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Potentiating antilymphoma efficacy of chemotherapy using a liposome for integration of CD20 targeting, ultra-violet irradiation polymerizing, and controlled drug delivery
- Cong Wu†1,
- Huafei Li†1, 2Email author,
- He Zhao†3,
- Weiwei Zhang1,
- Yan Chen1,
- Zhanyi Yue1,
- Qiong Lu1,
- Yuxiang Wan1,
- Xiaoyu Tian1 and
- Anmei Deng1Email author
© Wu et al.; licensee Springer. 2014
Received: 9 June 2014
Accepted: 23 August 2014
Published: 28 August 2014
Unlike most malignancies, chemotherapy but not surgery plays the most important role in treating non-Hodgkin lymphoma (NHL). Currently, liposomes have been widely used to encapsulate chemotherapeutic drugs in treating solid tumors. However, higher in vivo stability owns a much more important position for excellent antitumor efficacy in treating hematological malignancies. In this study, we finely fabricated a rituximab Fab fragment-decorated liposome based on 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC), which can form intermolecular cross-linking through the diacetylenic group by ultra-violet (UV) irradiation. Our experimental results demonstrated that after the UV irradiation, the liposomes exhibit better serum stability and slower drug release with a decreased mean diameter of approximately 285 nm. The cellular uptake of adriamycin (ADR) by this Fab-navigated liposome was about four times of free drugs. Cytotoxicity assays against CD20+ lymphoma cells showed that the half maximal (50%) inhibitory concentration (IC50) of ADR-loaded immunoliposome was only one fourth of free ADR at the same condition. In vivo studies were evaluated in lymphoma-bearing SCID mice. With the high serum stability, finely regulated structure, active targeting strategy via antigen-antibody reaction and passive targeting strategy via enhanced permeability and retention (EPR) effect, our liposome exhibits durable and potent antitumor activities both in the disseminated and localized human NHL xeno-transplant models.
Non-Hodgkin lymphoma (NHL) is a type of blood cancer, which presents not only as a solid tumor of lymphoid cells in lymph nodes and/or extranodal lymphatic organs such as spleen and bone marrow, but also as free lymphoma cells in circulating blood [1–3]. Particularly, most patients can be cured with chemotherapy and/or radiation, which revealed the important status of chemotherapy in the treatment of NHL [4–6]. Currently, while various chemotherapeutic agents are validated to be effective in the treatment of lymphoma in preclinical studies, clinical applications are often limited for their side effects to normal tissues because of the systemic administration. As a result, finding more effective strategy to maximize the curative effect while minimizing the side effects of chemotherapy against lymphoma is of great importance and urgency [7, 8].
In the past decade, nanocarriers, including liposomes, polymeric nanoparticles, micelles, nanogels etc., with an appropriate diameter of tens to hundreds of nanometers, have received widespread attention for the specific delivery of bioactive reagents in the diagnosis and treatment of cancer [7, 9–12]. Encapsulation of bioactive reagents in nanocarriers can result in significant accumulation and retention in solid tumor tissues relative to administration of drug in conventional formulations through the enhanced permeability and retention (EPR) effect, which was firstly described by Maeda and colleagues[13–17]. What's more, the drug loading nanocarriers owns high serum stability, which can contribute to long-time circulation in the blood vessels, resulting in long-lasting antitumor activities, especially for the killing of free malignant cells in circulating blood [12, 17, 18]. However, more and more laboratory researches and clinical studies have demonstrated that passive targeting strategy alone is not enough for more sufficient and efficient accumulation of drug-loading nanocarriers in some tumor types [19–21].
Following the FDA approval of anti-CD20 mAb Rituximab for CD20+ NHL treatment, monoclonal antibody (mAb)-based targeting therapy has revolutionized the treatment of malignancies for the specific antitumor activity and low cytotoxicity against normal tissues [22, 23]. In the last decade, more and more studies have confirmed that the combination of mAb-based active targeting and nanoparticle-based passive targeting can improve drug concentration in tumor tissues and tumor cells in a shorter time with greater accuracy [7, 24, 25].
In this study, we have developed an adriamycin (ADR)-loaded liposome using the diacetylenic phosphatidylcholine 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC, hereafter referred to as PC), which can form intermolecular cross-linking through the diacetylenic group to produce a conjugated polymer within the hydrocarbon region of the bilayer by ultra-violet (UV) irradiation (Additional file 1: Figure S1) [26, 27]. For the sake of active targeting, the Fab fragments of rituximab were conjugated onto the liposomal surface. Our experimental results demonstrate that this well-modified liposome, which owns good serum stability and prolonged circulation time, can accumulate in the tumor tissues and malignant cells with high specificity and sufficient amount, which can bring out exceptional excellent and durable therapeutic efficacy against CD20-positive lymphomas.
Cell lines and materials
Two human B cell lymphoma cell lines, Raji and Daudi, were obtained from the American Type Culture Collection (ATCC). Cells were propagated and maintained in RPMI 1640 supplemented with 10% (v/v) fetal bovine serum (FBS, GIBCO, Invitrogen, Carlsbad, CA, USA) in a controlled atmosphere incubator at 37°C with 5% CO2. The DC8,9PC and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (Mal-PEG) were purchased from Avanti Polar Lipids (Williamsport, PA, USA). The anti-CD20 antibodies rituximab was purchased from Roche (Basel, Switzerland).
Fabrication of Fab fragment-conjugated liposome (Figure 1)
Formation of drug-loaded liposomes
Total lipids mixtures of 2 mg DC8,9PC and 0.25 mg Mal-PEG were dissolved in 500 μL mixed solvent of chloroform and methyl alcohol with the volume ratio at 1:1. Then, the solvent was evaporated under vortex and flashed with nitrogen to obtain the lipid film, followed by washing-out with 2 mL of ADR (doxorubicin HCl, Melonepharma CO. LTD., Dalian, China) solution (0.5 mg/mL in PBS) to obtain ADR-loaded multilamellar vesicles [26]. The collected liposome solution was dialyzed against PBS using a membrane (molecular weight cutoff 3 kDa) at 4°C for 12 h to remove uncombined ADR resulting in the ADR-loaded liposome stocking solutions.
Thiolation of mAbs
The Fab fragment of rituximab was prepared as reported previously [25]. Briefly, 10 mg/mL Rituximab was incubated with 0.25 mg/mL de pepsin at 37°C overnight following with a centrifugation and dialysis against TBS (145 mM NaCl and 10 mM Tris, pH 7.5) for 18 h. The Staph A-Sepharose column (Pharmacia, Kalamazoo, MI, USA) was used to remove the undigested mAbs at pH 8.0 resulting in the rituximab F(ab)2. The obtained F(ab)2 was further purified by the Sephadex G-150 column (Pharmacia, MI, USA) which was pre-equilibrated by the buffer 1 (0.1 M NaCl, 0.1 M borate, 0.05 M citrate and 2 mM EDTA, pH 5.5). Such F(ab)2 solution was concentrated to 10 mg/mL and further digested by the enzyme papain. The Fab fragment solution was purified by the same procedure as mentioned above resulting in the single Fab fragment stocking solution storing at 4°C.
To activate the Fab fragments of rituximab for reactivity toward the maleimide, the above stocking solutions were incubated with 2-iminothiolane (2-IT, Sigma-Aldrich, St. Louis, MO, USA) with a mass ratio of 1:0.15 (Fab/2-IT) at room temperature for 2 h under a gentle shake. Unreacted 2-IT was removed by dialysis. The bovine serum albumin (BSA) ~ SH was produced in the same way. The resulting reactive Fab ~ SH and BSA ~ SH were stored at 4°C for future usage [28].
Fabrication of rituximab Fab-conjugated liposome
