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Transplantation of induced pluripotent stem cell-derived renal stem cells improved acute kidney injury
Qing Li1,
Shou-fu Tian2,3,
Ye Guo4,
Xin Niu1,
Bin Hu1,
Shang-chun Guo1,
Nian-song Wang2 &
Yang Wang1
Acute kidney injury (AKI) is a severe disease with high morbidity and mortality. Methods that promote repair of the injured kidney have been extensively investigated. Cell-based therapy with mesenchymal stem cells or renal progenitor cells (RPCs) resident in the kidney has appeared to be an effective strategy for the treatment of AKI. Embryonic stem cells or induced pluripotent stem cells (iPSCs) are also utilized for AKI recovery. However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.
In this study, we induced iPSCs differentiation into RPCs using a nephrogenic cocktail of factors combined with the renal epithelial cell growth medium. We then established the rat ischemia–reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel. Next, we examined the renal function-related markers and renal histology to assess the therapeutic effect of the injected cells. Moreover, we investigated the mechanism by which iPSC-derived RPCs affect AKI caused by IR.
We showed that the differentiation efficiency of iPSCs to RPCs increased when cultured with renal epithelial cell growth medium after stimulation with a nephrogenic cocktail of factors. The transplantation of iPSC-derived RPCs decreased the levels of biomarkers indicative of renal injury and attenuated the necrosis and apoptosis of renal tissues, but resulted in the up-regulation of renal tubules formation, cell proliferation, and the expression of pro-renal factors.
Our results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.
Acute kidney injury (AKI) is characterized by acute tubular injury and a rapid decline in renal function [1]. Renal ischemia is one of the most common causes of AKI. AKI has recently received increasing attention due to the high mortality and morbidity rates of the syndrome [2]. Although pharmacological therapy, modern dialysis techniques, and intermittent or continuous renal replacement therapies exist, the therapeutic approaches for AKI remain very limited. Thus, the establishment of novel therapeutic strategies for ischemic AKI is urgently needed.
In response to acute injury, the adult kidney shows some level of regeneration characterized by the proliferation of the surviving cells and the replacement of the necrotic tubular cells with functional tubular epithelium [3]. The process is hypothesized to involve epithelial cell dedifferentiation, interstitial cell transdifferentiation and/or activation of quiescent stem cells. Over the last few years, renal progenitor cells (RPCs) have been isolated from the kidney [4–7]. Several studies have indicated that RPCs appear to play important roles in kidney repair under various pathological conditions [4, 8–10]. However, progenitor cells in the adult kidney are rare, which limits the application of these cells. Therefore, we resorted to other types of stem cells.
Stem cells, including embryonic stem cells (ESCs) and adult stem cells, have the potential of self-renewal and differentiation into multiple cell types and therefore hold great promise in regenerative medicine [11–13]. It was recently reported that stem cells exhibit therapeutic potential for AKI [14–17]. Several studies have demonstrated that the exposure of ESCs to factors required for renal specification, such as retinoic acid, activin A and bone morphogenic proteins (BMPs), does induce their differentiation into renal lineage cells in vitro [18–20]. Vigneau et al. [10] showed that the transplantation of mouse ESCs-derived RPCs can result in the stable integration into proximal tubules with normal morphology and normal polarization injection into developing live newborn mouse kidneys, suggesting the potential of ESCs for application in regenerative therapies. However, the use of ESCs for human therapy raises several safety and ethical concerns.
Induced pluripotent stem cells (iPSCs) are a type of newly defined stem cell with properties similar to those of ESCs in terms of self-renewal and differentiation. These cells were first generated by Yamanaka and colleagues [21]. Since their discovery, iPSCs have shown their advantages in regenerative medicine. iPSCs have also been reported to be effective for AKI. Lee and colleagues [16] showed that the injection of iPSCs into the kidney improves renal function and attenuates renal tubular injury in AKI caused by ischemia–reperfusion injury (IR) and eventually improves the survival rate of rats with AKI. Although iPSCs are an alternative potential cell source for stem cell therapy to protect against AKI, there is also a risk of tumor formation. Therefore, we investigated whether iPSC-derived RPCs have a therapeutic effect on AKI.
