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Linkage Specific Fucosylation of Alpha-1-Antitrypsin in Liver Cirrhosis and Cancer Patients: Implications for a Biomarker of Hepatocellular Carcinoma
Mary Ann Comunale,
Affiliation Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virus Research, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
Lucy Rodemich-Betesh,
Julie Hafner,
Mengjun Wang,
Pamela Norton,
Adrian M. Di Bisceglie,
Affiliation Division of Gastroenterology and Hepatology, Saint Louis VA Medical Center, Saint Louis University School of Medicine, St Louis, Missouri, United States of America
Timothy Block,
Anand Mehta
* E-mail: anand.mehta@drexelmed.edu
Mary Ann Comunale Lucy Rodemich-Betesh ... Anand Mehta
We previously reported increased levels of protein-linked fucosylation with the development of liver cancer and identified many of the proteins containing the altered glycan structures. One such protein is alpha-1-antitrypsin (A1AT). To advance these studies, we performed N-linked glycan analysis on the five major isoforms of A1AT and completed a comprehensive study of the glycosylation of A1AT found in healthy controls, patients with hepatitis C- (HCV) induced liver cirrhosis, and in patients infected with HCV with a diagnosis of hepatocellular carcinoma (HCC).
Patients with liver cirrhosis and liver cancer had increased levels of triantennary glycan-containing outer arm (α-1,3) fucosylation. Increases in core (α-1,6) fucosylation were observed only on A1AT from patients with cancer. We performed a lectin fluorophore-linked immunosorbent assay using Aleuria Aurantia lectin (AAL), specific for core and outer arm fucosylation in over 400 patients with liver disease. AAL-reactive A1AT was able to detect HCC with a sensitivity of 70% and a specificity of 86%, which was greater than that observed with the current marker of HCC, alpha-fetoprotein. Glycosylation analysis of the false positives was performed; results indicated that these patients had increases in outer arm fucosylation but not in core fucosylation, suggesting that core fucosylation is cancer specific.
Conclusions/Significance
This report details the stepwise change in the glycosylation of A1AT with the progression from liver cirrhosis to cancer and identifies core fucosylation on A1AT as an HCC specific modification.
Citation: Comunale MA, Rodemich-Betesh L, Hafner J, Wang M, Norton P, Di Bisceglie AM, et al. (2010) Linkage Specific Fucosylation of Alpha-1-Antitrypsin in Liver Cirrhosis and Cancer Patients: Implications for a Biomarker of Hepatocellular Carcinoma. PLoS ONE 5(8): e12419. https://doi.org/10.1371/journal.pone.0012419
Editor: Wang-Shick Ryu, Yonsei University, Republic of Korea
Received: June 15, 2010; Accepted: July 22, 2010; Published: August 25, 2010
Copyright: © 2010 Comunale et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grant R01 CA120206-01 from the National Cancer Institute (NCI), grant UO1 CA084951-06 from the NCI Early Research Detection Network (EDRN), the Hepatitis B Foundation, and an appropriation from The Commonwealth of Pennsylvania. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is the major etiology of hepatocellular cancer (HCC) [1]–[4]. Both HBV and HCV cause acute and chronic liver infections, and most chronically infected individuals remain asymptomatic for many years [5]. About 10% to 40% of all chronic HBV carriers eventually develop liver cancer, and it is estimated that over one million people worldwide die because of HBV- and HCV-associated liver cancer [2], [6], [7]. Indeed, HBV and HCV infections are associated with over 80% of all cases of HCC worldwide and can be as high as 96% in regions where HBV is endemic [3].
The progression of liver disease to liver cancer is primarily monitored by serum levels of the oncofetal glycoprotein, alpha-fetoprotein (AFP), or the core fucosylated glycoform of AFP, AFP-L3. AFP can, however, be produced in many circumstances, including in relation to other liver diseases [8]–[10] and is not present in all those with HCC [11]. Therefore the use of AFP as a primary screen for HCC has been questioned [12], and more sensitive serum biomarkers for HCC are needed.
The glycosylation of proteins is cell specific. The N-linked glycosylation of a protein reflects modifications that occurred in the cell from which it came [13]. The glycosylation of the same protein secreted from diseased tissue, malignant cells or normal cells may, and often do, differ [14]. We, and others, have observed changes in N-linked glycosylation with the development of cirrhosis and HCC [15]–[19]. Specifically, the amount of core fucosylated N-linked glycan derived from total protein preparations isolated from the serum of individuals chronically infected with HCV and from those with a diagnosis of HCC was consistently greater than that in healthy patients or in those with HCV and "inactive" disease [19].
Using fucose-specific lectins to identify the proteins that become fucosylated in patients with liver disease, we identified more than 100 glycoproteins from patients with HCC and/or cirrhosis that contained increased fucosylation [19]. One of these proteins was alpha-1-antitrypsin (A1AT). We analyzed the N-linked glycosylation of the five major isoforms of A1AT and discovered, in addition to increased levels of core fucosylation, significant increases in outer arm fucosylation with the development of liver cancer. Using a lectin-based assay, we measured this change in over 400 patients with liver disease and found AAL reactive A1AT could detect HCC with a sensitivity of 70% and a specificity of 86% using a cut-off of 5 relative units. Glycan analysis of the false positives identified outer-arm fucosylation as being the cause of false positivity. In contrast, increases in core fucosylation were found only in patients with cancer. The reasons for this change and the clinical usefulness of this change are discussed.
Both the Drexel University College of Medicine and the Saint Louis University Institutional Review Boards approved the study protocol, which was consistent with the standards established by the Helsinki Declaration of 1975. Written informed consent was obtained from each participant.
Serum samples were obtained from the Saint Louis University School of Medicine (Saint Louis, MO). Demographic and clinical information along with a blood sample was collected from each participant in a serum separator tube. The sample was spun within 2 hours, and the serum was stored at –80°C until testing. Patients were enrolled in the Saint Louis University Liver Cancer Clinic and HCC were diagnosed using the same criteria established for the HALT-C trial [20]. Participants had HCC identified by biopsy, by a new hepatic defect showing vascular enhancement on one imaging modality (ultrasound [US], magnetic resonance imaging [MRI], or computed tomography [CT]) with AFP levels >1000 ng/ml, or by presumed HCC. Participants were presumed to have HCC if they had a discrete hepatic defect on US with AFP levels <1000 ng/ml and either two other scans (MRI, CT, angiography) indicating malignancy with at least one of the following characteristics: hypervascularity, arterial to portal vein shunts, portal vein thrombosis near the defect, tumor in the portal vein, or one other scan (MRI or CT) showing features characteristic of HCC and either an increase in size over time after initial discovery (at least doubling if less than 1 cm) or an increase in the level of AFP to >200 ng/ml. Tumor staging was determined using the United Network of Organ Sharing-modified (UNOS) TNM staging system for HCC. For the cirrhosis group, patients with hepatitis C and biopsy-proven cirrhosis were enrolled. All cirrhotic controls were screened for HCC using US, CT, or MRI prior to enrollment. Patients who were HBsAg+ (with or without HBV DNA were classified into the HBV group. Similarly, patients who were HCV RNA positive, with no evidence of cirrhosis, were classified into the HCV group. Patients with other non viral liver disease but without cirrhosis were classified into the other liver disease group (OLD). Control patients were healthy patients recruited by the study to act as controls.
Two-Dimensional (2-D) Gel Electrophoresis
A total of 7 µl of serum was diluted in 330 µl of solubilization buffer containing 7 M urea, 2 M thiourea, 4% CHAPS, 65 mM DTT, 5 mM tributylphosphine, and a 0.4% mixture of carrier ampholytes (Servalyt pH 2–4, pH 3–10, pH 9–1, 1∶2∶1). Samples were vortexed periodically for 1 h and applied to an 18-cm pH 3-7 NL immobilized pH gradient (IPG) strip (Amersham, Piscataway, NJ, USA). Gel rehydration was carried out for 14 h at 50 V and focused using the IPGPhor (Amersham) isoelectric focusing apparatus. After focusing, gel strips were first reduced then alkylated in 6M urea, 2% SDS, 30% glycerol, 50 mM Tris, pH 6.8, and either 30 mM DTT or 75 mM iodoacetamide for 10 min each. The second dimension was resolved with an 8% to 18% acrylamide–0.8% PDA gradient gel on a Protean II xi Cell (Biorad Laboratories Headquarters, Hercules, CA, USA) with the running conditions set to 20 mA/gel for 20 min and 40 mA/gel for 4 h. Gels were fixed and stained with colloidal Coomassie. Gels were imaged using the Odyssey Infrared Imaging System (Li-Cor Biosystems, Lincoln, Nebraska) and analyzed using NonLinear Dynamics Progenesis Workstation gel imaging software (NonLinear Durham, NC, USA).
Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry
Protein spots were excised from colloidal Coomassie blue stained gels, destained, and digested with trypsin. Recovered peptides were concentrated and desalted using ZipTip C18 (Millipore, Bedford, MA, USA) according to the manufacturer's directions and prepared for MALDI-TOF mass spectrometry by mixing 0.5 mL of peptide mixture with 0.5 mL of 10 mg/mL α-cyano-4-hydroxycinnamic acid and 1% formic acid in 50% acetonitrile and allowing the droplet to dry on the MALDI plate. Peptide mass maps were obtained using a Voyager-DE Pro Mass Spectrometer (Applied Biosystems, Life Biotechnologies, Carlsbad, CA) operated in positive ion reflectron mode. Proteins were identified from the peptide mass maps using the MASCOT online database (www.matrixscience.com) to search the nonredundant protein database.
The 2DE gel spots were excised and destained using 40% methanol 7% acetic acid. The gel plugs were dehydrated with acetonitrile, the acetonitrile was removed and 25mM DTT was allowed to absorb into the plug. The plug was heated to 100°C for 5 min, allowed to cool, and alkylated in the dark for 30 min with 75mM iodoacetamide. The gel plugs were washed using two repeats of acetonitrile dehydration and 20 mM ammonium bicarbonate rehydration. After a final dehydration, the gel plugs were dried in a speed vac. Peptide∶N-glycosidase F (PNGase F) was diluted with 20 mM ammonium bicarbonate pH 7 and allowed to adsorb into the gel plug. The gel plug was then covered with the same solution and allowed to incubate overnight at 37°C. The glycans were eluted from the gel plug by sonication in Milli-Q water three times; the elutant was pooled, dried down, and labeled with a 2AB dye (Ludger, Oxford, UK) according to the manufacturer's instructions. The glycans were then cleaned up using paper chromatography and filtered using a 0.22-µm syringe filter. Fluorescently labeled glycans were subsequently analyzed using the Waters Alliance high-performance liquid chromatography system with a normal phase column (TSK amide 80 columns) complemented with a Waters fluorescence detector and quantified using the Millennium Chromatography Manager (Waters Corporation, Milford, MA). The mobile phase consisted of solvent A (50 mM ammonium formate, pH 4.4) and solvent B (acetonitrile). The gradient used was as follows: linear gradient from 20% to 58% solvent A at 0.4 mL/minute for 152 min followed by a linear gradient from 58% to 100% solvent A for the next 3 min. The flow rate was increased to 1.0 mL/minute; the column was washed in 100% solvent A for 5 min. Following the wash step, the column was equilibrated in 20% solvent A for 22 min in preparation for the next sample. Glycan structures were identified by calculating the glucose uptake value and exoglycosidase digestion, as described previously [21].
Lectin-Fluorophore-linked Immunosorbent Assay (FLISA)