The Fab fragment-conjugated liposome was prepared by coupling the reactive Fab ~ SH onto the liposomal surface via the reaction between the ~ SH and Mal-group at 4°C and N2 environment overnight; the un-conjugated Fabs were removed by dialysis. The BSA-conjugated liposome was fabricated in the same way. For UV irradiation, pure liposome solutions were exposed to 20 irradiation cycles at 4°C, with a 254-nm UV light dose of 360 mJ/cm2 per cycle using a Stratalinker-UV 1800 [26]. The concentration of Fab fragments in the liposome solution was quantified by measuring the A260/A280 using Nano VueTM (GE Healthcare, Wilmington, MA, USA).
Characterization of Fab fragment-conjugated liposome
The hydrodynamic diameter and size distribution were determined by ZetaSizer (Nano-ZS, Malvern Instruments, Worcestershire, UK) equipped with a HeeNe laser (633 nm) at the scattering angle 173°. To prepare stained specimens for TEM (H-7000 Electron Microscope, Hitachi, Tokyo, Japan) experiments, about 5 μL liposome solution was dropped on 200-mesh Formvar-free carbon-coated copper grids (Ted Pella Type-A; nominal carbon thickness 2 to 3 nm). After the water evaporating by exposing to air at room temperature, the sample was inversely covered on a small drop of hydrodated phosphotungstate (PTA) solution with a mass fraction of 2%. The conventional TEM images were obtained at 100 kV.
Weight-average molecular weight analysis by SLS
where K = [4π2n2(dn/dC P )2]/NAVλ4 is optical contrast, with n being the refractive index of solvent, C p the liposomal concentration, dn/dC p the refractive index increment against C p determined by a double beam differential refraction meter (DMR-1021) (Otsuka Electronics, Tokyo, Japan), λ the incident wavelength, and NAV the Avogadro's number. R(q) is the Rayleigh ratio at a specific measurement angle. By measuring R(q) for a set of θ and C p , values of M w and A2 were estimated from typical Zimm plots.
ADR releasing profile
Serum stability evaluation by DLS
For evaluating the effect of UV irradiation on the liposomal stability, a bovine serum albumin (BSA) solution in RPMI 1640 with a concentration of 50% (m/v) was used as an in vitro serum model to mimic the in vivo status. Then, the irradiation (irrad) and non-irrad liposome solutions were separately mixed with the resulting serum model at 37°C for 24 h. The dynamic light scattering (DLS) was used to measure the size and size distribution profile of BSA/liposome mixture at 0 and 24 h, respectively.
Cellular uptake and internalization assays
Raji and Daudi cells were seeded into a 48-well microplate (1 × 105 cells) and incubated with 1 μg/mL free ADR, ADR-loaded liposomes decorated with Fab fragments (PC-ADR-Fab), or BSA (PC-ADR-BSA) in cell culture medium containing 1% (v/v) antibiotics at 37°C for 4 h. Cells incubated with culture medium were used as a negative control. After washing with PBS for twice, a FACScan Flow Cytometer (Becton Dickinson, San Jose, CA, USA) was used to assess the cellular uptake of ADR or ADR-loaded liposomes by detecting the mean fluorescence intensity (MFI) of FL-2 (ADR fluorescence). Additionally, each sample was also visualized using an inverse fluorescent microscopy.
In vitro cytotoxicity assay
where Absample, Abcontrol, and Abblank are the absorbance values of each sample, the cells cultured in culture medium without any additional substances, and the culture medium without cells in wells, respectively.
Healthy female SCID mice aged about 4 weeks were purchased from Shanghai Experimental Animal Center of Chinese Academic of Sciences (Shanghai, China), housed in specific pathogen-free conditions, and treated in accordance with guidelines of the Committee on Animals of Changhai Hospital affiliated to the Second Military Medical University (Shanghai China).
Pharmacokinetics and in vivo distribution analysis
The pharmacokinetics (PK) and in vivo distribution analysis was done following Joseph M. Tuscano's study with minor revisions [31]. Briefly, Daudi cells (1 × 107) were inoculated subcutaneously into the right flank of 6-week-old SCID mice. For PK assays, when tumors reached about 50 to 60 mm3 in volume (approximately 14 days), mice were randomly administrated tail vein injection of free ADR, non-irrad or irrad ADR-containing immunoliposomes at a dosage of 5 mg ADR/kg (n = 3 mice per treatment). Then, 10 μL of blood were collected through tail vein nicking from each mouse at 5, 15, and 30 min and 1, 2, 4, 6, 8, 12, 24, and 48 h after treatment, respectively. Samples were immediately diluted into 250 μL of 0.5 mmol/L EDTA-PBS, followed by a centrifugation (300 g × 5 min). Plasma was collected and ADR was extracted by acidified isopropanol (75 mmol/L hydrochloric acid in 90% isopropanol) at 4°C for 20 h. The ADR concentrations were measured by UV at 480 nm and expressed as micrograms per milliliter (ADR/blood plasma). The data were analyzed by the PK solver software [32]. For biodistribution assays, tumor-bearing mice were randomly administrated tail vein injection of free ADR, PC-ADR-BSA, or PC-ADR-Fab at a dosage of 5 mg ADR/kg (n = 3 mice per treatment). Mice were sacrificed 24 h after treatment; part of tumor, heart, liver, spleen, kidneys, and lungs were removed, washed, and weighed; and single-cell suspensions were made. ADR was extracted from cells by the abovementioned acidified isopropanol for 20 h at 4°C. The ADR concentrations were determined as described above and expressed as micrograms per gram (ADR/tissue). What's more, part of the tumor tissues were collected and subjected to frozen sections, which were detected by a confocal microscrope (Zeiss, Oberkochen, Germany).
In vivo antitumor activity assessment in disseminated human NHL xeno-transplant models
Six-week-old SCID mice were injected via the tail vein with 5 × 106 Daudi cells in 100 μL PBS. Then, the inoculated mice were randomly assigned to 4 groups with 10 each for the treatment of PBS, free ADR, PC-ADR-BSA, and PC-ADR-Fab (with an equivalent amount of 5 mg/kg ADR) via the tail vein weekly for 3 times after 48 h. Post-operation monitoring was exercised at least once a day until natural death in a range of 120 days. Survival curves were plotted with the Kaplan-Meier method and compared by using a log-rank test [33, 34].
In vivo antitumor activity assessment in localized human NHL xeno-transplant models
where length and width refers to the longest and the shortest diameters of tumors, respectively.
Statistical analysis
Data were expressed as the means ± standard deviation (SD). Statistical analysis was performed by Student's t test or one way ANOVA to identify significant differences unless otherwise indicated. Differences were considered significant at a P value of <0.05.
Characterization of the liposome
Fab fragment loading
The number of Fab fragments per liposome was estimated on the basis of Kozlowska's ideas according to the following equation [35]:
Physicochemical parameters of ADR-loaded immunoliposomes
R h (nm)
M w (g/mol)
N agg
ADR (ng)/liposome
1.22 × 107
3.1 × 10-9
The number of Fab fragments (24 kDa) per milliliter calculated in the same way was 2.2 × 10-9 mol [52.2 μg/(2.4 × 104 g/mol)] or 1.3 × 1015. Hence we can estimate that there are on average ~31.3 Fab fragments per liposome (1.3 × 1015 Fab fragments/4.15 × 1013 liposomes), which is also shown in Table 1.
Drug loading and releasing properties
It was well expected that our liposome could be an excellent drug carrier which benefits from the stable structure following by self-assembling and UV irradiation functions. For the validation of this expectation, we firstly evaluated the ADR loading content (LC) of our liposomes according to the following function: . The results revealed a relative high LC of 16.27% with our immunoliposomes. Besides, the amount of ADR per liposome was estimated to be 3.1 × 10-9 ng (Table 1), which was calculated according to the following equation:
Low cytotoxicity of liposomes
For the determination of the cytotoxicity, different concentrations of empty liposomes decorated by BSA (PC-BSA) and rituximab Fab fragments (PC-Fab) were incubating with Raji cells at 37°C for 48 h following by a CCK-8 detection. As illustrated in Figure 2D, both the PC-BSA and PC-Fab showed low cytotoxicity to Raji cells in concentrations of up to 32 μg/mL. It is worth mentioning that the cell viability of PC-Fab-incubated cells had a little decrease compared with PC-BSA-incubated cells, which may be related with the weak tumor suppression effect of rituximab Fab fragments.