In the present study, we examined whether iPSC-derived RPCs can protect against AKI in a rate model of IR. We showed that the differentiation efficiency of iPSCs to RPCs increased when cultured with Renal Epithelial Cell Growth Medium after stimulation with a nephrogenic cocktail of factors. The injection of iPSC-derived RPCs combined with hydrogel, which provides a 3-D structure to the cells, into the kidney of rats with IR could improve renal function and attenuate tubular injury by forming renal tubules in the recipient rat kidney directly, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.
Efficient differentiation of RPCs from mouse iPSCs
To investigate whether iPSC-derived RPCs can improve AKI, we first used a nephrogenic cocktail of factors (including retinoic acid, activin A, and BMP7) to induce iPSCs differentiation into RPCs (Additional file 1: Figure S1). The iPS cell line used in this study is tagged with a ubiquitously expressed gfp gene. The real-time PCR analysis showed that the expression of the RPC markers PAX2, WT1, Six2 and CD24 increased after RAB treatment (Fig. 1a), indicating that RPCs were successfully induced. As shown by flow cytometry analysis, the PAX2, WT1 and CD24 positive cells were 33.16, 19.56 and 27.82 % respectively (Fig. 1b). Additionally, the mature renal markers AQP1 and E-cadherin were up-regulated upon RAB stimulation (Fig. 1a). To improve the differentiation efficiency of iPSCs into RPCs, the cells were cultured in renal epithelial cell growth medium for another 5 days (Additional file 1: Figure S1). As expected, the expression of the RPCs markers was further up-regulated compared with that of the RAB group, as shown by real-time PCR analysis after 5 days of differentiation in RAB medium (Fig. 1a). Moreover, the PAX2, WT1, and CD24 single-positive cells increased to 52.56, 27.8 and 36.24 % respectively (Fig. 1b), indicating that more RPCs were generated in the RAB + REGM group.
Efficient differentiation of renal progenitor cells from mouse induced pluripotent stem cells (iPSCs). The renal differentiation of mouse iPSCs was initiated by the formation of embryoid bodies (EBs). After 2 days, retinoic acid, activin A, and BMP7 were added to the differentiation medium, and the cells were exposed to this supplemented media for 5 days (RAB group). After incubation with growth factors for 5 days, the EBs in the RAB + REGM group were cultured in renal epithelial cell growth medium for another 5 days. a Real-time PCR analysis of the expression of mesoderm (Bry) and renal lineage genes (Pax2, Osr1, WT1, Six2, CD24, Sal1, AQP1, E-cad and PDGFR). b Flow cytometry analysis of the expression of mesoderm renal progenitor-related genes. Black line, cells stained with isotype control; Red line, cells stained with indicated antibodies. *P < 0.05
Therapeutic effect of iPSC-derived RPCs in rats with IR-induced AKI
Next, the rat IR model was generated by occlusion of the left renal artery followed by reperfusion and right kidney removal. iPSC-derived RPCs from the RAB + REGM group were injected directly into the renal parenchyma of the injured rats in combination with the hydrogel. The control group (IR-control) was injected with PBS combined with the hydrogel. The levels of BUN and Scr were detected at the indicated times. The plasma levels of BUN and Scr reached their peak levels at day 1 of renal IR in all groups and then decreased gradually (Fig. 2a, b). After RPC transplantation, the plasma levels of BUN and Scr were lower than those of the IR-control group (Fig. 2a, b). To test whether the RPC transplantation has beneficial effects on regeneration after IR, the rats were sacrificed on days 3, 7, 14, and 28, and the renal histology was examined. H&E staining showed that the proximal tubule in the renal cortex in the control group exhibited acute injury and necrosis 3 days after surgery (Fig. 3a): the brush border of some epithelial cells disappeared; the lumen expanded; some of the tubular epithelial cells detached from the basement membrane; the tubule was obstructed with cellular debris; and the interstitial tubule was infiltrated with inflammatory cells. The histological features of necrotic injury were still severe 7 days after ischemia and began to improve on days 14 and 28. The injury phenotype was decreased in the rat kidney as a result of RPC transplantation. The quantitative analysis of the renal tubular necrosis using the grading scores of Paller et al. [22] is shown in Fig. 3b. These results suggest that the transplantation of iPSC-derived RPCs could improve renal regeneration and function after AKI.