The capture antibody (mouse antihuman A1AT, AbD Serotec, Raleigh NC, USA), was incubated with 10 mM sodium periodate for 1 h at 4°C. This treatment ensures the lectin is unable to react with the glycosylation of the antibody and does not affect antibody substrate binding. An equal volume of ethylene glycol was added, and the oxidized antibody was brought to a concentration of 10 µg/mL with sodium carbonate buffer, pH 9.5. Antibody (5 µg/well) was added to the plate and, following incubation, was washed with 0.1% Tween 20mM phosphate buffered saline pH 7.4. The plate was blocked overnight with 3% bovine serum albumen/phosphate buffered saline. For analysis, 5 µl of serum was diluted in 95 µl blocking reagent in Heterophilic Blocking Tubestm (Scantibodies Laboratory, Inc. Santee, CA, USA) and was incubated at room temperature for 1 h. Subsequently, samples were added to the plates for 2 h and washed 5 times in lectin incubation buffer (10 mM Tris pH 8.0, 0.15M NaCl, 0.1% Tween 20). Fucosylated A1AT was detected with a biotin conjugated Aleuria aurantia lectin (AAL) (Vector Laboratories, Burlingame, CA). Bound lectin was detected using IRDye 800 conjugated streptavidin; the signal intensity was measured using the Odyssey infrared imaging system (LI-COR Biotechnology, Lincoln, Nebraska). In all cases, signal intensities were compared to those of signals detected with commercially purchased human serum (Sigma Chemicals). The lectin-FLISA detects the amount of fucosylation present on an equal quantity of molecules captured from each patient sample and is performed in a manner independent of the total amount of protein in any given patient.
Descriptive statistics for staged patients were compared by scatter plots that included the outliers. All values were reported as mean values plus or minus the standard error unless otherwise stated. Because the data did not follow typical Gaussian distribution, a nonparametrical test (two-tailed, 95% confidence, Mann-Whitney test) was used to determine statistical difference between the groups. To determine the optimal cutoff value for each marker, the receiver operating characteristic curves were constructed using all possible cutoffs for each assay. The area under the receiver operating characteristic curve was constructed and compared as described previously. A two-tailed P value of 0.05 was used to determine statistical significance. All analyses were performed using GraphPad Prism (San Diego, CA, USA).
Levels of A1AT and Degree of Sialyation in Patients with Liver Cirrhosis and HCC
Pooled sera from healthy patients (n = 20), patients with liver cirrhosis (n = 20) and patients with HCC with a background of cirrhosis (n = 20) were resolved via 2-D gel electrophoresis (2DE) (Table 1). Figure 1A shows a representative 2-DE of normal human serum and Figures 1B, 1C and 1D show a focus on the 5 isoforms (M1, M2, M4, M6, and M7) of A1AT from the three patient groups. Three major and two minor A1AT isotypes are commonly seen when human serum is isoelectrically focused and run on a 2-D gel [22], [23] and these are not altered in the three patient groups. The A1AT concentrations in each patient group were comparable (Figures 1E–1G) and fell within normal serum concentrations. This result was confirmed by analyzing A1AT an Enzyme-linked immunosorbent assay (ELISA), whereby the A1AT levels were 3.2 mg/mL in the composite from the healthy patients, 3.3 mg/mL in the composite from the cirrhotic patients, and 3.3 mg/mL in the composite from the HCC patients.
Figure 1. Two-dimensional gel purification of alpha-1-antitrypsin isoforms.
Sera from pools of healthy controls (A, B, E) and cirrhosis (C, F) and cancer (D, G) patients were focused using IPGPhor 3–7 NL first dimension strips followed by SDS-PAGE separation on 8% to 18% acrylamide gels. The pI of selected gel spots are M1 = 4.91, M2 = 4.95, M4 = 5.00, M6 = 5.05, and M7 = 5.10. Panels E, F, and G show the relative abundance of each gel spot.
Table 1. Patients Utilized in Study.
We performed glycan analysis on the M1, M2, M4, M6, and M7 isotypes from the pools of sera from normal participants and cirrhotic and HCC patients (Figures 1B–1D) and examined the sialylation patterns of each isotype. Figure S1 shows a representative glycan profile for the M4 isotype from the controls. Consistent with results of previous studies [24], the biantennary glycan is the most abundant species. Figure S1-B shows the level of the sialyated biantennary and triantennary glycan associated with each isoforms from each patient group. As S1-B shows, the level of sialyation on the bi-anntennery glycan (A2G2S1 or A2G2S2) was similar in the different patient groups. Similarly, the level of sialyation was not altered on the triantennary glycan. However, there was an increase in the level of the tri-sialyated α-1,3 linked fucosylated outer arm fucosylated glycan (A3F(3)1G3S3) on A1AT from the cancer patients, as compared to the healthy and cirrhotic patients. These peak are indicated in figure S1A & B with an asterisk.
Increased Levels of Core and Outer Arm Fucosylation Are Observed on A1AT from Patients with HCC
To test if the increased level of tri-sialyated α-1,3 linked fucosylated outer arm fucosylated glycan (A3F(3)1G3S3) was the result of an increase in sialyation or an increase in the total amount of parent glycan, sialic acid was removed enzymatically and the sample re-analyzed. Figure 2 shows the simplified desialylated glycoprofile of the five major isoforms for each of patient group following treatment with neuraminidase (Arthrobacter ureafaciens). Three peaks of interest, indicated with a star in Figure 2, are reproducibly altered in the M1, M2, and M4 isoforms as the diseased liver progresses from cirrhosis to cancer. Sequential exoglycosidase digestion (data not shown) showed these peaks to be a core fucosylated biantennary glycan (F(6)A2G2), a triantennary glycan (A3G3), and a triantennary glycan with a single α 1,3 linked outer arm fucose residue (A3F(3)1G3). Figure 3A shows a representative desialylated profile with the corresponding glycan structure identified for each peak. Table 2 is a quantitation of each glycan structure present on the five major isoforms for each patient group. Specific changes in glycosylation are observed in the A1AT isoforms with the progression to cirrhosis and HCC. On M6, the isoform with very little tri and tetra-antennary structures, the biantennary core fucosylated glycan (F(6)A2G2), represents 4.48% in normal patients, 4.37% in patients with cirrhosis, and 7.04% in patients with cancer, a trend seen across each isoforms (Table 2, glycan 3). The percent change between healthy and cirrhosis and between cirrhosis and cancer is given in Figure 3C and shows that this structure changes with cancer only. In M4, the triantennary glycan with an outer arm fucose residue (A3F(3)1G3) increases from 4.34% in normal participants to 6.78% in patients with cirrhosis, and 13.18% in patients with cirrhosis plus cancer. Again, this trend is seen in each of the isoforms, with the exception of the M6 due to the total lack of triantennary structures (Table 2, glycan 8). The relative increase in each of these fucosylated glycan structures as a function of disease is shown in Figure 3B and shows that this structures changes in both liver cirrhosis and HCC. The increase in outer arm fucosylation was also associated with a decrease in the parent N-linked glycan. That is, the increase in the outer arm fucosylated triantennary glycan, A3F(3)1G3, was associated with a decrease in triantennary glycan A3G3. (Table 2, glycan 6).
Figure 2. The desialylated N-linked glycan profile for each of the five A1AT isoforms from normal controls (top) and cirrhotic (middle) or HCC patients (bottom).
The major peaks that are altered are indicated with an asterisk and are (from left to right) a core fucosylated bianntennary glycan (F96)A2G2), a trianntennary N-linked glycan, and a trianntennary N-linked glycan with a single outer arm fucose residue (A3F[3]3). The percent of each of these peaks in the different isoforms and in the different patient groups is shown in Table 2.
Figure 3. Specific changes in glycosylation on A1AT can be observed with the progression from liver cirrhosis to liver cancer.
(A) A representative N-linked glycan profile from a normal control patient. The 11 major glycan structures identified are indicated and given a number. This number is used in Table 2 with structure names provided. The relative change in the level of the trianntennary N-linked glycan with a single outer arm fucose residue (A3F[3]G3) (B) and the core fucosylated bianntennary glycan (F[6]A2G2) (C) in normal to cirrhotic and cirrhotic to HCC is shown as percent change. As this figure shows, increases in outer arm fucosylation are associated with both cirrhosis and HCC, whereas increased core fucosylation is only observed with HCC.
Table 2. The N-linked Glycans Found on A1AT Isoforms from Controls, Patients with Cirrhosis, or Patients with HCC.
Analysis of Fucosylated A1AT by Lectin-FLISA in a Cohort of 458 Patients
To further examine if the changes in both core and outer arm fucosylation could be seen in individual patients and potentially used as a diagnostic marker of cancer, we analyzed a patient cohort consisting of 458 patients for the level of fucosylated A1AT using a lectin-FLISA based assay. In this assay, A1AT was captured using a monoclonal antibody and the level of fucosylation was determined using the fucose-binding AAL. AAL recognizes both outer arm and core fucosylated glycan. Twenty patients with no evidence of liver disease were used as controls; 33 patients infected with HBV had an unknown level of liver fibrosis; 215 patients infected with HCV had an unknown level of liver fibrosis; 65 patients had liver cirrhosis; 62 patients had other liver diseases; and 63 patients had liver cancer (Table 1). Figure 3A shows the relative level of fucose lectin-reactive A1AT in the six patient groups. Values are given as -fold increase in relation to the level in commercially purchased "normal" sera. The mean and 95% confidence interval of the mean are shown for each group. We found a clear statistical difference between the HCC group and all other groups (P<0.0001) and between the cirrhotic group and the control group (P = 0.0173) but not between any other groups (Figure 3A). The mean level of lectin-reactive A1AT was 1.4-fold (±0.80) above sigma in the control group, 1.7-fold (±0.1.8) in the group infected with HBV, 1.9-fold (±1.8) in the group infected with HCV, 2.6-fold (±2.3) in the group with cirrhosis, 2.6-fold (±2.0) in the group with other liver diseases, and 7.70-fold (±4.45) in the group with HCC. Surprisingly, there was no difference in the mean level of AAL-reactive A1AT in HCC patients in regards to the stage of HCC (data not shown). That is patients with stage 1 HCC, as defined as a single lesion of less than 2cm [11], had a 9.1 fold (±4.70) increase in the level of AAL reactive A1AT while patients with stage 4 HCC (those with multiple lesions >6cm in diameter) had a mean of 6.7 fold (±5.54), which was not different than that observed in stage 1 patients (p = 0.114).
In this cohort, fucosylated A1AT could distinguish between HCC and non-HCC cases with an area under the receiver operator curve (AUROC) of 0.871. When comparing only HCC versus cirrhosis, the discriminatory ability was 0.867. Using a cut-off of 5 relative units AAL reactive A1AT could differentiate HCC from cirrhosis with a sensitivity of 70% and a specificity of 86%. In contrast, AFP, when analyzed in this cohort, had an AUROC of 0.764 and could differentiate HCC from cirrhosis with a sensitivity of 59% and a specificity of 93% using a cut-off of 20 ng/mL.
False Positives Have Increased Levels of Outer Arm Fucosylation Whereas Core Fucosylation Is Specific for HCC