Serum stability evaluation
Intracellular uptake of liposomes
In vitro cytotoxicity assays
Pharmacokinetics of ADR-containing liposomes in tumor bearing SCID mice
Tumor bearing nude mice serum pharmacokinetic parameters comparing free and liposomal ADRs ( n = 3)
Free ADR
0.20 ± 0.02
0.19 ± 0.04
0.21 ± 0.05
0.98 ± 0.19
3.89 ± 0.79
1.57 ± 1.31
9.56 ± 4.06
21.13 ± 1.50
34.53 ± 2.63
30.96 ± 5.86
8.82 ± 4.54
6.63 ± 3.74
C max
50.45 ± 5.54
54.13 ± 4.34
53.04 ± 5.68
(μg/mL) · h
79.97 ± 11.36
447.19 ± 54.19
713.49 ± 120.51
6.37 ± 2.15
27.54 ± 1.53
48.58 ± 4.67
In vivo distribution and tumor accumulation assays
In vivo antitumor activity assessment
For the evaluation of in vivo antitumor activities, both the disseminated and localized human NHL xeno-transplant models were set up. In the localized model, Daudi cells were inoculated subcutaneously in the right flank of SCID mice. When the tumors reached about 50-60 mm3 in volume, mice were randomly treated with free ADR, PC-ADR-BSA and PC-ADR-Fab with an equivalent ADR amount of 5 mg/kg [25, 38]. The mice were treated once a week for SCID mice based on previous study and our preliminary experimental results [39]. The tumor volume was recorded and illustrated in Figure 6C. Our results indicated that mice treated with PC-ADR-Fab and PC-ADR-BSA demonstrated a remarkable decrease in tumor burden compared with free ADR and control treatment as measured by tumor volume. Otherwise, PC-ADR-Fab exhibit a more excellent antitumor ability comparing with PC-ADR-BSA, with 2/4 mice of complete remission (CR) indicated by no measurable mass.
The excellent antitumor activity of our liposome is validated using a disseminated model, in which Daudi cells were transplanted intravenously into SCID mice via tail vein. After 48 h, these mice were randomly administered injections of PBS, free ADR, PC-ADR-BSA, and PC-ADR-Fab for three times once a week. Survival curves were plotted with the Kaplan-Meier method and were compared by using a log-rank test [33, 34]. As illustrated in Figure 6D, ADR-loaded liposome (PC-ADR-BSA and PC-ADR-Fab) treatment significantly prolonged the survival of tumor-bearing mice compared to free ADR and PBS control treatment (*p < 0.05). As our expectation, comparing with PC-ADR-BSA treatment, the administration of PC-ADR-Fab led to significant prolongation of graft survival days (*p < 0.05), with a CR percentage of 4/10 indicated by long-term survival (>120 days post-treatment).
NHL presents not only as a solid tumor of lymphoid cells in lymph nodes and/or extranodal lymphatic organs, but also as free lymphoma cells in circulating blood [1–3]. Unlike most other malignancies, chemotherapy but not surgery plays the most important role in curing NHL [4–6]. Currently, more and more studies are focusing on finding out novel drug delivery system for treating solid tumors [7, 11, 17, 25]. However, for the elimination of free malignant cells in circulating blood, high serum stability and specificity to tumor cells are of great importance.
In this study, we have successfully fabricated a rituximab Fab-conjugated liposome based on PC, of which the well-defined spherical morphology was observed under TEM. Because PC is a kind of diacetylenic lipids, which can form intermolecular cross-linking through the diacetylenic group by UV irradiation to form chains of covalently linked lipids in the liposomal bilayers (Additional file 1: Figure S1) [26], this covalently union between lipid chains leads to a relatively more compact structure; thus, an important impact on the stability of the polymerized drug delivery system can be obtained. This enhanced serum stability can result in longer-time circulation and slower clearance of encapsulated drugs in vivo. Further experimental results revealed a favorable biological compatibility of the liposome. All the abovementioned properties are of vital importance for an ideal drug delivery system in eliminating malignant lymphoma cells, especially those in the peripheral blood.
In order to determine the antitumor activities, we took two lymphoma cell lines, Raji and Daudi, as study targets. The experimental results demonstrated that the in vitro cytotoxicity of ADR-loaded targeting liposome (PC-ADR-Fab) was significantly promoted due to the enhancement of drug uptaking compared with free drugs and ADR-loaded non-targeting liposome. The result may be ascribed to the following two reasons. Firstly, previous studies have proven that nanoparticles are taken up by cells via clathrin and/or caveoli-mediated endocytosis unlike small molecule drugs, which were taken up by passive diffusion [40, 41]. Thus, most nanoparticles can obviously enhance the intracellular uptake of chemotherapeutic agents, which was confirmed by previous studies and recognized as an important advantage of nanosized drug delivery system [25, 42, 43]. Secondly, the intracellular uptake could be further improved by the Fab fragments of rituximab based on the active targeting strategy by antigen-antibody identification and combination.
In vivo experimental results indicated that the immunoliposomes are selectively accumulated in tumor tissues, while the administration of free drugs resulted in high concentration of ADR in either normal or malignant tissues with no specificity. This remarkable discrepancy can significantly improve the bioavailability and reduce the detrimental cytotoxicity of chemotherapeutic agents. The in vivo antitumor experiments carried out both in the localized and disseminated human NHL xeno-transplant models suggest that our immunoliposome was significantly more effective than either free ADR or non-targeting liposomal ADR in inhibiting primary tumor growth and prolonging the graft survival. What's more, our immunoliposome still showed great advantage in tumor suppressing efficacy when compared with other drug delivery systems. For example, comparing with the anti-CD30 antibody-conjugated liposomal doxorubicin constructed by Ommoleila Molavi et al., the treatment of which can respectively decrease the tumor burden to approximately 1/7 and approximately 1/2 in comparison with PBS and free ADR treatment [44]; our immunoliposome can remarkably decrease the tumor burden to approximately 1/14 and approximately 1/4, respectively. In our opinion, this exceptional excellent in vivo antilymphoma activity of the ADR-loaded Fab fragment-decorated liposome is the cooperative action of the following effects: (1) enhanced intracellular uptake due to effective endocytosis based on well-defined liposomal structure and size distribution; (2) enhanced serum stability and controlled drug release (as a result of UV irradiation polymerizing) can contribute to long circulation time and durable antilymphoma activity; (3) enhanced tumor accumulation and retention in vivo through dual targeting function, passive targeting through EPR effects and active targeting through antigen-antibody reaction.
In this study, we have identified a novel liposomal drug delivery system, PC-Fab, for improved chemotherapy of CD20-positive NHL. The in vitro and in vivo experimental results clearly suggested that this Fab fragment-decorated liposome can be a promising weapon in combating NHL, which deserves further investigation for clinical application.
This research was supported by grants from 973 Foundation (2013CB531606), National Science Foundation of China (81371786), Shanghai Municipal Commission for Science and Technology (11JC1410902), Youth fund of the Second Military Medical University (2013QN14), and Wujieping Grant (320.6750.13147).
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text:
Whole Lotta Lotta wrote:One thing you have to realize at many Buxibans in Taiwan is that you are not really a teacher. You are a Customer Service Representative.
For many of the students you're just someone to gawp at, purvey a few giggles, and perhaps transmit some words of English, to while away otherwise empty time in a barren, constricted, tedium-laden, semi-somnambulistic life.

