) compared to its high-speed craft.
These two new documents show that IMECH researchers have continued to evolve their concept to be more adaptive to different flight conditions. If the shape of the so-called HCW seems rudimentary until then, it is in January 2016 that CUI and his colleagues published a study in which the various possible forms of HCW are optimized and analyzed.
If we now compare the theoretical schemes in these publications with the black machine appeared in the real test of September 21 this year, we can practically certain that they are the same thing and that the IMECH, after several years of research funded by the National Natural Science Foundation of China (NSFC) ¹, decided to take the step to conduct evaluation tests.
This is probably because it would be the first conceptual test that the machine seems to be greatly simplified - the integration with the Waverider configuration for the fuselage part is totally absent, likewise for a more complex form HCW without speaking the device that adjusts the height between the HCW and the main fuselage.
The test conditions, from a balloon and with small-scale free-scale models, suggest that the tests are only in their infancy, so far from what some media claim, according to which China has tested "several military gear in hypersonic speed ".
On the subject of speed, the CCTV-7 report is very clear on this, the machines whatever they have "crossed the wall of sound", which is also very far from the hypersonic regime, but everything to makes consistent for a very first physical concept test. As a result, it's a safe bet that the balloon did not climb very high in the stratosphere, because theoretically only 6,000 meters in free fall would have been enough for the machines to exceed Mach 1. But given the need for Data collection, the gear could have dropped two to three times higher before the balloon is torn by the expansion of gas stored.
As for the two other gears in green color, the documents published since 2012 show that IMECH also worked with the CASIC Chinese Missile Group Academy No. 3 on a "hypersonic aircraft" with double side air intakes. And there is some physical resemblance between these two green gear and the CFG_C configuration studied in these publications.
But since the mere argument of physical resemblance too often gives random and unreliable conclusions, it is necessary to wait for other elements to confirm this hypothesis.
It should be noted that the IMECH is strengthening its means of testing on high-speed machines, in other words the hypersonic domain. Indeed, the Chinese institute has just launched a public tender to acquire a set of multispectral and optical tracking systems for "high-speed" targets, with a rather modest budget of 3 million Yuan. , or 377 thousand euros.
Behind the relative modest sum hides a certain ambition of the IMECH Institute to enter durably into this very closed club of institutions in China that are able to conceive, and especially materialize, gear in a hypersonic regime.
It was recalled that it was this Chinese institution that put into orbit, in August 2016, a "satellite of scientific experiments of the rarefied atmosphere" (稀薄 大气 科学 实验 卫星) named LiXing-1, which was used to analyze and map the detailed composition of the upper atmosphere around the Earth, data both sensitive and necessary for hypersonic flight.
It is also in this same institute where is one of the most advanced hypersonic wind tunnels in China, the famous JF-12. This 1,000-tonne, 2.5-meter diameter wind tunnel is capable of reproducing flight conditions between 25 and 45 km altitude, at a speed between Mach 5 and 9, for a duration greater than 100 ms and a Reynolds number between 1 × 10 ^ 5 and 5.9 × 10 ^ 7 / m.
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The acquisition of monitoring means shows that IMECH will now leave its laboratory and extend the scope of its research until the products are realized. So we will certainly have the opportunity to come back on the subject and learn more about the next tests of the three machines revealed in September.
¹ NSFC is a foundation directly attached to the Chinese Ministry of Science and Technology. Since 2010, it has managed more than 10 billion yuan (about 1.3 billion euros) in annual budgets allocated to national research programs.
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Conducted the first flight test of mode transiting combined engine.
The project is to build multiple use, horizontal take off and landing spaceplane.
The report is on September 29th.
CCTV news reported on 26th.
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high supersonic and high altitude (near space).
The application of such engine and aircraft is not only for space launching, but also for global strike within one hour as US has envisioned and been doing.
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Here's a video. Maybe we'll get better quality.
Here's another but they added some documentary on hypersonic weapons segment.