Some patients do not have cancer but have elevated levels of lectin-reactive A1AT (Figure 4A). Because we observed changes in outer arm fucosylation on A1AT from patients with cirrhosis, it was of interest to determine if those with false positive results had core or outer arm fucosylation. Figure 4A shows the results of glycan analysis from purified A1AT from three cirrhotic patients (out of nine) and three patients with stage 1 or 2 HCC (out of nine) and analyzed as before. The results from these patients are shown in Figure 4A, and a representative glycan profile of one of these patients is shown in Figure 4B, along with the level of 4 major glycan structures indicated. As Figure 4B shows, consistent with the results presented in Table 2 and in Figures 3A–3C, the three cirrhotic patients have levels of core fucosylation (F(6)A2G2) similar to those observed in healthy controls. However, these patients have significant increases in outer arm fucosylation (A3F(3)1G3), similar to the highest levels seen in patients with HCC. That is, the level of outer arm fucosylation in these patients ranged from 10% to 17%, which is similar to the level observed in patients with HCC (13%). In contrast, three patients with HCC who had very strong positive results from the lectin FLISA test had increased core and outer arm fucosylation. For example, the core fucosylated bianntennary glycan represented 9.55% on A1AT purified from patient H27. Similarly, this glycan represented more than 9% on A1AT purified from patients H18 and H23. Increases in outer arm fucosylation ranging from 14.03% to 15.97% of the total glycan on A1AT were also observed in these patients. Figure 4D shows the results of all 18 patients with a focus on the level of outer arm (α-1,3) and core (α-1,6) fucosylation. When examining all 9 cirrhotic false positives the mean level of core fucosylation was 3.77%±0.25 and the mean level of outer arm fucosyalation was 11.88%±2.79. In the case of the cancers the mean level of core fucosylation was 8.62%±1.2 and the mean level of outer arm fucosylation was 14.26%±1.9. There was statistical difference between the level of core α-1,6 fucosylation between these nine cirrhotic and nine HCC patients (p<0.0001) but not with α-1,3 linked fucosylation (p = 0.07). Importantly, the maximum level of core fucosylation observed in the false positive cirrhotics was 4.01%, similar to what was observed in healthy controls (3.62%).
Figure 4. Increase in lectin-reactive A1AT with the development of HCC and identification of core fucose as a specific marker of liver cancer.
(A) The level of lectin-reactive A1AT in patients with HCC, HBV infection, HCV infection, or other liver diseases (OLD) and in controls. The solid line represents the mean value. The x-axis represents the patient group. The y-axis shows the -fold increase in lectin-reactive A1AT compared with that in commercially purchased serum. (B) Glycan analysis of A1AT isoform M4 from patient 21. (C) Quantification of glycan analysis from three cirrhotic patients (01,21 and 27) and three patients with stage 1 or 2 HCC (HCC-23, HCC 27 and HCC 18). The levels of 4 major glycan structures are shown. As this figure shows, in cirrhotic false positives, there is an increase in outer arm but not core fucosylation. Consistent with data shown in Figures 2 and 3, increases in core fucosylation on AAT were observed only from patients with HCC. (D) Scatter plot of the level of α-1,3 or α 1,6 linked fucose from 9 cirrhotic false positives and 9 patients with either stage 1 or 2 HCC.
Recent reports have indicated that increased core and outer-arm fucosylation could be observed following glycomic analysis of either total human serum or serum depleted of immunoglobulin [18], [19], [25]. We examined the glycosylation of a single protein, A1AT, as a function of liver cirrhosis and liver cancer. To this end, we found some changes that were consistent with our previous findings such as an increase in core fucosylation as well as changes in outer arm fucosylation.
The observation that changes in both core and outer arm fucosylation occur may provide clues to the molecular basis of this change. That is, although the exact mechanisms for increased core fucosylation in HCC are unknown, they are thought to involve increases in both the levels of the enzyme and the substrates involved in core fucosylation [17].
It is also possible that these markers reflect some alteration in the Golgi apparatus. Recent reports have suggested that, in regards to the liver, the fucosylation of proteins is involved in protein sorting to the bile [26]. Thus, it is conceivable that the appearance of fucosylated proteins in the serum may reflect a common defect in protein sorting. It is interesting to note that the glycosylation of A1AT in the serum of patients with liver cancer (Figures 2, 3 and 4) is similar to that observed in the bile of healthy individuals [26].
It is also interesting to note that lectin reactivity was greater than the total change observed in fucosylation. For example, patient 27 had either core or outer arm fucose on 22.82% of his or her N-linked glycans. In contrast, A1AT from a healthy individual had fucose (core or outer arm) on 9% of the N-linked glycans. Hence, using the lectin FLISA, we should have observed closer to a 2.5-fold increase and not the 11-fold increase that was obtained. This difference may be an artifact of the lectin-FLISA, the result of other proteins attached to A1AT, increased or modified O-glycosylation, or increased accessibility of the lectin to the fucose residues. All of these possible scenarios are under investigation.
It is also important to note that increased outer arm fucosylation was observed both in patients with cirrhosis and in those with HCC. This finding implies that outer arm fucosylation was not specific to cancer but rather was probably associated with inflammation, first from the liver cirrhosis and then from the presence of the HCC lesion. Indeed, the level of outer arm fucosylation may be a more specific marker of inflammation and may be predictive of cancer development [27], [28]. In contrast, increases in core fucosylation are observed only in patients with HCC, suggesting that this change is cancer specific.
As Figure 4A shows, many patients in the non-HCC groups have elevated levels of lectin-reactive AAL. Analysis of three patients with elevated AAL levels from the cirrhosis group indicated that they had changes primarily in outer arm fucosylation, not in core fucosylation. To that end, core fucosylation may be a more specific target for the detection of cancer [29]. Efforts to use lectins such as lens culinaris and Pisum sativum agglutinin, which will not bind outer arm fucosylated glycan, in the lectin FLISA proved problematic because these lectins have much weaker binding affinities and do not actually bind fucose directly. Efforts to make recombinant AAL with specificity only to core-linked α-1,6 fucose are currently underway.
In summary, we have analyzed the glycosylation of A1AT as a function of HCC and used a lectin FLISA to measure this change in a cohort of more than 400 patients. These data need to be confirmed in larger cohorts of patients to determine if these markers are truly reliable serum markers of early HCC, to compare their accuracy with AFP in patients of diverse gender, ethnicity, etiologies of liver disease, and to determine their role in HCC surveillance. Future studies should also test the benefit of combinatorial analysis with other potential markers of HCC, such as des-gamma-carboxy prothrombin as well as to examine how the level of core and outer arm fucosylation varies as a function of anti-cancer treatment.
The sialylated N-linked glycan profile for each of the five A1AT isoforms from normal, cirrhotic, or HCC patients. (A) A representative sialyated profile of the M4 A1AT isoform from healthy individuals. (B) The relative percent of sialyated bi-antennary or tri-antennary glycan in each A1AT isoform.
Conceived and designed the experiments: MAC AM. Performed the experiments: MAC LRB JH MW AM. Analyzed the data: MAC MW PN AMDB TB AM. Contributed reagents/materials/analysis tools: AMDB AM. Wrote the paper: MAC AM.
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7. Sarbah SA, Gramlich T, Younoszai A, Osmack P, Goormastic M, et al. (2004) Risk factors for hepatocellular carcinoma in patients with cirrhosis. Dig Dis Sci 49: 850–853.
8. Alpert ME, Uriel J, de Nechaud B (1968) alpha fetogloblin in the diagnosis of human hepatoma. N Engl J Med 278: 984–986.
9. Ruoslahti E, Salaspuro M, Pihko H, Andersson L, Seppala M (1974) Serum alpha-fetoprotein: diagnostic significance in liver disease. Br Med J 2: 527–529.
10. Di Bisceglie AM, Hoofnagle JH (1989) Elevations in serum alpha-fetoprotein levels in patients with chronic hepatitis B. Cancer 64: 2117–2120.
11. Marrero JA, Romano PR, Nikolaeva O, Steel L, Mehta A, et al. (2005) GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma. J Hepatol 43: 1007–1012.
12. Sherman M (2005) Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 25: 143–154.
13. Rudd PM, Dwek RA (1997) Glycosylation: heterogeneity and the 3D structure of proteins. Crit Rev Biochem Mol Biol 32: 1–100.
14. Aoyagi Y, Suzuki Y, Igarashi K, Yokota T, Mori S, et al. (1993) Highly enhanced fucosylation of alpha-fetoprotein in patients with germ cell tumor. Cancer 72: 615–618.
15. Naitoh A, Aoyagi Y, Asakura H (1999) Highly enhanced fucosylation of serum glycoproteins in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 14: 436–445.
16. Aoyagi Y, Isokawa O, Suda T, Watanabe M, Suzuki Y, et al. (1998) The fucosylation index of alpha-fetoprotein as a possible prognostic indicator for patients with hepatocellular carcinoma. Cancer 83: 2076–2082.
17. Noda K, Miyoshi E, Gu J, Gao CX, Nakahara S, et al. (2003) Relationship between elevated FX expression and increased production of GDP-L-fucose, a common donor substrate for fucosylation in human hepatocellular carcinoma and hepatoma cell lines. Cancer Res 63: 6282–6289.
18. Block TM, Comunale MA, Lowman M, Steel LF, Romano PR, et al. (2005) Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans. Proc Natl Acad Sci U S A 102: 779–784.
19. Comunale MA, Lowman M, Long RE, Krakover J, Philip R, Seeholzer S, Evans AA, Hann HWL, Block TM, Mehta AS (2006) Proteomic analysis of serum associated fucosylated glycoproteins in the development of primary hepatocellular carcinoma. Journal of Proteome Research 6: 308–315.
20. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, et al. (2008) Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 359: 2429–2441.
21. Guile GR, Rudd PM, Wing DR, Prime SB, Dwek RA (1996) A rapid high-resolution high-performance liquid chromatographic method for separating glycan mixtures and analyzing oligosaccharide profiles. Anal Biochem 240: 210–226.
22. Jeppsson JO, Einarsson R (1992) Genetic variants of alpha 1-antitrypsin and hemoglobin typed by isoelectric focusing in preselected narrow pH gradients with PhastSystem. Clin Chem 38: 577–580.
23. Brooks KP, Iammarino RM (1985) Determination of alpha-1-antitrypsin phenotypes and M subtypes by isoelectric focusing in immobilized pH gradients. Clin Biochem 18: 280–284.
24. Kolarich D, Weber A, Turecek PL, Schwarz HP, Altmann F (2006) Comprehensive glyco-proteomic analysis of human alpha1-antitrypsin and its charge isoforms. Proteomics 6: 3369–3380.
25. Liu XE, Desmyter L, Gao CF, Laroy W, Dewaele S, et al. (2007) N-glycomic changes in hepatocellular carcinoma patients with liver cirrhosis induced by hepatitis B virus. Hepatology 46: 1426–1435.
26. Nakagawa T, Uozumi N, Nakano M, Mizuno-Horikawa Y, Okuyama N, et al. (2006) Fucosylation of N-glycans regulates the secretion of hepatic glycoproteins into bile ducts. J Biol Chem 281: 29797–29806.
27. Abd Hamid UM, Royle L, Saldova R, Radcliffe CM, Harvey DJ, et al. (2008) A strategy to reveal potential glycan markers from serum glycoproteins associated with breast cancer progression. Glycobiology 18: 1105–1118.
28. Arnold JN, Saldova R, Hamid UM, Rudd PM (2008) Evaluation of the serum N-linked glycome for the diagnosis of cancer and chronic inflammation. Proteomics 8: 3284–3293.
29. Peracaula R, Sarrats A, Saldova R, Pla E, Fort E, et al. (2010) Glycosylation of liver acute-phase proteins in pancreatic cancer and chronic pancreatitis. PROTEOMICS - Clinical Applications. In press.
Is the Subject Area "Hepatocellular carcinoma" applicable to this article?
Is the Subject Area "Cirrhosis" applicable to this article?
Is the Subject Area "Lectins" applicable to this article?
Is the Subject Area "Liver diseases" applicable to this article?
Is the Subject Area "Glycosylation" applicable to this article?
Is the Subject Area "Hepatitis C virus" applicable to this article?
Cancers and neoplasms
Is the Subject Area "Cancers and neoplasms" applicable to this article?
Is the Subject Area "Hepatitis B virus" applicable to this article?