Generation of rat renal ischemia–reperfusion model. The rat renal ischemia–reperfusion injury (IR) model was generated by occlusion of the left renal artery followed by reperfusion and right kidney removal. iPSC-derived renal progenitor cells were injected into the renal parenchyma of the injured rats in combination with a hydrogel. The Scr (a) and BUN (b) levels in the plasma were detected at the indicated times. *P < 0.05 vs. IR-Control
Transplantation of iPSC-derived renal progenitor cells improved renal tubular damage caused by ischemia–reperfusion. a Pathological changes in the kidney on the third day after surgery, as shown by H&E staining. Luminal debris, loss of brush borders and lumen expansion are observed in the injured groups (black arrow). b The transplantation of iPSC-derived renal progenitor cells reduced the acute tubular necrosis scores. c The immunohistochemistry analysis indicated that the injected GFP-positive cells formed a tubular structure (black arrow) in the recipient organ at the indicated times after transplantation. *P < 0.05 vs. IR-Control. Scale bar 50 μm
Mechanistic study of the improvement in the renal tubular damage caused by IR as a result of iPSC-derived RPC transplantation
We further investigated the mechanism through which RPCs relieve acute renal injury caused by IR. Previous studies have reported that mouse kidney progenitor cells accelerate renal regeneration after ischemic injury by differentiation into epithelial cells and incorporating into the renal tubule [9, 23–25]. Thus, we first examined the localization of the transplanted iPSC-derived RPCs. Because the iPS cell line used in our study carries a ubiquitously expressed gfp gene, it is convenient to trace the injected cells. Using immunohistochemistry, we showed that GFP-positive cells began to form a tubular structure in the recipient kidney 7 days after injection (Fig. 3c). Importantly, no tumor was detected even 3 months after transplantation. Next, the effects of the RPCs on the proliferation and apoptosis of cells in the injured kidney were examined by PCNA staining and TUNEL analyses, respectively. The results showed that the number of PCNA-positive cells increased in the transplanted group compared with that found in the control group on days 7 after injection (Fig. 4a, b), indicating the presence of a greater number of proliferating renal tubular epithelial cells in the kidney after RPC transplantation. In contrast, the cell apoptosis on days 7 was reduced in the RPC-transplanted group, as shown by TUNEL analysis (Fig. 4c, d). Furthermore, we detected the expression levels of the anti-inflammatory factors interleukin-10 (IL-10), basic fibroblast growth factor (bFGF), and transforming growth factor β1 (TGF-β1) and growth factors promoting renal tubular cell repair, namely epidermal growth factor (EGF), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF). The real-time PCR analysis showed that the expression of these genes was upregulated to different extents after RPC transplantation (Fig. 5). Altogether, these data indicate that iPSC-derived RPC transplantation improves renal function after IR by directly incorporating into the renal tubule, promoting cell proliferation, reducing apoptosis, and upregulating the expression of pro-renal factors.
Cell proliferation was increased and apoptosis was decreased in the transplanted renal parenchyma. a The proliferation of renal tubular cells was increased 7 days after cell transplantation, as determined by PCNA staining. b Quantitative analysis of PCNA-positive cells in a. c Renal tubular cell apoptosis was decreased 7 days after cell transplantation, as determined by TUNEL assay. d Quantitative analysis of c. *P < 0.05 vs. IR-Control. Scale bar 50 μm
Anti-inflammatory factors and pro-renal tubular repair factors increased after renal progenitor cell transplantation. Real-time PCR analysis of the expression of anti-inflammatory factors (IL-10, FGF, and TGF-β) and pro-renal tubular repair factors (EGF, HGF, and PDGF) on D3, D7, D14, and D28. The anti-inflammatory factors and pro-renal tubular repair factors in the renal cortex of rats after cell transplantation are up-regulated compared with the levels observed in the control group. *P < 0.05 vs. IR-Control
AKI is an emerging worldwide public health problem with high mortality and morbidity rates and has thus attracted increasing attention. Although traditional therapies show benefits in the treatment of AKI, the therapeutic approaches are still very limited. Recently, stem cell-based therapy appeared to be a potential strategy for the prevention of AKI [26]. In the present study, we provide the first demonstration that the transplantation of iPSC-derived RPCs improves renal regeneration and function in a rat model of IR-induced AKI, and the protective effect of the RPCs was mediated by their direct differentiation into renal lineage cells and incorporation into the renal tubule, which resulted in the promotion of cell proliferation and the reduction of apoptosis in the damaged zone. Furthermore, the transplantation of iPSC-derived RPCs promoted the expression of anti-inflammatory factors and pro-renal tubular repair factors, suggesting that RPCs can regulate the microenvironment and facilitate cell survival in the injured kidney.