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The last three days have been marked by several strange military tests that have taken place in the west of China, in any case what suggests a series of messages to aircrafts (NOTAM) active between Saturday 20 and the Monday, October 22, 2018. Even if nothing is officially confirmed yet and all are only working hypotheses at the moment, there is reason to believe that the force of Chinese rockets would have led some shots for the least curious, including three that could possibly be assimilated to flights of hypersonic glider.
The first of these five events is relatively traditional and is signaled by two NOTAMs, which indicate the presence of four closed air segments at any altitude between the Taklamakan Desert and the northwestern part of Qinghai Province.
1. W112: 100KM EAST OF HOTAN VOR 'HTN'- 20KM WEST OF QIEMO VOR 'QIM'.
Note that the NOTAM A4471 / 18 is active on two well-distinguished time slots - the first between 09:50 and 11:00 hours in Beijing, and the second from 16:15 to 17:10, all in the same day Saturday, October 20.
This first event is followed quickly by a second one that comes just three hours later, but this time with a rather clear indication that it is a ballistic missile launch. Indeed, one of the two NOTAMs that are active from 12:47 to 13:55 Beijing time highlights a fallout area located about 173 km from the Taiyuan Space Center (TSLC). It is since this installation inaugurated in 1968 that the Chinese army conducts part of its ballistic tests or hypersonic flying machine.
It should be noted that this fallout area is small compared to other ballistic missile fire observed so far. But it is thanks to her that one can suppose that the missile or the launcher left the TSLC in direction northwest-west. If we draw a straight line from the center of Taiyuan and cross this fallout zone, it will reach a firing range about 1,500 km farther, where there are several targets simulating US military infrastructure in Asia. 'Is, especially in Japan.
CLSD AT 6000M AND BELOW.
If this second launch that took place on Saturday, October 20 suggests that it could be a "simple" ballistic missile test, a third group of NOTAMs of the same day came to make the attempt to analyze more difficult, but also more interesting.
Indeed, the six NOTAMs that were active from 4:10 pm to 5:10 pm local time this day, that is to say a little more than four hours after the previous shot, report the presence of not one but two areas of fallout , from here is added some forbidden hover segments.
The two drop zones in question have several peculiarities, the most striking being that they are not on the same axis of fire but shifted to each other more than 370 km. The first, much smaller area is about 560 km from the TSLC center. The second is located in the south and measures 157,293 km² in area, 13 times larger than the Île-de-France, and nearly 1,300 km long.
If the first zone indicates quite explicitly that it is a fallout zone of a military launcher, the second zone seems much too large for it to be only that of a ballistic test. Note that the only comparable over the last 12 months dates back to July 2017, when the Chinese army conducted a gigantic coordinated shooting exercise to celebrate the 90th anniversary of its founding .
One of the possible explanations is that the Chinese People's Army has made a new fire from its "DF-17", the name given by US intelligence to designate the missile carrier and the Chinese hypersonic glider militarized. The large area would then represent the area of hypersonic leveling flight, once the machine has detached from the carrier and performed lateral maneuvers to change completely direction of flight.
This is of course only a working hypothesis that remains to be confirmed for the moment. We do not rule out the possibility that the first shot of October 20th is of the same nature, because the two actually share the same NOTAM, the A4471 / 18.
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text:
Proteinase-3 as the major autoantigen of c-ANCA is strongly expressed in lung tissue of patients with Wegener's granulomatosis
Holger Brockmann1,
Andreas Schwarting1,
Jörg Kriegsmann2,
Peter Petrow2,
Andreas Gaumann2,
Klaus-Michael Müller3,
Peter Robert Galle1 and
Werner Mayet4Email author
Arthritis Research & Therapy20024:220
https://doi.org/10.1186/ar410
© BioMed Central Ltd 2002
Accepted: 4 January 2002
Proteinase-3 (PR-3) is a neutral serine proteinase present in azurophil granules of human polymorphonuclear leukocytes and serves as the major target antigen of antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA) in Wegener's granulomatosis (WG). The WG disease appears as severe vasculitis in different organs (e.g. kidney, nose and lung). Little is known about the expression and distribution of PR-3 in the lung. We found that PR-3 is expressed in normal lung tissue and is upregulated in lung tissue of patients with WG. Interestingly, the parenchymal cells (pneumocytes type I and II) and macrophages, and not the neutrophils, express PR-3 most strongly and may contribute to lung damage in patients with WG via direct interaction with antineutrophil cytoplasmic antobodies (ANCA). These findings suggest that the PR-3 expression in parenchymal cells of lung tissue could be at least one missing link in the etiopathogenesis of pulmonary pathology in ANCA-associated disease.