text:
Council Member Belal Aftab
Belal Aftab
Email Belal Aftab
Belal Aftab was elected to the City Council in 2022.
Prior to his election, Belal served on Saratoga's Traffic Safety Commission for 5 years, which he chaired twice, and worked with residents in more than 50 neighborhoods to make Saratoga a safer place to walk, bike, and drive. During this time, he also worked on the City's Safe Routes to School and Local Road Safety Plan programs. Belal was also Vice Chair of the Citizens Advisory Committee at the Transbay Joint Powers Authority (Salesforce Transit Center) in San Francisco, where he provided oversight and influence on the Bay Area's long-term public transit plans. Belal has been a regular volunteer at a number of local community organizations, such as Martha's Kitchen, the Rahima Foundation, Glide Memorial, and the West Valley Muslim Association.
Brought up in Saratoga, Belal was raised by an engineer and preschool teacher who taught him the importance of good character, hard work, faith, and a strong community. Belal's parents immigrated to the United States from Pakistan. He is the first member of the City Council to be elected from the El Quito neighborhood.
Belal currently works in the technology industry. His career has spanned roles including finance, investment banking, strategy, operations, sales, business development, and executive leadership. Belal is passionate about working to solve the problems that affect all of us.
Belal studied at UC Berkeley, where he majored in Business Administration and minored in English.
Association of Bay Area Governments
Hakone Foundation Board
Santa Clara County Housing and Community Development Advisory Committee
Valley Transportation Authority (VTA) Policy Advisory Committee
Saratoga Historical Foundation