subset: commoncrawl


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In the National Park of Aconcagua there are some good acclimatization peaks which are used as a warm-up for the main target - Aconcagua.
On the east side Ameghino, Rico and Ibañez are the best options before attempting the "Polish Side".
On the western side where you find The Normal Route of Aconcagua you find Bonete. The peak, possibly together with Manso, is the most common acclimatization target on this side of the "Big One".
The altitude gain of 650 meters from Plaza de Mulas is perfect for getting ready for higher goals. You reach the peak by walking easy and well-travelled paths from Aconcagua's Base Camp and the peak can easily be summited in a leasurly manner in a day.
The views from Bonete's summit is great in all directions. To the west you look down into the Cuevas Valley and you get a good overview idea of how the normal route on Aconcagua looks like.
Some hikers have described the scree slopes on Bonete as a bit scary and the summit ridge airy and exposed. For any "normal" climber who has Aconcagua in mind, there should be no problems whatsoever and if you only look at gradient and the difficulty of the slopes - Bonete is slightly harder than its 2000m higher neighbor.
See Bonete as a little test.
When you feel fine on its summit, you're ready to move upwards on Aconcagua.
It got its first ascent in 1950.
The peak has sometimes been mixed up with Bonete Chico, the much higher peak on the Puna and the obscure Bonete Grande, also located hundreds of km north of Bonete.
The peak is easy to recognize. Looking past Restaurant 4372 from Plaza de Mulas you see a ridge with sharp tooth of a summit in the end of the valley - Bonete.
Getting There
To the area
There are two main entry points to the area: Santiago de Chile-Chile and Buenos Aries-Argentina.
Regardless of which of these you choose, you have to go to Mendoza (Argentina) and apply for a permit for Aconcagua National Park where Bonete is situated. A majority of visitors are joining commercial expeditions and if that is your choice, all the travel to the peak will be taken care of.
If you want to take care of the travel arrangements by yourself, here are some alternatives.
If you're on a commercial expedition with a set program, Bonete may not be included in the plan.
To the peak - in civilization
1). Buy all you need for the expedition in Mendoza and pay the permit fee. (See below for details).
2). Go to the main bus station in Mendoza and buy a ticket to Potrerillos if you want to acclimatize in the Cordon del Plata area. See map for an overview.
3). Regardless if you go to Cordon del Plata first, Uspallata is a good place to stay if you want to break up the journey in two parts or rest a bit after your acclimatization trip.
4). Continue by bus to Puente del Inca, from where you start walking towards the peak.
To the peak - the walk in
Walk from Puente del Inca to Horcones, the park gate. This stretch is 4 km and is on very broad walking paths. Most people has transport arranged for this quite boring stretch. Register at the park gate.
An easy walk in a sometimes quite narrow canyon takes you to Confluencia. Walking times varies a lot, but count on anything from two to five hours, depending on how much you carry and how well acclimatized you're. Confluencia is a good place to spend the night and you have to register at the ranger's hut here.
The water in Confluencia has a high content of magnesium and minor stomach upsets are common.
The next step of the walk is to Plaza de Mulas, which is a five to ten hours walk away. Down into a river valley to start with. Be sure you walk to the left when you see the river, otherwise you may end up in Plaza Francia, the base camp at Aconcagua's south face. There's a primitive bridge over the river. After the steep uphill from the river valley, you'll walk in a wide valley for a couple of hours. Water is accessible most of the way, but it's smart to fill up when you have the chance. This water can be full of sand and sediment. There are nice views of Piramidal and De Los Dedos on the way.
The last part up to Plaza de Mulas is steeper and you better watch out for arrogant mulateros on their mulas the sometimes narrow paths. Check in at the gate and find yourself a camp spot. On your left, in the end of the valley you'll see Bonete.
Red Tape
A permit for entering the Aconcagua National Park is necessary. The only place to obtain it is in Mendoza. The Permit office is located on one of Mendoza's main streets; San Martin. Ask for: Subsecretaria De Turismo or San Martín 1143. The permit office is not in the park anymore!
The prices for the 2005/2006 season were:
HIGH SEASON:From 15th December of year 2005 to 31st January 2006, a permit costs
• Climbing USD$ 330 20 days
• Long Trekking USD$ 50 7 days
• Short Trekking USD$ 30 3 days
MEDIUM SEASON: From December 1st to December 14th, 2005, and from February 1st to February 20th, 2006 a permit costs:
• Climbing USD$ 220 20 days
• Long Trekking USD$ 40 7 days
• Short Trekking USD$ 20 3 days
LOW SEASON: From November 15th to November 30th and from February 21st to March 15th of each year: 2005 - 2006
• Climbing USD$ 110 20 days
• Long Trekking USD$ 30 7 days
• Short Trekking USD$ 20 3 days
Note that the prices above are for foreigners. Argentinean citizens pay half of what's stated above.
Validity of the climbing permits is 20 days from the day of entry to the park.
The permit has to be paid in cash over the counter in the permit office and is ready in ten minutes. A thing to think about is to have the whole amount of cash in one currency. I showed up with about 60% in Pesos and the rest in USD. It did not work and I had to rush off and change. There are money exchange bureaus nearby. Casa de Cambio, in Spanish.
The following is to be found on the back of your climbing permit:
You will have to pay a U$S 100 fine if you:
* Do not use the baths provided by the park.
* Throw garbage along the park, leave or do not use the numbered plastic bags provided by the park.
* Pollute rivers, streams or waterfalls.
* Enter either with bicycles or pets.
* Damage wildlife, plants and natural, cultural or archeological features which are protected by the park regulations.
You will have to pay a U$S 200 fine if you:
* Throw garbage, forget or loose the numbered bags in the high camps or during your expedition.
* Gather or burn wood in the park.
* Carve insriptions in the stones.
You will have to pay the equivalent of a 2nd permit or an ascent permit if you:
* Go beyond the limits of the length if the stay allowed in the permit or go higher than 4300 mts with short trekking (3 days), long trekking (7 days).
* Maximum stay is 20 days with ascent permit.
* Horcones ranger station open daily from 8 A.M. - 6 P.M.
* For your safety always check out.


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Bumpity bump, friends. Who wants to come out and watch me slaughter HedgeWizard at Champion Pub? Who wants to have a martini with the real Julian "rabbit" Murdoch? Who wants to kick it in the bustling metropolis of Alameda?
You do, that's who.
Whatevs, sweet cheeks! The only game I'm gonna play is Fireball, and I will own joo all!
Champion Pub is gone =(
They have had a decent amount of turnover of the GWJer favs.
Fireball is in the front room though. Someone was hogging it all night a couple weeks ago.
There is a 3d (no glasses required) alien invasion/abduction one that is neat.
That is the one!
edit: Have fun tonight guys! I'll be there in spirit.
That is the one!
edit: Have fun tonight guys! I'll be there in spirit.
Eewww. I don't want to taste blackbone in my liquor. That's just wrong.
I'll be getting home from work at 6ish, picking up the car and heading over through traffic, so I'll see you guys in the 6:45-7 range! Excited!
Who has two thumbs and a 370 page report to push out tonight? Sorry guys. It's close but not close enough.
Have fun tonight!
I might be there early. Like right now. Who will save me from boredom first?
Thanks for the fun, tonight! Good to see all of you again. I'm honestly surprised I convinced my wife and kid to come. Max's first pinball outing was a success. He declares pinball to be "Awesome" and "Fabulous".
Glad you enjoyed it rabbit! I hope you didn't drop all your cash there ;P
Had a blast last night, everyone. Thanks for coming out!
Had a blast last night, everyone. Thanks for coming out!
Ditto! It was good seeing everyone!
Thread arise!
Just wanted to let you guys know that the bar across the street, (rabbit's favorite?) Fireside Inn has Taco and Trivia Tuesdays. I went last week and had a complete blast! The drink special was $4 Jameson shots and I think they had 12 year? Jameson shots for $7. The tacos are from a great taqueria 2 doors down and the bar is open to bringing your own food in.
The trivia was diverse and thankfully not brain dead. The games and prizes were a lot of fun. My team jumped out of the gate and was leading until the last 2 rounds. Of the 10 rounds, we were first for 1-8, tied in the 9th and lost in the 10th. Not winning was a good thing because I think they were trying to kill us with the first place prize! (PBR's and shots for the whole team)
Anyways, it is a great place and I can't imagine if Rabbit ever comes back to the Bay Area, not going to the Fireside Inn before/during/after pinball!
edit: did this work in not so subtly provoking rabbit to make another west coast trip?