granuloma
pneumocytes
proteinase-3
Wegener's granulomatosis
Proteinase-3 (PR-3) is a 29,000 Da neutral serine proteinase stored in the azurophil granules of polymorphonuclear leukocytes [1]. An increasing number of physiological and pathological properties of PR-3 have been reported. PR-3 has broad proteolytic activity and degrades a variety of extracellular matrix proteins, including fibronectin, type IV collagen and laminin [2, 3]. PR-3 is identical to myeloblastin, which is a growth-promoting protein from myeloid cells [4]. Via a nonproteolytic mechanism, PR-3 has potent antimicrobial activity both against bacteria and fungi [5, 6]. PR-3 was recently shown to induce apoptosis in cultured human endothelial cells [7]. PR-3 is also identical to the target antigen (antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern [c-ANCA]) associated with some systemic vasculitides such as WG and microscopic polyarteritis [8]. It is not yet known whether antineutrophil cytoplasmic antibodies (ANCA) are directly involved in the pathogenesis of WG or are merely an epiphenomenon [9–11].
It has previously been thought that PR-3 expression was confined to the promyelocytic/myelocytic stage of hematopoiesis [12]. However, other cells are also capable of de novo synthesis of PR-3 mRNA. In vitro studies revealed that PR-3 expression can be induced by cytokines in human endothelial cells [13, 14].
The lung is the organ most frequently involved in WG, and in some cases it is the only organ affected [15]. Given the potential importance of PR-3 in the pathogenesis of WG, we sought to define the expression pattern of PR-3 in lung tissue.
Normal tissues were obtained from five patients undergoing total pneumonectomy because of lung cancer. Tissue samples were snap-frozen in OCT Tissue Tek embedding medium (Leica Instruments, Hamburg, Germany).
We also obtained samples from five patients with WG and a proven lung involvement from the Institute of Pathology, University of Bochum/Clinic Bergmannsheil. All of these patients had a c-ANCA titer of more than 1:160 (indirect immunofluorescence on alcohol-fixed neutrophils).
Northern blot analysis
Total RNA was isolated from normal lung tissue with RNeasy (Quiagen, Hilden, Germany) and used for preparation of mRNA with the mRNA isolation kit (Hoffmann-La Roche, Grenzach-Whylen, Germany). The northern blot was performed as described by Müller-Ladner et al. [16].
Preparation of the single-strand PR-3 RNA probe
The cDNA sequences, used as probes for the mRNA of PR-3 components, were obtained by RT-PCR of total cellular mRNA of HL-60 cells, a myelomonocytic cell line [5]. The following primers were used in this study: PR-3 'sense', 5'-ATC-GTGGGCGGGCACGAGGCG (at the beginning of exon 2, corresponding to bases +82 to +101 of the cDNA); and PR-3 'antisense', 5'-GCGGCCAGGGAACGAAAGTGCA (at the end of exon 4, corresponding to bases +553 to +582). The expected size of the fragment was 500 base pairs. The cDNA fragment was extracted and purified from a preparative gel using the Wizard PCR preps DNA purification system (Promega A 7170, CA, USA) and subcloned into the polylinker site of bluescript SK+ (Stratagene, CA, USA).
Antisense and sense RNA probes were transcribed by T3 and T7 RNA polymerase using a commercially available RNA transcription kit, according to the protocol recommended by the manufacturer (Stratagene). Probes were labeled with Digoxigenin-UTP (Hoffmann-La Roche).
Frozen sections (4–6 μm) were cut, air-dried and fixed immediately in acetone for 15 min. Formaldehyde-fixed sections were deparaffinized according to standard procedure. The sections were prepared according to the method of Müller-Ladner et al. [16].
Immunological detection
The slides were washed in Tris-NaCl (pH7.6) and incubated in Tris-NaCl containing 2% normal goat serum (to block nonspecific binding) for 30 min at room temperature, followed by incubation with antidigoxigenin-alkaline phosphatase-antibody complex (Hoffmann-La Roche) in Tris-NaCl (pH7.6) for 1 hour at room temperature. Then 45 μl NBT (Boehringer Mannheim, Germany), 35 μl BCIP (Hoffmann-La Roche) and 24 μl Levamisole (Hoffmann-La Roche) were solved in 10 ml polyvinyl alcohol in a darkened chamber. Two hundred milliliters were applied to each section and incubated for between 12 and 24 hours. The sections were then mounted with aqueous gel (Faramount; Dako, Glostrup, Denmark) or stored at 4°C in Tris (pH7.6) for double-labeling by the alkaline phosphatase–antialkaline phosphatase (APAAP) method (see later).
Immunohistochemical double-labeling (APAAP method)