redpajama_set_name: RedPajamaCommonCrawl


with every softube plugins I own (modular, heartbeat, amp room, tsar…), I experience spikes of CPU loap with sound interruption.
It doesn't seem to happend with any other plugins.
My laptop is on "best performances"
I own an Asus Pro with a i7 8565u and 16gb of ram, a focusrite scarlett 2i2 2nd gen.
Is there anything I can do to use my beloved plugins ?
I ran some tests, apparently there's something wrong between these plugins and bitwig.
Even the smallest softube plugins will introduce CPU spikes… when heavier plugins from other brands will run smoothly.
Same problem here. It seems related to the VST3 versions of the plugins. I've no problem with the VST2 Softube plugins.
Sadly I tried both VST2 and 3 with both openGL on and off with no noticeable improvement.
Glad it worked for you tho.
Ho ok, I'm on OSX with a Vegas64, maybe related.. Anyway I also sent a message to the Bitwig support.
hey guys I just upgraded to a new macbook pro and had DSP spikes and crackle with the projects. had no luck with all previous suggestions and it didn't matter if the plugins were bypassed or suspended. still spikes and crackle. eventually I deleted and reloaded every instance of softube plugins (TAPE) in the channelstrips and that worked for me. hope that helps anybody !!!!


If you have purchased one or several items from Defshop (Existing customer) we would like to e-mail you other carefully selected offers for similar items in our product line. For that we will use private data as first name, name, birthday as well as your contact details and actual sales data (as your coupons and memberships). By registering for the newsletter you confirm that you are at least 14 years old. You may always object to receiving offers by e-mail by clicking the link "Unsubscribe newsletter" at the end of the respective e-mail or contacting our customer support (Tel.: +49(0)30 40998241, Fax: +49(0)30 409982401, e-mail: [email protected]).This will not result in additional costs beyond the base rate transmission costs.
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For shared computers that are set to accept cookies and flash cookies, we recommend that you log out completely at the end of each session.


29 August 2016 Complete the Pandaria raid achievements listed below while in a guild group.
21 November 2014 Complete the heroic Draenor dungeon achievements listed below while in a guild group.
5 October 2014 Complete the heroic Pandaria dungeon achievements listed below while in a guild group.
12 November 2012 Obtain 600 skill points in all professions and secondary professions.
20 June 2012 Craft 500 Epic items with an item level of at least 359.
15 September 2011 Complete the classy achievements listed below.
26 August 2011 Owner of Dragonwrath, Tarecgosa's Rest.
1 April 2011 Purchase the 7th guild bank tab.
18 March 2011 Create 3,000 Cataclysm flasks.
23 January 2011 Complete 15,000 daily quests.
11 January 2011 Complete the Cataclysm raid achievements listed below while in a guild group.
7 January 2011 Create 1,000 Cataclysm flasks.
7 January 2011 Catch 10,000 fish from fishing pools.
29 December 2010 Loot 100,000 gold from creatures.
27 December 2010 Obtain 525 skill points in all professions and secondary professions.
21 December 2010 Reach max level on each of the classes listed below.
17 December 2010 Cook 5,000 Cataclysm cooking recipes.
12 December 2010 Complete the slayer achievements listed below.
11 December 2010 Complete the heroic Cataclysm dungeon achievements listed below while in a guild group.


text:
import numpy as np

def export_obj(vertices, triangles, filename):
    """
    Exports a mesh in the (.obj) format.
    """

    with open(filename, 'w') as fh:

        for v in vertices:
            fh.write("v {} {} {}\n".format(*v))

        for f in triangles:
            fh.write("f {} {} {}\n".format(*(f + 1)))

def export_off(vertices, triangles, filename):
    """
    Exports a mesh in the (.off) format.
    """

    with open(filename, 'w') as fh:
        fh.write('OFF\n')
        fh.write('{} {} 0\n'.format(len(vertices), len(triangles)))

        for v in vertices:
            fh.write("{} {} {}\n".format(*v))

        for f in triangles:
            fh.write("3 {} {} {}\n".format(*f))

def export_mesh(vertices, triangles, filename, mesh_name="mcubes_mesh"):
    """
    Exports a mesh in the COLLADA (.dae) format.

    Needs PyCollada (https://github.com/pycollada/pycollada).
    """

    import collada

    mesh = collada.Collada()

    vert_src = collada.source.FloatSource("verts-array", vertices, ('X','Y','Z'))
    geom = collada.geometry.Geometry(mesh, "geometry0", mesh_name, [vert_src])

    input_list = collada.source.InputList()
    input_list.addInput(0, 'VERTEX', "#verts-array")

    triset = geom.createTriangleSet(np.copy(triangles), input_list, "")
    geom.primitives.append(triset)
    mesh.geometries.append(geom)

    geomnode = collada.scene.GeometryNode(geom, [])
    node = collada.scene.Node(mesh_name, children=[geomnode])

    myscene = collada.scene.Scene("mcubes_scene", [node])
    mesh.scenes.append(myscene)
    mesh.scene = myscene

    mesh.write(filename)