text:
TMG-L ArchivesArchiver > TMG > 2003-06 > 1054855010
From: "Teresa Ghee Elliott" <>
Subject: [TMG] WISHLIST RESEARCH LOG
Date: Thu, 5 Jun 2003 18:16:56 -0500
When you edit a task, and save, the log goes back to the top of the
list. It would be nice if it took you back to where you were in the
list before you edited that task. It takes a while to find your place
in a large group of tasks.
Teresa Ghee Elliott
For examples of TMG sentences <http://www.tmgsentences.home-page.org
<http://www.tmgsentences.home-page.org/> >
Interested in Rutherford County, TN cemeteries?
<http://www.rutherfordcemeteries.home-page.org/> >
This thread:
|[TMG] WISHLIST RESEARCH LOG by "Teresa Ghee Elliott" <>


text:
From Official Website
Doherty wins on final day of qualifiers
Former world champion Ken Doherty was among the winners on the final day of the International Championship qualifiers in Sheffield.
Doherty outclassed China's Liu Chuang with a 6-3 victory in the morning session to book a place at October's brand new ranking event in Chengdu.
During the day Marco Fu, Jamie Cope, Ryan Day and Dominic Dale also sealed tickets on the plane to China, while Ali Carter and Peter Ebdon progressed from the evening session.
The International Championship has the highest level of prize money ever at a tournament in China. The winner will receive £125,000.
Morning session
Barry Hawkins 5-6 Michael White
Dominic Dale 6-3 Paul Davison
Ken Doherty 6-3 Liu Chuang
Ryan Day 6-3 Anthony Hamilton
Andrew Higginson 6-3 David Gilbert
Michael Holt 4-6 Pankaj Advani
Afternoon session
Marco Fu 6-3 Alfie Burden
Mark Davis 6-2 Kurt Maflin
Fergal O'Brien 6-3 Mark King
Jamie Cope 4-6 Aditya Mehta
Robert Milkins 6-1 Liang Wenbo
Evening session
Tom Ford 3-6 Cao Yupeng
Marcus Campbell 3-6 Jamie Burnett
Peter Ebdon 6-5 Nigel Bond
Joe Perry 5-6 Barry Pinches
Allister Carter 6-3 Dave Harold


text:
A recent story observed that the oil and gas industry in Illinois opposes a severance tax, but supporters claim such a tax is necessary to maintain and upgrade roads that would be subject to increased truck traffic.
This suggests the industry does not already pay for those things, which is categorically false.
In addition to income taxes, sales taxes, business taxes and permitting fees, the industry also pays an ad valorem tax that funds infrastructure, including roads and bridges. That tax is levied as a percentage of production, meaning increased production would also be accompanied by increased public funds to pay for infrastructure upgrades and maintenance.


text:
Adding to the history of patent wars between the two companies, Covidien plc leveled another lawsuit against Johnson & Johnson (JNJ - Free Report) subsidiary Ethicon Endo-Surgery Inc. Filed in the U.S. District Court for the District of Connecticut, the lawsuit alleges that Ethicon's latest ultrasonic surgical product – Harmonic ACE+7 – infringes three Covidien patents.
The patent infringement lawsuit asks the court to order Ethicon to terminate production and sale of the Harmonic ACE+7 devices and grant damages for the same.
In 2010, Covidien accused that Ethicon's Harmonic line of ultrasonic surgical devices infringed three of the company's patents. In Mar 2013, the U.S. District Court held that Covidien's patents were valid, enforceable and infringed by Ethicon.
The 2010 lawsuit resulted in a $176.5 million verdict against Ethicon. The amount of the verdict, which is currently under appeal, is based on an 8% royalty rate on infringing sales through Mar 2012, plus prejudgment interest.
In Dec 2011, Ethicon also brought infringement charges against Covidien's Sonicision cordless ultrasonic dissection system. According to a ruling issued by the U.S. District Court for the Southern District of Ohio on Jan 22, 2012, Covidien did not infringe any of the seven Ethicon patents in dispute.
In the 2012 ruling, the Court declared that five of Ethicon's patents were not valid. Based on this judgment, Ethicon's patent infringement action was dismissed and Covidien was allowed to continue selling its Sonicision system.
Earlier this month, medical technology giant, Medtronic Inc. (MDT - Free Report) announced its plans to acquire Covidien for $42.9 billion. Medtronic's rationale behind this merger is to offset the impact of high U.S. corporate tax rate by shifting its tax base overseas, to Ireland. Subject to certain customary conditions, the acquisition is expected to close in the fourth quarter of 2014 or early 2015.
Post-merger, the combined entity will be known as Medtronic plc and will boast a comprehensive product portfolio, a diversified growth profile and broad geographic reach. On successful completion of the transaction, Medtronic plc is expected to report at least $850 million of annual pre-tax cost synergies by the end of fiscal 2018.
Presently, Covidien carries a Zacks Rank #3 (Hold). OraSure Technologies, Inc. (OSUR - Free Report) is a better-ranked stock in the medical products industry with a Zacks Rank #1 (Strong Buy).
In-Depth Zacks Research for the Tickers Above
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text: I've been an iPhone user for a couple of years, but I've just about had it with AT&T service problems. I'm seriously considering switching to an Android phone, and Verizon is the only provider with reliable service at my location. I don't mind the extra large size, as long as it fits in my jeans pocket. I can accept that it won't be quite as "smooth" as the iPhone. I do have a couple of issues, however. One, I use my 32GB iPhone as my MP3 player, and I use most of the storage for music. How much can I store on a Droid X? Two, I use the Safari web browser a lot on the iPhone. How comfortable is web browsing on Android? It seems like it's probably fast enough, but I'm used to pinch-zooming on the iPhone to navigate. Any other switchers care to comment on using a web browser on Android, especially on non-mobile-enhanced sites?