Double-labeling was performed using the APAAP method, with monoclonal antibody against CD68 (macrophages mouse IgG, 1:50; Dako), CD15 (granulocytes IgM, 1:50; Dianova, Hamburg, Germany), CD20 (B lymphocytes, 1:50; Dako), CD3 (T lymphocytes, 1:50; Dako), and Cytokeratin 8 and 19 (mouse IgG1, 1:25 and 1:200; Hoffmann-La Roche). Paraffin sections were prepared as described by Müller-Ladner et al. [16].
Double-labeling with biotin/fluorescence-coupled lectins
PR-3 hybridized sections were overlaid with fluorescein isothiocyanate/biotin-coupled Bauhinia purpurea and Maclura pomifera lectin diluted 1:200 and 1:500, respectively, for 30 min. Subsequently, slides were sequentially analyzed with light and fluorescent microscopy. The lectin of B. purpurea binds specifically to pneumocytes type I, whereas the lectin of M. pomifera binds to pneumocytes type II.
Microscopic evaluation and semiquantitative analysis of PR-3 mRNA expression
Sections were examined and photographed with a Leica Microscope DMRX (Leitz, Wetzlar, Germany). For quantitative analysis, a representative area between 1000 and 10,000 cells depending on the specimen was defined. In the representative areas, positive cells for PR-3 mRNA were scored in a semiquantitative fashion as follows: -, no positive cells; (+), <5% of cells positive; +, between 5% and 30% of cells positive; ++, between 30 and 60% of cells positive; +++, >60% of cells positive.
We searched for PR-3 mRNA expression in different human tissues. We confirmed the presence of a strong single 1.3 kb band (the expected size for PR-3 mRNA), especially in lung tissue. We found just a very weak signal in the heart and brain, and could not detect a band in liver tissue (Supplementary Fig. 1).
Supplementary Figure 1
Northern blot containing approximately 2 μg polyA RNA per lane from four different human tissues. Lanes 1–4 contain, in order, RNA from human heart, brain, liver and lung tissue. RNA size marker bands are indicated in the left margin of the blot (M).
In situ hybridization for PR-3 mRNA in normal lung
Nearly all PR-3 mRNA-positive cells were located at the alveolus covering cell layer (Fig. 1). PR-3 mRNA expression was mostly focused in areas showing macrophages in alveoles. The results obtained by in situ hybridization were reproducible in all biopsies. No hybridization signals were detected in the control experiments using a sense RNA probe (Supplementary Fig. 2).
Proteinase-3 (PR-3) mRNA is expressed in alveolar epithelial cells in a human lung specimen (arrows). The expression of PR-3 mRNA was detected by nonradioactive in situ hybridization. Double-labeling with CD15 revealed some infiltrating neutrophils (red cells), different from the PR-3 mRNA expressing cells (magnification, 40 × 2.5).
Human lung tissue (sense control; magnification, 20 × 2.5).
Characterization of PR-3 mRNA-positive cells in normal lung
With regard to the histomorphological appearance and localization of the PR-3-positive cells, these cells appeared to be mostly pneumocytes. Double-staining with fluorescent lectins of M. pomifera and B. purpurea lectins confirmed the PR-3 mRNA expression in pneumocytes type I and II (Figs 2 and 3). Double-staining with markers for granulocytes and macrophages revealed that the majority of the PR-3 mRNA-positive cells were different from these cells (Fig. 1). Only a few CD68-positive and CD15-positive cells also showed a signal for PR-3 mRNA (Fig. 4).
Proteinase-3 (PR-3) mRNA is expressed in pneumocytes type I in human lung tissue (arrows). The expression of PR-3 mRNA was detected by nonradioactive in situ hybridization, and the pneumocytes type I were detected by double-labeling with biotin-labeled lectins of Bauhinia purpurea (magnification, 60 × 2.5).
Proteinase-3 (PR-3) mRNA is expressed in pneumocytes type II in normal lung tissue (arrows). The expression of PR-3 mRNA was detected by nonradioactive in situ hybridization, and the pneumocytes type II were characterized by double-labeling with fluorescent lectins of Maclura pomifera (magnification, 60 × 2.5).
Proteinase-3 (PR-3) mRNA is expressed in macrophages (arrows). Some cells express the PR-3 mRNA detected by nonradioactive in situ hybridization and double-labeling with CD68, a marker for macrophages (magnification, 40 × 2.5).
In situ hybridization for PR-3 mRNA in lung tissue of WG patients
We studied lung tissue from five patients with histologically and clinically proven WG and lung involvement. We found a very pronounced PR-3 expression throughout the whole slide in all cases. In comparison with the normal lung tissue where the PR-3 expression was confined to just a few spots, the expression in WG tissue was nearly ubiquitous (Fig. 5). We also observed a strong positive PR-3 mRNA signal at the sites of granulomas, inflammatory infiltration and vasculitis (Supplementary Fig. 3).
Proteinase-3 (PR-3) mRNA expression in a Wegener's granulomatosis lung specimen. The PR-3 mRNA was found strongly expressed and dispersed all over the lung tissue. The expression of PR-3 mRNA was detected by nonradioactive in situ hybridization (magnification, 20 × 2.5).