redpajama_set_name: RedPajamaGithub


Love Bombing by Oliver James – does this book present a new concept, reheated advice from other 'parenting gurus', or just plain common sense?
As the animated thread on Mumsnet shows, books that tell us parents what we are doing wrong and how to fix it are met with suspicion, hope, derision and praise. The 'Holy Grail' of parenting advice simply does not exist. While some parents reach for a book from the Attachment Parenting shelf, others will head for F for Gina Ford.
Oliver James's new book 'Love Bombing', according to the blurb will reset our children's 'emotional thermostat' and is advertised as a way to help children with behavioural problems, ADHD and Autism.
Now, I won't comment on the ADHD/Autism part of this, as I don't have the necessary experience and knowledge – there are a few posters on the MN thread who are scathing of this and I hope that some parenting bloggers will join the debate. I will say that aiming this book at parents whose children have behavioural problems could be seen as a craven attempt to take advantage of desperate parents.
My own experience shows that giving children more attention does not mean that they will take over the household. When my daughter was around three or four years old, she went through a trying period. I talked to her nursery teacher about this, and was rather taken aback by her reply. I should spend more time with my daughter and give her more attention.
When you have 2 young children at home, it is tempting to reject this advice. How much MORE attention can I give them, I hardly have any free time at all. When my husband and I sat down and talked about it, we realised that attention is more than just being there and occasionally saying, 'Oh, lovely painting dear. What a large nose Papa has!'.
I had a three year old dynamo, a one year old toddler, a household, was trying to set up my own business teaching English, friends to see, a busy life. And she was simply not getting the attention she needed, and was causing chaos to get that attention. Looking back on it, it was incredibly obvious, but lost in day to day life, I hadn't notice.
We resolved to spend more time with her, and we soon saw a marked improvement in her behaviour. We didn't do the full 'love bombing' that James recommends – he suggests taking a day or a weekend to spend one on one with your child, and allowing them to set the agenda.
I am a bit concerned that the Love Bombing idea seems to involve nights away in a hotel, or spending a whole day out with one child. How does this work within the family then? We have two children who absolutely love spending time together. I cannot see how I could take one of them away for the weekend to do fun stuff, and leave the other child at home with my husband. And there does seem to be the implication that it is the mother who is dealing with this issue.
Weekends are precious, and we like to spend the time together. I could see us doing a Family Love Bomb, where we let the kids take charge for the weekend – that sounds like fun.
Parenting books* are odd buggers, really. It goes against everything that I have learned on this parenting journey to sign up to one particular parenting philosophy and stick to it, as rigidly as a Gina Ford devotee to her schedule.
Every family is different, every child is different. While Gina Ford may work for some families, it doesn't work for all. Attachment Parenting might be great for some, but other children might hate it.
When I see how totally different my children are, I realise that I adapt my parenting methods for each child.
My son is organised, methodical and stubborn. To get him to move in the morning, I need to set rules, 'Right, lets get dressed, have breakfast and get ready for school and if there is time left, you can play on the iPad for 10 minutes, but we have to leave at 8:45am'.
My daughter is scatty, disorganised and easy going. She needs to be reminded to take her dinner money, asked if she has her swimming stuff and cajoled to stop playing with the bloody dog and have her breakfast.
Son needs a timetable, which he will work through. Daughter needs more attention and gentle humour to jolly her along.
To be fair, Oliver James does not say that his way is the only way, and it may be something that is worth trying, even on a smaller scale. You don't even need to buy the book, as the general idea is already in the articles that he has written. If it works for you, and you wish to know more about it then you can buy the book afterwards.
One thing I have noticed is that my children's behaviour improves when I have an iPhone free afternoon. As hard as I find it to give up my Twitter addiction for the day, it really does improve communication between parent and child when neither are glued to a screen. It is stating the obvious, as is James's advice to bomb your child with love, but a gentle reminder is needed now and again.
What do you think? If you have tried, or would like to try 'Love Bombing', please let me know how you got on.
*If you are going to read a parenting book then I would recommend the Mumsnet bible Why Did Nobody Tell Me which included advice from their users. Real women, mothers of real children, giving their advice. It is condensed MN Talk really, with slightly less swearing.


text:
Eastern & Oriental Hotel
E&O Gourmet
Adult(s) 1 2 3 4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 January February March April May June July August September October November December 2021 2022
Number of nights 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Number of adults 1 2 3 4 5 6
Number of children 0 1 2
E&O Hotel Welcomes First Female General Manager
Penang, 8 January 2019 – The Eastern and Oriental Hotel is delighted to announce the appointment of Ms Alison Fraser to the position of General Manager. In the 134 years since the E&O was established by the Sarkies brothers, we are proud to have a lady general manager helm the social beacon of George Town for the first time.
Alison, a British national, comes from a wide and varied background in luxury hospitality and innovative lifestyle concepts, spanning three decades of experience in the United Kingdom, Middle East and Asia, in key positions with InterContinental Hotels and Resorts, London and in general management positions with GHM Hotels and Resorts in Langkawi, Kuala Lumpur and Bali.
In 2008, Alison became a partner in Brand Bon Ton Sdn Bhd, where she supported Bon Ton and Temple Tree resorts in Langkawi, and a small heritage hotel in Penang, expanding three years later into ChinaHouse, a multi-food and beverage platform in support of the burgeoning art scene on the island. She was appointed Director of Bon Ton Sdn Bhd in 2016.
Alison was past President of the Malaysian Association of Hotels (MAH) in Kedah and Perlis from 2006 – 2010.
Following her success in hospitality, she set up BT Zinc Sdn Bhd in 2013, a Malaysian partner of InVision Hospitality, a South East Asian strategic Hotel Management Company, she has successfully operated 3 properties in Malaysia since.
Alison Fraser said, "I am honoured to be part of this legendary hotel and I look forward to working with the E&O team to ensure the preeminent style and elegance of this heritage icon continues to thrive."
10, Lebuh Farquhar
+(6) 04 222 2000
Email: luxury@eohotels.com
The E&O Group
Copyright Ⓒ 2021 Eastern & Oriental Hotel. All rights reserved.


text:
New Signs of Chinese Efforts to Improve Labor Relations in Africa?
Tanzanians working on Chinese-built road (2011) photo: DB
May 1 is International Labor Day almost everywhere except the USA. Today I noticed media reports from several African countries such as Uganda and Tanzania that local Chinese Chambers of Commerce were giving awards for the best workers in Chinese companies, and to Chinese companies for being the best employers. Chinese ambassadors spoke at several of these award ceremonies.
Interesting to see that Chinese embassies are urging Chinese employers to do more to train their African workforce, investing in their skill development; boost incomes (pay higher wages?); and deliver benefits in accordance with local laws.
Although some African countries (South Africa, Mauritius, possibly others) have longstanding Chinese Chambers of Commerce, I noticed around 2006 and 2007 that Chinese embassies were pushing leading state-owned enterprises in African countries to take on the role of heads of these Chambers and to use them as ways to help socialize Chinese companies into local laws and regulations. The evolving role of these business associations would be an interesting research topic.
Kai Xue June 22, 2016 at 5:04 PM
Do you think the Chinese population in Africa is on the decline?
Working class wages are still rising quickly in China. The average monthly wage in 2015 for a migrant worker was 3,072 yuan ($473). Migrant worker wage increases in 2014 and 2013 were particularly impressive with gains of 9.8 percent and 13.9 percent in 2013 respectively.
I think this has surely slowed down new arrivals and attracted Chinese residents in Africa to re-settle in China.
However, I have noticed in places like Ethiopia, the population has jumped a lot in the last few years (maybe tripling).
Deborah Brautigam July 29, 2016 at 12:43 PM
I doubt it is on the decline -- the labor export data (see our website: sais-cari.org) shows 305,665 total Chinese workers in Africa in 2010; we don't have a figure for 2011, then 280,545 for 2012; 243,922 for 2013; 252,059 for 2014. But most of the decline here came from projects in Libya collapsing.
New Essays: China-Africa, A Maturing Relationship?...
Seeking China-Africa Practicum Clients for 2016-20...
Guest Post: Report from Yiwu: Made in Africa, By C...
New Signs of Chinese Efforts to Improve Labor Rela...


text:
Saphenista tufinoa is a species of moth of the family Tortricidae. It is found in Ecuador in the provinces of Cotopaxi and Carchi.

References

Moths described in 1999
Saphenista

redpajama_set_name: RedPajamaWikipedia


text:
struct uiCombobox {
	uiDarwinControl c;
	NSPopUpButton *pb;
	NSArrayController *pbac;
	void (*onSelected)(uiCombobox *, void *);
	void *onSelectedData;
};

@interface comboboxDelegateClass : NSObject {
	struct mapTable *comboboxes;
}
- (IBAction)onSelected:(id)sender;
- (void)registerCombobox:(uiCombobox *)c;
- (void)unregisterCombobox:(uiCombobox *)c;
@end

@implementation comboboxDelegateClass

- (id)init
{
	self = [super init];
	if (self)
		self->comboboxes = newMap();
	return self;
}

- (void)dealloc
{
	mapDestroy(self->comboboxes);
	[super dealloc];
}

- (IBAction)onSelected:(id)sender
{
	uiCombobox *c;

	c = uiCombobox(mapGet(self->comboboxes, sender));
	(*(c->onSelected))(c, c->onSelectedData);
}

- (void)registerCombobox:(uiCombobox *)c
{
	mapSet(self->comboboxes, c->pb, c);
	[c->pb setTarget:self];
	[c->pb setAction:@selector(onSelected:)];
}

- (void)unregisterCombobox:(uiCombobox *)c
{
	[c->pb setTarget:nil];
	mapDelete(self->comboboxes, c->pb);
}

@end

static comboboxDelegateClass *comboboxDelegate = nil;

uiDarwinControlAllDefaultsExceptDestroy(uiCombobox, pb)

static void uiComboboxDestroy(uiControl *cc)
{
	uiCombobox *c = uiCombobox(cc);