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My 100% F-22 is now done and weighs about 16.5oz with no battery, I'd fly it up to 22oz and it should still be fine. I'll up-load photos as soon as I've cleaned it up and let the last of the glue settle. It looks pretty cool and can only look better in the air, the full fuse was really quick and easy and adds so much of that unique raptor character to the plane.
I'll be back...
A New F-22...
Well it's done - almost, I still have to put a strip of covering where the wing meets the belly and tape the hinges, then I'm ready to go... as long as these high winds that have been here for the last two weeks go away (gale-force! )
So just a brief word on what I've done... I used the 100% plans as a base for the f-22 I then drew a couple of formers that were all right angled triangles and sheeted the fuselage with 3mm depron, the nose tip is solid balsa (and 2cm longer than it should be! ) and to get a nice curve for where the sheeting meets I cut of excess sheeting flush with the profile then glued a strip of 2mm balsa on and that sands really well as well as making the nose strong and transferring any bumps along the outside of the nose up to the wing.
The Rest of the plane is made from EPP off cuts that I sanded down to 8mm in thickness and most surfaces are rounded at the front and sharpened at the back along with everything neatly tucked away inside the belly of the beast. I intend to use it mainly for fast flying so this all done to increase top speed but I still tried to keep it light enough to float to a soft landing. Of course though having the electronics all neat inside doesnt do much for drag reduction as the air is still flowing through the intakes but it just looks nice and streamlined (intimidating! ).
Now the programming - I have got ailerons as well as the standard elevons that all have their own servo so I decided to program in spolierons and ailerons that run off the aileron stick and gear switch. I then put the elevons on the rudder stick for fine low speed control (so I hope both rudder and aileron input will make an ultra fast roll! ) and that just leaves the elevator... Oh and don't forget the throttle, I'm using a Motrol-fly DM22-10 that tried to pull it vertical out my hand with the big battery aboard (AUW 22.5oz!)
Well thats it for the theory I'll report back with a report on what happened in practise, I just can't wait!
In anticipation...
Update on 65% build
My suspicions are coming true, I didn't need to use the 50K tow nor should I have put Kevlar tissue on both sides of the main wing or bottom piece. I will now struggle to make the 170g (6oz) target. I think I'm going to be about 16g over at this stage. I will definitely make the target with number 2 aircraft and my mate says he 's happy to have the heavier one.
I still have to remove all the tabs sticking through the wing and the tabs on the bottom piece. I can't do too much more as I'm still waiting for parts delivery to finish her off.
I like to have the LiPo inside the fuse area so you can't see it. Therefore there are two things that are fixed (motor & LiPo), which leaves two things (servo's & ESC) that can assist in achieving the correct CoG. Hopefully the servo's don't need to come too far forward to achieve the correct CoG. But if they do I will use Gold-n-cable to drive the Tailerons and keep everything inside the fuse area.
So far happy with the looks and definitely happy with the strength and rigidity. What you see in the pic's weighs 105g.
ImagesView all Images in thread
it looks like a tank!
Thanks everyone... looks like today could be ideal for testing a new plane! I just hope it holds...
batusaix - Very nice! The F-22 will be your aerobatic flier, doing all kinds of insane flips and rolls. Your F-18 will be fast, but also very maneuverable. But your Draken will be your drag racer! Mine did 78mph on two radar passes!
I have the same love/hate relationship with foam cutting. To date I have probably hand cut at least 30 models (and probably more). Now most of mine go to my local laser cutter, and I sure am glad I have him! But I will still hand cut a model if I need it right away.
nrg2go - Even at 190g you should be just fine. Most of mine are 155-170g and I have unlimited vertical and awesome performance. You should have no problems flying your mini.
Glider-man - Holy cow! (pun intended ). Nice finishing scheme, should be highly visible. I've always wanted to do Steve Shumate's full fuse F-22, but it's always seemed like a daunting build with all the parts and curves. But I may do another tomhe F-22 in a similar fashion as yours. Good luck on the maiden!
Hahaha, thanks Pat! Well I flew it today... started with a glide test, it floated perfectly to a soft plop with no need for trim. So half throttle and a biff sent it above the trees and into a very steady and beautiful flight. It's not really that fast looking in the air probaly because it is reasonably big but also because there must be quite a bit of drag in that belly however it is exactly what I intended and it is very fun the fly around on half throttle with the occasional WOT fly-by.
I did however manage to get it locked into a spiral then it disappered behind a hill! But no damage was caused however I will be changing the way I mounted my servos - they find it easier to push themselves instead of the surface.
I think I'll be getting the RC timer motor because the 2210 doesn't give it unlimited vertical in when in the air. It has just enough to hover the plane (not enough for me )
A good plane though.
Thanks Tomhe.
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text:
Sidelined Crisp shows improvement
Sidelined Crisp shows improvement
ARLINGTON -- A's outfielder Coco Crisp, who has been sidelined by pinkeye, showed enough improvement on Tuesday to take part in baseball activities for the first time in nearly a week. Crisp hit in the inside batting cages at Rangers Ballpark and joined teammates for their pregame workout, even shagging a few balls in the outfield seemingly without much trouble. A's manager Bob Melvin said Crisp is now seeing out of his left eye well but that his right eye remains an issue. Still, some improvement is better than none.
"This is kind of the day we were targeting to get him some baseball activity," Melvin said. "Where it goes from here we're not sure but certainly more encouraging than yesterday."


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Shoppers and KL.FM listeners will have the chance to join the fun at a live broadcast in Lynn High Street tomorrow, with a chance to beat the bedmaking competition.
Artertons Furniture Store, opposite Debenhams, will host the broadcast between 11am and 2pm when a giant Silentnight Hippo and the KL.FM bear will be waiting.
Shoppers can join in the contest to see who can make the bed in the window in the fastest time and win Silentnight Hippo beanies or a Hippo cuddly toy or a mattress protector.
KL.FM's Simon Rowe will also be drawing the winning entry to win a luxury double or kingsize Silentnight Ravel mattress. Get down to the store early and fill in a form to be included in the draw.


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Airborne pollutants formed in industrial processes
While some processes simply liberate natural elements and compounds, others create new toxic substances.
Dear Control Engineering: In your posting about mercury from power plants, you mentioned that there are other pollutants that are created in industrial processes, notably dioxin. So what is that story?
There are two key groups of similar toxic gasses that are a particular concern: dioxins and furans (D/F). These include tetra-, penta-, hexa-, hepta-, and octa- chlorinated dibenzo dioxins and furans. There are more than 200 variations of these in total, with some regarded as the most toxic substances known. They form in combustion processes, particularly where there are sufficient levels of precursors and when the combustion gas has gotten down to the 450 to 650 °F range. Allow me to quote a concise explanation from a Dow Website:
"Dioxins and furans are unwanted by-products of incineration, uncontrolled burning, and certain industrial processes. Industrial sources of dioxin to the environment include incinerators, metal smelters, cement kilns, the manufacture of chlorinated organics, and coal burning power plants. Dioxin is also produced by non-industrial sources (now considered by the U.S. EPA to be the greatest source in the U.S.), like residential wood burning, backyard burning of household trash, oil heating, and emissions from diesel vehicles. According to the EPA, cigarette smoke also contains a small amount of dioxin. Of the 210 dioxin and furan compounds, 17 are generally the focus of regulatory action.
"Just as combustion provides a means for dioxin formation, so too does it allow for its destruction, through careful controls. A high combustion temperature, adequate combustion time, and turbulence to distribute heat all contribute to maximize dioxin destruction. Dioxin formation following combustion is prevented by quickly cooling combustion gases, and minimizing the presence of certain metals known to promote dioxin formation. Dow has worked to prevent dioxin formation in its processes by shutting down older, less efficient units; adding new equipment to existing units; and employing advanced controls. Dow has also implemented new technology to recycle wastes as useful raw materials, thereby minimizing the need for incineration."
Dow makes the point that well-regulated burning combined with rapid cooling of combustion gasses to minimize the time spent in the prime formation temperature range goes a long way to preventing formation. Counter that with some guy burning trash in a barrel. Throw a few plastic bottles into the pile and the D/F formation could be more than a full-scale cement plant with an effective control system.
Peter Welander, email@example.com
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Annual Salary Survey
Before the calendar turned, 2016 already had the makings of a pivotal year for manufacturing, and for the world.
There were the big events for the year, including the United States as Partner Country at Hannover Messe in April and the 2016 International Manufacturing Technology Show in Chicago in September. There's also the matter of the U.S. presidential elections in November, which promise to shape policy in manufacturing for years to come.
But the year started with global economic turmoil, as a slowdown in Chinese manufacturing triggered a worldwide stock hiccup that sent values plummeting. The continued plunge in world oil prices has resulted in a slowdown in exploration and, by extension, the manufacture of exploration equipment.
Read more: 2015 Salary Survey