Proteinase-3 (PR-3) mRNA expression in vasculitic structures. Nonradioactive in situ expression of PR-3 mRNA is shown in the infiltrating and surrounding cells of the vessel (magnification, 40 × 2.5).
To obtain a semiquantitative estimation of PR-3 expression difference, we counted all cells positive for PR-3 mRNA. We found an approximately double to threefold PR-3 expression in WG tissues compared with normal lung tissue (Table 1).
Semiquantitative analysis of proteinase-3 mRNA expression in normal lung and Wegener's granulomatosis (WG) lung specimens.
Normal lung
WG lung
A representative area between 1,000 and 10,000 cells depending on the specimen was defined. In the representative areas, positive cells for PR-3 mRNA were scored in a semiquantitative fashion: -, no positive cells; (+), < 5% of cells positive; +, between 5% and 30% of cells positive; ++, between 30 and 60% of cells positive; +++, > 60% of cells positive.
Characterization of PR-3 mRNA-positive cells in WG tissue
We found PR-3 mRNA expression mostly in pneumocytes type I and II. In comparison with normal tissue, however, there was a higher number of infiltrating, PR-3 expressing cells, different from pneumocytes.
Double-staining with different markers (CD20, CD3, CD15, and CD68) for inflammatory cells such as B cells, T cells, granulocytes and macrophages helped in the characterization of these cells. We detected B cells in some secondary lymphoid follicles and a few scattered in the tissue. T cells were virtually absent in the tissue. The B cells and T cells did not express PR-3 mRNA at all. Apart from some PR-3 mRNA expressing granulocytes, most of these infiltrating PR-3 mRNA expressing cells were macrophages (Supplementary Fig. 4). We found this kind of distribution of PR-3 mRNA expressing cells at sites of inflammatory infiltration, granulomas and vasculitis. At the site of vasculitis, we detected PR-3 mRNA-positive cells that were different from inflammatory cells. From their histopathological appearance, these cells could be endothelial cells (Supplementary Fig. 4).
Proteinase-3 mRNA expression in macrophages and endothelial cells in a Wegener's granulomatosis lung specimen. The macrophages are double-labeled with CD68 (red cells). The histomorphological appearance of the marked cell points to an endothelial cell (arrow) (magnification, 60 × 2.5).
Expression of the PR-3 protein in normal lung and WG tissue
To visualize the PR-3 protein expression, we performed immunohistological experiments with a monoclonal antibody (WGM2) from mice, specific for PR-3.
We found the PR-3 protein in only a few cells in normal lung tissue. According to the strong PR-3 mRNA expression, we also found an increased PR-3 protein expression in WG tissue (Fig. 6 and Supplementary Fig. 5).
Proteinase-3 (PR-3) is also expressed on the protein level (brown cells). The PR-3 protein was detected by WGM2 antibodies, specific for PR-3 (magnification, 60 × 2.5).
The proteinase-3 (PR-3) protein is expressed in pneumocytes type I in Wegener's granulomatosis tissue (arrows). The expression of PR-3 protein was detected by immunohistological staining with WGM2 antibodies, and the pneumocytes type I were detected by double-labeling with fluorescent lectins of Bauhinia purpurea (magnification, 60 × 2.5).
The diagnosis and classification of WG and related vasculitides were advanced considerably by characterization of serum antibodies that react with PR-3 (c-ANCA) [17]. It is not yet known whether ANCA are directly involved in the pathogenesis of WG or are merely an epiphenomenon [10]. One of the unresolved issues is the inability to explain the nonrandom, selected organ injury that defines the WG vasculitis and the concurrent, seemingly random, nature of injury within 'targeted' organs [18]. Little is known about the expression and distribution of PR-3 in the normal lung and in the lung tissue of patients with WG.
To contribute to this little-known issue, we examined the PR-3 expression in normal lung and lung tissue of WG patients, as the lung is the most frequent organ involved in WG [15]. In normal lung tissue, mainly pneumocytes type I and type II and just a few granulocytes and macrophages express PR-3. We could detect the PR-3 mRNA expression in pneumocytes especially at sites with an increased number of infiltrating macrophages. Speculatively, these cells could be responsible for initiating PR-3 mRNA expression; probably through changing the microenvironmental cytokine levels. Cytokines like interleukin-1 and tumor necrosis factor-α, secreted from macrophages, can induce PR-3 mRNA in nonhematopoietic cells [19].