	[comboboxDelegate unregisterCombobox:c];
	[c->pb unbind:@"contentObjects"];
	[c->pb unbind:@"selectedIndex"];
	[c->pbac release];
	[c->pb release];
	uiFreeControl(uiControl(c));
}

void uiComboboxAppend(uiCombobox *c, const char *text)
{
	[c->pbac addObject:toNSString(text)];
}

int uiComboboxSelected(uiCombobox *c)
{
	return [c->pb indexOfSelectedItem];
}

void uiComboboxSetSelected(uiCombobox *c, int n)
{
	[c->pb selectItemAtIndex:n];
}

void uiComboboxOnSelected(uiCombobox *c, void (*f)(uiCombobox *c, void *data), void *data)
{
	c->onSelected = f;
	c->onSelectedData = data;
}

static void defaultOnSelected(uiCombobox *c, void *data)
{
	// do nothing
}

uiCombobox *uiNewCombobox(void)
{
	uiCombobox *c;
	NSPopUpButtonCell *pbcell;

	uiDarwinNewControl(uiCombobox, c);

	c->pb = [[NSPopUpButton alloc] initWithFrame:NSZeroRect pullsDown:NO];
	[c->pb setPreferredEdge:NSMinYEdge];
	pbcell = (NSPopUpButtonCell *) [c->pb cell];
	[pbcell setArrowPosition:NSPopUpArrowAtBottom];
	// the font defined by Interface Builder is Menu 13, which is lol
	// just use the regular control size for consistency
	uiDarwinSetControlFont(c->pb, NSRegularControlSize);

	// NSPopUpButton doesn't work like a combobox
	// - it automatically selects the first item
	// - it doesn't support duplicates
	// but we can use a NSArrayController and Cocoa bindings to bypass these restrictions
	c->pbac = [NSArrayController new];
	[c->pbac setAvoidsEmptySelection:NO];
	[c->pbac setSelectsInsertedObjects:NO];
	[c->pbac setAutomaticallyRearrangesObjects:NO];
	[c->pb bind:@"contentValues"
		toObject:c->pbac
		withKeyPath:@"arrangedObjects"
		options:nil];
	[c->pb bind:@"selectedIndex"
		toObject:c->pbac
		withKeyPath:@"selectionIndex"
		options:nil];

	if (comboboxDelegate == nil) {
		comboboxDelegate = [[comboboxDelegateClass new] autorelease];
		[delegates addObject:comboboxDelegate];
	}
	[comboboxDelegate registerCombobox:c];
	uiComboboxOnSelected(c, defaultOnSelected, NULL);

	return c;
}


text:
Q: Find a particular regex word and linkify to open an activity in android I am getting the text from API, can be random, but It contains expressions like on FB
@xyz hi, @abc how u??
1. I need to create a regex expression starts with @, ends with space.
2. Linkify it to open the user activity like XYZ or ABC.
Please help me, I have tried to create a class like,
import android.text.Spannable;
import android.text.SpannableString;
import android.text.Spanned;
import android.text.method.LinkMovementMethod;
import android.text.method.MovementMethod;
import android.text.style.ClickableSpan;
import android.view.View;
import android.widget.TextView;

public class ClickSpan extends ClickableSpan {

    private OnClickListener mListener;

    public ClickSpan(OnClickListener listener) {
        mListener = listener;
    }

    @Override
    public void onClick(View widget) {
        if (mListener != null) mListener.onClick();
    }

    public interface OnClickListener {
        void onClick();
    }

    /**
     * To clickify a textview
     * @param view
     * @param clickableText
     * @param listener
     */
    public static void clickify(TextView view, final String clickableText,
            final ClickSpan.OnClickListener listener) {

        CharSequence text = view.getText();
        String string = text.toString();
        ClickSpan span = new ClickSpan(listener);

        int start = string.indexOf(clickableText);
        int end = start + clickableText.length();
        if (start == -1) return;

        if (text instanceof Spannable) {
            ((Spannable)text).setSpan(span, start, end, Spanned.SPAN_EXCLUSIVE_EXCLUSIVE);
        } else {
            SpannableString s = SpannableString.valueOf(text);
            s.setSpan(span, start, end, Spanned.SPAN_EXCLUSIVE_EXCLUSIVE);
            view.setText(s);
        }

        MovementMethod m = view.getMovementMethod();
        if ((m == null) || !(m instanceof LinkMovementMethod)) {
            view.setMovementMethod(LinkMovementMethod.getInstance());
        }
    }

}

And call like,
clickify(textView, clickText,new ClickSpan.OnClickListener()
     {
        @Override
        public void onClick() {
           startActivity here..
        }
    });

I need help as to how I can get this to work on my activity creating a loop of regex.

A: public class ClickableURLSpan extends URLSpan {
    public ClickableURLSpan(String url) {
        super(url);
    }

    @Override
    public void onClick(View widget) {
        String clickedText = getURL();

            // START your activity here
    }
}

Now you can linkify your text:
CharSequence input = "@xyz hi, @abc how u??!";
SpannableStringBuilder builder = new SpannableStringBuilder(input);

Pattern pattern = Pattern.compile("@.*?\\s");
Matcher matcher = pattern.matcher(input);
while (matcher.find()) {
    int start = matcher.start();
    int end = matcher.end();

    String text = input.subSequence(start, end).toString();

    ClickableURLSpan url = new ClickableURLSpan(text);
    builder.setSpan(url, start, end, 0);
}

textView.setText(builder);
textView.setMovementMethod(LinkMovementMethod.getInstance());

redpajama_set_name: RedPajamaStackExchange


I am a yellow lover through and through but it's a wildly under-utilised colour in fashion in general. Occasionally in the vintage inspired realm you'll get a plain yellow dress on offer or maybe a print or two, but it's definitely under represented on the whole. Imagine my excitement, then, when I saw this multi-yellow toned striped cutie available from Joanie Clothing. If this dress were a person, it would have been an 'our eyes locked across a crowded room' love story. The reality of that is that I felt the jolt of an immediate 'Add to cart' impulse as soon as I saw the product photo pop up on Joanie Clothing's New In page, but let's not dampen the romance of a new found love with reality, shall we?
I may dress in 50s styles predominantly but I have a fond appreciation for the vintage clothing of many a past era. I tend towards big skirts and small waists, bold colours and vibrant patterns, but I can still appreciate a sleek 40s skirt suit, a cute 60s mini dress, an example of exquisite beading of the 20s.
One of my favourite pieces of clothing that just doesn't get utilised enough in modern day fashion is the capelet, whether a toasty warm one made for winter in a heavy tweed or a luxe decorative cropped number worn entirely for glitz and glamour on an evening out. It's a taste of the latter I'm pleased to be indulging in this post, with this gorgeous beaded capelet on offer from Joanie Clothing.
As much as I love bright colours, I'm not much one for clashing. I've actually been known to say before how much I hate pink and red paired together, with an unnecessary amount of passion. Turns out, that dislike is more of a contextual thing, because when I spotted this Eden frilly fronted cardigan I was totally on board. I immediately pictured it paired with a sky blue skirt and a wicker basket handbag, and then when it arrived I styled it exactly so. It's just like I pictured it would be. Don't you just love it when a plan comes together?


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It's important to look at more than price when you're comparing trauma insurance cover providers. Sometimes you can get better value from a higher-end company over a cheap trauma insurance cover company because the quality of the service that a top company can provide is much better. When you take the time to carefully compare what different trauma insurance cover businesses offer, you'll be able to determine the right balance between cost and quality.
Choosing the right trauma insurance cover company is important, so make sure you have detailed quotes from a number of providers so that you can make an informed decision.