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Recipe: Baked Spaghetti Squash Carbonara
How do you feel about spaghetti squash? Do you consider it a bad joke of a vegetable, promising carbs without remorse, but actually offering a bowl of slippery, slimy strings? Or do you love it for its teasing imitation of spaghetti, still holding its own with sweetness and a toothsome bite?
Actually — never mind. I don't really care how you feel about spaghetti squash. Because I know how everyone feels about spaghetti carbonara, and this baked spaghetti squash carbonara is going to warm your pasta-loving heart in exactly the same way. Except, with way fewer calories. And isn't that really the point of spaghetti squash, if we're all being honest?
A few years ago I wrote a big book on healthier casseroles, called Not Your Mother's Casseroles (no canned cream of chicken soup, I promise). In the process of developing 225 recipes I scavenged about for every last way to pack vegetables into casseroles, and eventually lit upon spaghetti squash. I wrote a recipe that mixed up spaghetti squash, ricotta, and a few sprigs of sage, and banged it into the oven. I didn't have high hopes, to be honest, but its tender, rich, and creamy texture made it one of my favorite recipes in the book.
This casserole came to mind, suddenly, as I sat at a traffic light on the way to the grocery store, and I had a massive brainwave: spaghetti squash carbonara. Could I turn spaghetti squash into everyone's favorite eggy, porky, over-the-top delicious pasta dish? Just maybe.
I started by consulting a few authentic pasta carbonara recipes, beginning with Sara Kate's. True spaghetti carbonara has just a few simple ingredients: eggs, cured pork, fresh-grated Parmesan or Pecorino, and a hefty dose of black pepper.
I stuck closely to the classic elements, mixing eggs and Parmesan with spaghetti squash strings scraped out of the baked halves, but I also added a cooked onion and a dollop of ricotta to make up for the lack of richness in plain baked squash.
I baked it until crisp and golden on top, then dug in. It hit every note I look for in spaghetti carbonara: peppery, creamy, bits of rich bacon mixed in. And yet it didn't weigh me down in the same way. I have nothing against pasta — love the stuff — but this baked carbonara is a new favorite in the house. Even my pasta-desirous husband gobbled it up. It might not be pasta, but it's some serious carbonara. Spaghetti squash lovers (and haters), rejoice!
Baked Spaghetti Squash Carbonara
1 medium spaghetti squash (about 3 pounds)
8 ounces bacon (8 to 10 slices), diced
1 small yellow onion, diced
4 large eggs
1/2 cup ricotta cheese
1 1/4 cups Parmesan cheese, or mix of Parmesan and Pecorino, divided
1 teaspoon salt
1 teaspoon black pepper
Heat the oven to 350°F. Cut the squash in half lengthwise with a sharp chef's knife. Scrape out the seeds and seed flesh with a spoon and discard. Pour 1/2 cup water into a 9x13-inch baking dish and place the squash cut-side down in the water. Roast for 45 minutes or until tender. (Get step-by-step instructions: How To Cook Spaghetti Squash in the Oven.)
In a heavy skillet, cook the bacon over medium heat until the edges crisp. Add the onions and cook for 5 to 6 minutes or until soft and beginning to brown. Remove from the heat.
In a large bowl whisk the eggs, then whisk in the ricotta. Fold in the cooked bacon and onions, then 1 cup of grated cheese and the salt and pepper.
When the squash can be easily pierced with a fork, remove it from the oven and turn the heat up to 375°F. Remove the squash from the baking dish and let it cool slightly. Dump out any water left in the baking dish, wipe it dry, and then grease it lightly with cooking spray.
Shred the inside of the squash with a fork into spaghetti-like strings and remove from the outer shell. You should have approximately 6 cups. Mix the squash strings into the egg-and-onion mixture. Spread in the baking dish and top with the remaining 1/4 cup of cheese.
→ Make-ahead: At this point you can cover the dish and refrigerate overnight.
Bake for 45 minutes or until firm and golden on top.
This post was originally published February 2014.


text:
Dean et al.,
A few more interesting details about Greek prosgegrammeni:
1. The diphthongs in question (long-alpha+iota, eta+iota, omega+iota)
apparently ceased to be pronounced as diphthongs about 400 B.C.
2. The Greeks themselves stopped writing the prosgegrammeni
about 100 B.C.
3. Classical Greek was, of course, written entirely in what we
now consider to be "uppercase" Greek, so the prosgegrammeni was
in fact written AI, <ETA>I, <OMEGA>I when it was written. The
miniscule forms are basically medieval innovations, and the
practice of writing iota subscript on the lowercase Greek
letters dates from the 11th century A.D.
Moral of this story: Be careful what you write -- someone may have
to encode it two millenia in the future.
--Ken Whistler
This archive was generated by hypermail 2.1.2 : Tue Jul 10 2001 - 17:20:30 EDT


text:
1/2 cup brown sugar
1/4 cup flour
2 oz butter, melted
Combine ingredients and set aside.
1 1/2 cups flour
2 1/2 tsp baking powder
pinch salt
1 egg
3/4 cup sugar
3 oz butter, melted
1/2 cup buttermilk
1 tbsp vanilla extract
Mixed together all dry ingredients in a large bowl. Add wet ingredients and mix until batter comes together. Pour into a greased 8 inch pan. Sprinkle on topping. Bake at 350 degrees for 30 minutes or until toothpick comes out clean.


text:
The trial for a soldier charged with planning to bomb a restaurant filled with Fort Hood troops has been delayed until May.
Pfc. Naser Jason Abdo's trial had been scheduled for later this month. But U.S. District Judge Walter Smith issued a written ruling Monday saying the delay will give defense attorneys more time to prepare.
The judge had approved Abdo's request for a new attorney last month.
Abdo faces up to life in prison if convicted of attempting to use a weapon of mass destruction and eight other charges.
He was arrested in July at a Killeen motel near the Texas Army post. Authorities say they found a handgun and the ingredients for an explosive device in his room and backpack and that he told investigators about his plot.


text:
HOPKINTON, Mass. and PALO ALTO, Calif. -- EMC Corporation (NYSE:EMC), the world leader in information infrastructure solutions, and VMware, Inc., the leading provider of virtualization solutions and an EMC subsidiary, today announced that VMware has filed a Form S-1 Registration Statement with the United States Securities and Exchange Commission relating to the initial public offering (IPO) of Class A Common Stock of VMware.
VMware will be offering approximately 10% of its Class A Common Stock in the IPO. VMware and EMC expect the IPO will unlock more of VMwares value for EMC shareholders, as well as strengthen VMwares ability to attract and retain the software industrys top talent and reinforce EMCs commitment to VMwares strategy of platform neutrality.
Citi, JPMorgan and Lehman Brothers are acting as the representatives of the underwriters and, together with Credit Suisse, Merrill Lynch & Co. and Deutsche Bank Securities will act as joint book-running managers of the offering.


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" Genre: Crime / Thriller / Author: Olen Steinhauer / Paperback / 386 Pages / Book is published 2009-08-01 by Harper "
* Prices may differ from that shown
Was the matter you? Why the long face? I'll tell you exactly what is wrong with me; my name is Midge Ure and my seminal 80s hit song 'Vienna' has failed to get to number one because of an irritating novelty song about an aggressive Italian - so shaddap you face! The fury that must have risen in the members of Ultravox as they spent 4 weeks at number 2, but never managed to get to number 1 must have been immense. Surely there is enough here to write a book? Perhaps there is, but you will not find this story in Olen Steinhauer's 'The Vienna Assignment'. Instead you will get a book about the Cold War during the early 60s and the bleak mistreatment of their own people by the member states of the Soviet Union. Could this mean something to me - ahhh Vienna Assignment.
The Soviet Union was fuelled by ambition and fear and Brano Sev is a patriot who buys into this whole heartedly. He is a committed Communist who spies for his country in the city of Vienna. However, his loyalty is not repaid when he is framed for the murder of another undercover agent. Fleeing back to the East he is given one last chance to clear his name by returning to the backwards village he grew up in and spying on a man that means to defect. With false allegations of treason and murder hanging over his head can Sev remain committed to his Communist ideals or will be drawn to flee with the man he has been sent to investigate?
As a reader from the West I have read my fair share of spy novels based around Americans and UK citizens. These spy books tend to be boys own adventures with lots of guns and men shouting at each other in surnames. What you do not get in these books is an authentic feel of how the Eastern spy networks ran. Steinhauer seeks to resolve this by using Brano Sev a committed man from the East. The book does paint a vivid and depressing view of the East during the Cold War as the people were more in fear of their own leaders than the West. Steinhauer makes the book work by making Sev a fanatic for the cause and therefore part of the problem. Wherever Sev goes he is mistrusted and disliked. This gave the book a darker and more interesting edge; more melodrama than thriller.
The spy networks of the 60s seemed to run on a set of unwritten rules where various sides would follow one another in plain view. You were allowed to torture an enemy within reason, only to release them with a handshake and knowing nod. The everyday use of lying, spying and dying is really well created by Steinhauer and gives the book a very real feel as if this is what really did happen. Sev epitomises this as he does his job without question and knows what rules are to be obeyed and which to be ignored.
By half way I began to realise that the book was less about the Cold War as a whole and more about the plight of one man - Sev. Sev is pushed from pillar to post and each time he is beaten or tortured for information. The book turns into classic film noir as our hero is unable to see the true scope of the situation be finds himself in. However, like a lot of classic noir it falls into the trap of becoming too confused in its own twists and turns. I was unable to really understand what was going on by the end of the book as Steinhauer was not clear enough in making the central story come out. This meant that the book felt like it had a good grip on the time and environment, but was unable to actually provide a coherent story.
With a strange blend of spy fiction, crime noir and melodrama it is a little uncertain to know what type of reader would enjoy 'The Vienna Assignment'. I liked it more as a way of discovering the East during the Cold War and less for the actually story. The character of Brano Sev is refreshingly grumpy, but his poor attitude and blind loyalty will put many people off. Steinhauer's portrayal of the post Stalinist spy network is just enough to make the book worth reading; it is a shame that it becomes too complex towards the end. There are later books in the series that follow Sev's career that I plan to check out and hope that Steinhauer is able to create a narrative that is of the same quality as his ability to create a sense of time and place.
Author: Olen Steinhauer
Year: 2005
Price: amazon uk - £9.49