The different expression of PR-3 in pneumocytes could also be due to variations of transcription factors. One possible candidate gene could be PU.1, which regulates the PR-3 transcription in B cells and macrophages. The expression in other nonhematopoietic cells, in particular pneumocytes, has not been extensively investigated [20, 21]. Although expressed in a very small amount in normal lung tissue, a question concerning the function of PR-3 in normal lung arose, since the occurrence of a proteolytic enzyme like PR-3 should not be favorable in this tissue [22]. It is tempting to speculate that PR-3 could also play a role in microbiologic defense, since the enzyme also has an antimicrobial function [6]. Further studies are clearly needed to elucidate the function of PR-3 in pneumocytes.
After we had proven that PR-3 mRNA is expressed in normal lung tissue, we questioned whether the expression pattern is different in the lung tissue of WG patients. The examined specimens of patients with WG showed strong PR-3 mRNA expression, with a double to threefold PR-3 mRNA increase compared with normal lung tissue. Similar to our findings in normal lung tissue, we could demonstrate in lung tissue of WG patients that PR-3 is mostly expressed in pneumocytes type I and type II. PR-3 expression was pronounced at sites of inflammatory infiltration, vasculitis and granulomas. In comparison with normal lung tissue, however, there was a higher number of infiltrating PR-3 expressing cells, which were not pneumocytes.
Apart from some PR-3 expressing granulocytes, most of the infiltrating PR-3 expressing cells were macrophages. One explanation for the occurrence of PR-3-positive macrophages in inflammatory tissue is the invasion of circulating monocytes to inflammatory sites. Just et al. showed an upregulation of PR-3 mRNA expression especially in circulating monocytes, but not in neutrophils, in patients with cystic fibrosis [23]. We found PR-3 mRNA expression in and around vascular structures and vasculitic lesions, where most of the infiltrating cells were characterized as macrophages. However, a few cells seemed to be endothelial cells. This is in line with our recent findings of de novo synthesis of PR-3 in endothelial cells [24]. On the contrary, most endothelial cells (even at multiple sites of acute vasculitis with inflammatory cells, invading the vessel and the surrounding tissue), were negative for PR-3 mRNA. Recent studies on the kinetics and stability of PR-3 transcripts revealed PR-3 mRNA expression is only transiently upregulated in endothelial cells [25].
The histological features within the WG specimens varied considerably with different inflammatory infiltrates and with or without granulomas. The only apparent issue the WG specimens have in common is the upregulation of PR-3 throughout the whole specimen. The upregulation of PR-3 in the lung of WG patients may therefore reflect the selected organ injury, whereas the histological heterogeneity may represent a multiplicity of concurrent immune responses to a unique disease precipitant like PR-3.
As it is most probable that pneumocytes, vascular endothelial cells and renal epithelial cells are no longer only innocent bystanders but active participants in inflammatory reactions of autoimmune vasculitides such as WG, it is very important to study the expression pattern of PR-3 in other organs or tissues that are involved in the manifestation pattern of WG [26]. Schwarting et al. showed the in vitro expression of PR-3 mRNA in tubular epithelial cells and glomerular epithelial cells of the kidney [25]. In vivo experiments in the kidney revealed a PR-3 expression in distal tubular epithelial cells and in the glomerulum. The PR-3 mRNA expressed by human glomerular epithelial cells correlates with crescent formation in patients with WG [25].
We thus envision that the upregulation of PR-3 in parenchymal lung tissue in patients with WG, probably through an altered cytokine pattern, can lead to PR-3/ ANCA-mediated lung damage. Further in vitro experiments and functional studies with pneumocytes will show whether the interaction of anti-PR-3 antibodies with pneumocytes will also activate signal transduction events or the expression of chemokines or adhesion molecules.
In conclusion, we report for the first time that PR-3 mRNA, the target antigen for c-ANCA, is expressed by normal lung parenchymal cells and is upregulated in lung tissue of WG patients. PR-3 mRNA may therefore contribute to lung damage in WG and other ANCA-associated diseases via direct interaction.
ANCA:
antineutrophil cytoplasmic antibodies
APAAP:
alkaline phosphatase–antialkaline phosphatase
c-ANCA:
antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern
PR-3:
WG:
reverse transcriptase-polymerase chain reaction.
The authors wish to thank Ms Huong Becker for excellent technical assistance and Dr E Csernok, Bad Bramstedt, for providing the monoclonal anti-PR-3 antibody WGM2.
Department of Medicine, University of Mainz, Mainz, Germany
Institute of Pathology, University of Mainz, Mainz, Germany
Institute of Pathology, Professional Associations Hospital, Ruhr-University, Bochum, Germany
Center of Internal Medicine, Nordwest Hospital, Sanderbusch, Germany
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redpajama_set_name: RedPajamaCommonCrawl