Objective: To review the current status of departments of medical education in all public and private medical colleges located in the city of Lahore, Pakistan.
Methods: This was a quantitative, cross sectional descriptive study; conducted from March to October 2015 in Pakistan Medical & Dental Council (PM&DC) recognized medical colleges located in Lahore, Pakistan. Respondents were the heads of departments of medical education or any other well-informed faculty member. A questionnaire was prepared to obtain information about the current status of the departments of medical education (DMEs). The investigator personally visited all medical colleges for data collection. Both verbal and written consents were obtained and the questionnaire was administered to the resource persons. The data was organized and entered in SPSS for descriptive analysis.
Results: Out of the 18 medical colleges in Lahore, six (33.3%) belonged to public sector and 12 (66.7%) were from private sector. All medical colleges reported to have a functional DME. However, eight had established DMEs during the past five years. Only one (5.6%) head of DME was working on full-time basis. Eleven (61.1%) heads of DMEs did not have any formal qualification in medical education. Eight (44.4%) colleges claimed to have adequate human resources for DME. Thirteen (72.2%) colleges mentioned that adequate financial resources were available for running DMEs. It is encouraging to see that DMEs in private sector medical colleges are playing increasingly significant role in managing educational activities. Similarly, the senior management of private sector seems to be relatively more eager to promote educational activities.
Conclusion: There is an increasing recognition towards establishing DMEs in the medical colleges, but their infrastructure, proper functioning and availability of human and financial resources are serious impediments requiring immediate attention.


text:
Obituary - Abdulkader Tayob
By Professor Abdulkader Tayob
In the Name of Allah, Most Gracious, Most Merciful.
Moving on the Exalted Friend is always a momentous occasion. But when a martyr to truth and justice moves to her Exalted Friend, it calls for more than a moment of reflection and gratitude. Perchance, we may not be counted among those who cover up (kafara).
Shamima, you have given us an opportunity to reflect on ourselves and our stations in this world. May the Exalted Friend grant you supreme satisfaction, forgiveness. May all your sins be forgiven, and transformed into righteous rewards.
O Allah, Possessor of Peace, to whom all Peace returns, grant her the Abode of Peace. Grant strength and perseverance to her family, her husband, her children, and her many friends.
Shamima reminds one of many things. As we read the Qur'an in this blessed month of Ramadan, it also provides us an opportunity to remember Rumi's insightful remarks about our cosmos. In reference to the names taught to primordial Adam about the true nature of things, Rumi told us that most of us often live in some form of deception. Death reveals the true nature of things, the names deeply imprinted onto our primordial selves.
He added though, that some people, like Umar (May Allah be pleased with him) had penetrated to their nature before death. And thus, while Umar was his common name, his true name was the fighter of the devil. Even the devil took another road in order not to cross the path of Umar.
Shamima, your everyday name was beautiful. But there are many of us who know that your true name was:
Fighter for Justice
Don't let grass grow under my feet.
You have met the Exalted Friend
Prof. Abdulkader Tayob
Department of Religious Studies


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Treatment aims to prevent hypoglycemia by taking snacks every 3-4 hours. Uncooked cornstarch can act as a 'slow release' form of glucose and may prevent hypoglycemia overnight. A diet higher than normal in protein may help with the cramping, tiredness and fatigue.


Lunch Boxes for Adults - RV Must Haves!
Lunch Boxes for Adults.. Why not?
If you're wondering why the need for cool lunch boxes for adults, then wonder no longer. I am here with all of the answers!
Have you ever thought to yourself, man, I miss those cool lunch boxes I used to have as a child? Remember having a metal batman or superman lunchpail with a matching thermos nested inside? Wasn't that the coolest? Showing up for lunch, opening up your work of art, and being the envy of your friends. All the while, eating some good pb&j to boot!
These Black and Blum Stackable Lunch Boxes for Adults are the answer, and they are AMAZING!
It's the perfect size for taking breakfast, lunch, or dinner with you when you're out and about exploring the country. When you return, they are dishwasher safe, stackable, and can be stored in a small space. Every RV owner knows the pains of limited storage space. Not to mention, you can also use them in the microwave.
No need to fear, Black and Blum lunch pots are here!
Check out this video by The Grommet that shows the thought & design quality instilled in every Black & Blum product.
What was that? You don't care about style? No worries. These lunch boxes serve more purpose than just looking sleek & stylish. They also do this crazy thing where they keep your food stored neatly, and provide you with not only storage, but a bowl, and a fork all wrapped up into this practical & utilitarian package.
Another great benefit of these cool lunch boxes is prepping your meals for the next day. Next time you're cooking dinner, and you have left overs, be sure to divide them up into these cool stackable lunch pots. Take them outside, sit in the cool shade of your RV awning, and have yourself some leftovers in style!
Or, cook your entire menu for the week on a Sunday night. Then, individually sort out every meal and have it ready to go when your hunger boils up to the surface.
But don't worry – These lunch boxes for adults, are also great for everyone in your family!
While you're shopping for the kitchen, be sure to check out these collapsible measuring cups & this RV spice holder /storage organizer.


text:
Q: List all elements of a class and store them in an array to set appearance properties in one shot Is there a method to list all elements of a kind in a class, store them in an Array and set them grouped styling properties ? For example, I would like to list all text UITextfields in the current class and set the border color, border width, ... I found the very useful code below, but you need to append explicitly each element in the Array.
// The extension code

extension UITextField {
    func setPreferences() {
        self.layer.cornerRadius = 5
        self.layer.borderColor = UIColor.grayColor().CGColor
        self.layer.borderWidth = 1
    }
}

// The following code in the class

var theTextFields = [UITextField]()

func setColorsAndBorders() {

    theTextFields = [tf1, tf2, tf3, tf4] // etc

    for item in theTextFields {
        item.setPreferences()
    }
}

// And the following code in the ViewDidLoad

setColorsAndBorders()

A: The simplest way to achieve this, assuming your class is a UIViewController, while still making use of your extension would be something like:
func setColorsAndBorders()
{
    for control in self.view.subviews
    {
        if (control is UITextField)
        {
            let thisControl = control as! UITextField
            thisControl.setPreferences()
        }
    }
}

Hope this helps.
EDIT:
Another way to do the same thing if you're programatically creating your UITextFields is with this extension:
extension UITextField
{
    convenience init(cornerRadius: CGFloat, borderColor: UIColor, borderWidth: CGFloat)
    {
        self.init()
        self.layer.cornerRadius = cornerRadius
        self.layer.borderColor = borderColor.CGColor
        self.layer.borderWidth = borderWidth
    }
}

And then you can, for example, create a text field in such a way:
private func loadTextFields()
{
    let thisField = UITextField(cornerRadius: 5, borderColor: UIColor.grayColor(), borderWidth: 1)
    thisField.frame = CGRect(x: 0, y: self.view.frame.height / 2.0, width: self.view.frame.width, height: 40.0)
    view.addSubview(thisField)
}


text:
Shannon Meilak
Director // Production Designer
Portfolio / Gallery
Production & Costume Design
On Set (Behind The Scenes)
Head Shots & Modeling
'Beyond The Pointy Hat'
Contact Shannon Meilak
(Film Review) 'Burning' (2021)
If not for the interviews in this film, you could quite honestly mistake this documentary for some sort of horror movie. The film opens...
(Film Review) La Strada (1954)
Fellini's 'La Strada' could be seen, as the title suggests, as the original road movie, or at least as an Italian neorealist version of...
(Film Review) Ladri Di Biciclette / The Bicycle Thieves (1948)
De Sica's 'The Bicycle Thieves' is a poetic story of personal struggle and tragedy that follows the journey of Antonio and his son Bruno,...
(Essay) Paranoid & Hysterical Hollywood of the 1950's and 2000s
How did Hollywood address the paranoid, hysterical political climate of the 1950's and is that being continued in post-9/11 Hollywood...
(Essay) Is the Australian Gothic a unique genre in Australia's National Cinema?
Is the Australian Gothic a unique genre in Australian's National Cinema. How does the use of landscape and themes work to connect with or...
(Video Essay) The HUAC Guide to Aliens & Pod People.
An exploration of cold war America in Hollywood's Science Fiction film.
(Video Essay) Australian National Cinema: Picnic at Hanging Rock.
An exploration of 'Picnic at Hanging Rock' as a Renaissance and Australian National Cinema film.
(Film Review) Godzilla (2014)
"The arrogance of men is thinking nature is in their control and not the other way around" - Dr. Ichiro Serizawa Disguised as a creature...
(Essay) The Horror Genre: 'What Ever Happened to Baby Jane?'
"Sister, sister, oh so fair, why is there blood all over your hair?" : A Look into 'What Ever Happened to Baby Jane?' and the Horror...
(Scene Analysis) An Exploration of Sound and Cause & Effect.
An Exploration of Sound and Cause & Effect in 'Invasion of the Body Snatchers' Dr. Miles Bennell returns home to a full schedule and a...
60's Horror
Australian Cinema
Australian Renaissance
Gothic Cinema
HUAC
Invaders from Mars
National Cinema
Neorealism
The Bicycle Thieves
The Day the Earth Stood Still
The Invasion
The Loved Ones
What Ever Happened To Baby Jane
© 2015-2020 Shannon Meilak


Thank you for coming, and thank you Aatish, Hina, Rukmini, Ragalekha, Nama Rupa, and the many others that are contributing daily to this website. Without you this blog would be empty and soulless.
Coming changes for a better future.
This blog has been started in jan 2008. Before that there was only the library108.com website to provide you with news about HH Kadamba Kanana Swami. In 2005 kkswami.com was started. And to download classes and videos you could go to another website media.library108.com.
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