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Phone numbers and addresses of more than a million people have also been taken.
Loyaltybuild runs reward schemes for companies across Europe, including one for the Irish supermarket chain SuperValu.
Some 70,000 SuperValu customers have had their full card details stolen, confirmed the Office of the Data Protection Commissioner (ODPC).
In a statement, it said: "The inspection team confirmed the extent of the breach in which the full card details of over 376,000 customers were taken of which over 70,000 were SuperValu Getaway customers and over 8,000 were AXA Leisure Break customers.
"The details of an additional 150,000 clients were potentially compromised.
"The inspection team also confirmed that name, address, phone number and email address of 1.12m clients were also taken."
The ODPC said early indications were that it was an "external criminal act".
Loyaltybuild said it had been the victim of a sophisticated criminal attack and that it was urgently investigating what had happened.
"We are working around the clock with our security experts to get to the bottom of this and to further enhance our security in order to protect our valued customers, who are of paramount importance to us," said the company.
"Unfortunately, the threat of cyberattacks is increasingly becoming a reality of doing business today and Loyaltybuild would like to sincerely apologise for any distress or inconvenience caused."
Loyaltybuild first raised concerns about a data security breach on October 25 and the problem was initially thought to be limited to customers in Ireland.
Fraud squad officers and data protection inspectors have spent the day at the company's headquarters and data centre in Ennis, Co. Clare.
Follow-up inspections are planned and the company has been warned that customers, banks and credit card firms must be notified.
"The ODPC continues to warn customers to be vigilant in relation to their accounts and to report any suspicious transactions to their card company," said Ireland's data commissioner Billy Hawkes.
"Clients should also be vigilant in relation to suspicious communication of any kind which they receive."
Mr Hawkes also said that Interpol may have to be called in.
Loyaltybuild operates both the SuperValu Getaway Breaks and Axa Leisure Breaks programmes.
SuperValu is now contacting customers to tell them there is a "high risk" that an unauthorised third party accessed details of payment cards used to pay for Getaway Breaks between January 2011 and February 2012.
Axa also promised to contact affected customers and will advise them to get in touch with their banks to check transactions for any suspicious activity.
- Related Stories
- Cyberattack On SuperValu Shop Loyalty Scheme


text:
Implementation - Project Management
- Specification
- Supplier selection
- 3PL selection
- Project management
- Change management
We support implementation of projects to ensure successful delivery
At Total Logistics, we support the development of a logistics or supply chain project from concept through to delivery, performance optimisation and benefits realisation.
Our logistics and supply chain consultants can provide technical support at both steering or project team level through to a dedicated, on-site project manager. Our global database of experienced and proven Project Managers provides the appropriate personnel to work closely with the client, construction professionals and suppliers to drive the project to a successful conclusion. Our project management toolbox provides all the instruments required to control and monitor any size of project in any location.


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Cake Design, 50 Must See Cake Designs
There is nothing more wonderful than a well designed cake. Below are a selection of some mind blowing cakes. Some of the cake designs are so incredible that I still don't believe that they are really cakes. For example the Meat and Frito's Chips bag look so realistic that I think the only way to tell if they are cakes are not would be to smell them. I found a few cakes from a company called Mike's Amazing Cakes and I could have filled this entire post with their cakes alone. These guys are serious about cake design. They have taken cake design to another level. Their cakes are incredible and yes they are the ones who made the Meat and Frito's Chips cakes. I hope the cakes below inspire you to try the incredible because these cake designs have opened my eyes to what I thought a cake could look like.
Here are a few more links to some awesome posts regarding Cake Designs. I used the best cakes from these post to help curate my list of 50 Amazing Cake designs. You should check them out below.


text:
Music based games have become all the rage over the course of the past few years and with more titles coming out regularly in both the rock and pop music genres, it is not surprising that a hip hop based game would be in the works. The upcoming title Def Jam Rapstar is a collective work which is pulling in the talent and resources from such big name video game companies as Konami Digital Entertainment, 4mm Games, Def Jam Interactive and Terminal Reality. The new title is being created in an effort to compete directly with other genre games such as Rock Star, Guitar Hero and Rock Band – all titles that have sold well into the millions thanks to their easy accessibility and promotion that includes a great many very popular songs familiar to those both in and outside of the gaming hobby. This new title will feature works by such artists as Kanye West, T.I., Young Jeezy, Slick Rick and Dr. Dre, among other Def Jam super stars. The goal is to bring the popular urban rhythms to the Xbox 360 and Playstation 3 systems.
More than 40 different tracks will be on the disc and players will be encouraged to not only play the role of MC and rap along to the beats, but to record their performances so that they can share them with others online. This is where the game seeks to be different than its competition because it is leveraging the power of social networking sites like YouTube and Myspace in order to let players not just have a temporary level of gaming fun, but to be able to share that with the world over the web.


text:
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Graft – Tales of an Actor
Editorial Staff • Edinburgh • 26 Aug 2011
Throughout Graft, in which Dillon has to do just that, we are treated to a multitude of stories, anecdotes, and rants: the overwhelming elation of acceptance into drama school, the frustration of relationships, learning to cope with the pain of rejection, the preparation for crucial auditions and roles, self-perception and awareness, the difficulty of making ends meet, and approaching the end of your career.
Many actors had filled up the rows behind me - most from Berkoff's Oedipus at the Pleasance - and were reacting tellingly; knowing chuckles, groaning sighs, and stunned silences, suggesting Berkoff had hit many theatrical nails squarely on the head.
Needless to say, Dillon is superbly compelling. At turns mocking, affectionate, witty, acerbic, and aggressive, his performance is never less than truthful and revelatory, a lyrically brutal monologue which does not only illuminate the many joys of the profession, but also the crushing blows encountered by so many along the path to success.
Dillon is best at driving the narrative forward, but although the frantically exaggerated act suits the piece, it can become a little tiresome. Saying that, he hardly stumbles once, defiantly ploughing through the dense and wordy speeches with gusto and a mock pretentiousness that elicits much laughter.
Graft can appear a tad thin in places and to my mind, cannot compare with some of Berkoff's earlier work, but there is no doubt that a bravura turn from Dillon makes this almost an unmissable afternoon at Merchants' Hall.
- Adam Elms
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Congress MPs from Maharashtra today sought the intervention of party President Sonia Gandhi to find solution to the ongoing strike by traders over LBT.
Congress MPs from Maharashtra today sought the intervention of party President Sonia Gandhi to find solution to the ongoing strike by traders over LBT. The business community has launched an agitation from April 22 against the levy of Local Body Tax (LBT) in place of octroi.
While octroi was payable by transporters on behalf of traders bringing their goods in city limits, the newly introduced LBT is payable by traders themselves and for which they are required to furnish all details of their businesses. Traders apprehend the new system would lead to corruption and harassment at the hands of local civic staff.
The MPs pointed out to Sonia Gandhi in a communication that in most states, octroi was abolished following introduction of Value Added Tax (VAT) in 2005 without any alternate levy of tax, a press release from office of Vilas Muttemwar said. The introduction of VAT led to increase in the revenues of the states which helped them compensate the loss suffered by municipal corporations following withdrawal of octroi, they pointed out.
The MPs have also demanded that the Chief Minister of Maharashtra Prithviraj Chavan should enter into a dialogue with the representatives of business community to find a workable solution to the problem. Vilas Muttemwar, Murli Deora, Gurudas Kamat, Vijay Darda, Eknath Gaikwad, Mukul Wasnik were among the MPs to have approached party president Sonia Gandhi seeking her intervention in the matter, according to the release.