text:
Q: ubuntu 13.10 won't install it just reboot the pc when terying to install im having a problem in installing any version of Ubuntu alongside Windows 7 or inside it, it seems that the only solution is to format my pc but I don't like to do that. When booting from the usb stuck the option install alongside Windows 7 doesn't appear in the list. So I just choose to install Ubuntu inside but it just shutdown and restarted to Windows. Is it there any solution?

A: Could be your hard drive. Try checking your Drive for Errors with "chkdsk" or any 3rd party tool.
It can also be an overheating issue.
You know there is something wrong when the installer doesn't see your existant Windows OS.

redpajama_set_name: RedPajamaStackExchange


Note: It is important to note we are only talking about the D Style in its "pure" sense. That is, the D Style described in isolation, without considering the effect of the other 3 factors.
Dominance This scale measures how you deal with problem and challenges.
The higher the score on the D scale, the more assertively a person will tend to tackle problems and challenges. The lower the score on the D scale, the less assertively they will approach problems and challenges.
High D's are often described as: Demanding, Driving, Ambitious, Pioneering, Strong-Willed, Forceful, Determined, Aggressive, Competitive, Decisive, Venturesome.
Low D's are often described as: Conservative, Calculating, Cooperative, Hesitant, Low-Keyed, Unsure, Undemanding, Cautious, Mild, Agreeable, Modest, Peaceful, Unobtrusive.
General Characteristics Of The "D" Behaviour The "D" style has an inherent need to direct and be in control. The "D" style likes to have options and make decisions for themselves. They don't like to be backed into a corner, and they will typically push and challenge others to move faster, work harder and achieve more. The "D" style will usually get bored quickly if their job becomes mundane or loses its challenge.
The "D" behaviour has a real desire to win and be on top. They tend to have a strong achievement drive and like to do the things people say can't be done. The "D" behaviour has a very direct way of communicating, sometimes to the point of being blunt or abrasive.
The "D" style will usually take responsibility for their actions – they often use the motto "do now and ask for forgiveness later". They are more focused on getting the desired results than the actual path to get there. To the "D" style it does not matter how you got there, just as long as you did.
The emotion of the "D" style is anger – this style tends to have a short fuse and are quick to anger when they are not getting the results they are looking for.


text:
// ==========================================================================
//                      DG.DocumentListController
//
//  Interface for tracking a list of available documents on the server.
//
//  Copyright (c) 2014 by The Concord Consortium, Inc. All rights reserved.
//
//  Licensed under the Apache License, Version 2.0 (the "License");
//  you may not use this file except in compliance with the License.
//  You may obtain a copy of the License at
//
//    http://www.apache.org/licenses/LICENSE-2.0
//
//  Unless required by applicable law or agreed to in writing, software
//  distributed under the License is distributed on an "AS IS" BASIS,
//  WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
//  See the License for the specific language governing permissions and
//  limitations under the License.
// ==========================================================================

/** @class
  Interface for tracking a list of available documents on the server.
  It's a SC.ArrayController, so you can just observe it like an array,
  and extract the .arrangedObjects() when you want to use them.

  @extends SC.ArrayController
*/
DG.DocumentListController = SC.ArrayController.extend(
/** @scope DG.documentListController.prototype */ {

  loadingMessage: 'DG.OpenSaveDialog.loading',
  noDocumentsMessage: 'DG.OpenSaveDialog.noDocuments',
  noResponseMessage: 'DG.OpenSaveDialog.error.noResponse',

  init: function() {
    sc_super();
    this.set('content', []);

    var loadingMessage = this.get('loadingMessage').loc();
    if( !SC.empty( loadingMessage))
      this.addObject({ name: loadingMessage, id: '' });

    DG.authorizationController.documentList( this);
  },

  receivedDocumentListResponse: function( iResponse) {
    //clear the loading message
    this.set('content', []);
    if (SC.ok(iResponse)) {
      var  serverText = iResponse.get('body'),
           docList = [],
           response;
      try {
          response = serverText && SC.json.decode(serverText);
      } catch (err) {
          response = {
              'valid' : false,
              'message' : 'error.parseError'
          };
      }
      if (response.valid === false) {
        //display the error code from the server as human readable message
        var error = response.message;
        this.addObject({ name: ('DG.DocumentListController.' + error).loc(), id: ''});
      } else if (response) {
        response.forEach( function( iDoc) {
                              if( iDoc.id && iDoc.name)
                                docList.push( { name: iDoc.name, id: iDoc.id });
                            });
        if (docList.length === 0) {
          var noDocumentsMessage = this.get('noDocumentsMessage').loc();
          if( !SC.empty( noDocumentsMessage)) {

            this.addObject({ name: noDocumentsMessage, id: '' });
          }
        } else {
          docList.sort( function( iItem1, iItem2) {
                          var canonical1 = iItem1.name.toLowerCase(),
                              canonical2 = iItem2.name.toLowerCase();
                          // Sort case-insensitive first so we get A,a,B,b,C,c,...
                          // rather than A,B,C,...,a,b,c,...
                          return canonical1.localeCompare( canonical2) ||
                                  iItem1.name.localeCompare( iItem2.name);
                        });
          this.set('content', docList);
        }
      }
    } else {
        //Error occured most likely due to interruption of connection to server
        var noResponseMessage = this.get('noResponseMessage').loc();
        this.addObject({ name: noResponseMessage, id: '' });
    }
  }

}) ;

redpajama_set_name: RedPajamaGithub


A wash gel to effectively refresh and protect your skin.
NIVEA MEN PROTECT & CARE REFRESHING FACE WASH throughly cleanses your skin and helps to clear away inpurities and oil. The formula with Aloe Vera and Pro-Vitamin B5 refreshes your skin while protecting your skin's natural barrier. "