After ischemic injury, RPCs and mesenchymal stem cells (MSCs) resident in the kidney are activated and show some level of regenerative ability. Several studies have shown the therapeutic potential of isolated primary RPCs or MSCs in experimental AKI models. However, these cells are not available in large volumes. Recent advances demonstrated that iPSCs may be more readily accessible for kidney regeneration [16]. Therefore, in our study, iPSCs were differentiated into renal lineage cells to obtain a sufficient number of RPCs. To the traditional induction medium, we added renal specific growth medium for further induction. Using this modified protocol, the differentiation efficiency of iPSCs into RPCs and mature renal epithelial cells increased. Because kidney regeneration requires many functionally distinct cell types of the nephron, the transplantation of all renal cell types derived from iPSCs may offer the advantage of generating more than one cell type of the adult kidney.
In previous studies, stem cells for the treatment of AKI were mainly injected through the tail vein or the intrarenal artery [9, 16], and the transplanted stem cells in the circulation are mobilized to the injury site in the kidney mediated by chemokines/cytokines and receptor interaction and thereafter enhance renal regeneration. However, the homing efficiency cannot be determined. In our study, RPCs were injected directly into the renal parenchyma in combination with a hydrogel. A hydrogel consists of a network of polymer chains, and the function and structure of a hydrogel are similar to those of a natural extracellular matrix. Therefore, hydrogels are currently widely used as scaffolds in tissue engineering [27–30]. The hydrogel used in our work is composed of polypeptides and can be degraded into natural amino acids in vivo; thus, the hydrogel has no hazardous effect on the injured tissue. After being injected into the renal parenchyma with the RPCs, the liquid hydrogel will quickly transform into a solid structure, which provides a three-dimensional microenvironment for RPC adhesion, migration, proliferation and differentiation. Our results showed that the exogenous cells formed a tubular structure in the injured kidney, indicating that the RPCs could migrate out of the hydrogel and participate in renal regeneration.
The therapeutic mechanisms of primary RPCs for AKI were recently investigated in several studies [9, 23, 31]. It has been reported that the transplanted RPCs can differentiate into renal tubule cells and vessel endothelial cells with the expression of E-cadherin and CD34 [23] and therefore accelerate renal regeneration and prolong survival after AKI. Our result that iPSC-derived RPCs can differentiate into renal tubule cells and form renal tubules in the injured kidney further supports this hypothesis. Moreover, we showed that the transplantation of iPSC-derived RPCs promoted cell proliferation and decreased apoptotic events. The cells also exhibited an anti-inflammatory effect by increasing the expression of anti-inflammatory factors, including TGF-β1. A recent study [32] reported that the presence of TGF-β1 in the homogenate of acute IR-injured renal tissue markedly increases the CXCR4 surface expression of MSCs and promotes the migration of MSCs to SDF-1. Therefore, we hypothesized that the transplantation of RPCs increased the level of TGF-β1 in the injured zone, which in turn regulated the CXCR4 expression of the RPCs, contributing to the migration of the RPCs out of the hydrogel to the injured sites. However, this proposed mechanism requires further investigation.
Collectively, the present study demonstrated that the transplantation of iPSC-derived RPCs is able to protect against kidney injury in an experimental IR rat model. These cells function in both differentiation-dependent and -independent manners by directly forming renal tubules and exerting pro-proliferative, anti-apoptotic, and anti-inflammatory effects. Our data suggest that iPSC-derived RPCs are a potential cellular resource for stem cell-based therapy for IR-induced AKI.
This study reports a modified method for the differentiation of iPSCs into RPCs and provides experimental evidence that iPSC-derived RPCs combined with a hydrogel can improve renal function in AKI and reduce tubular injury in an animal IR model. We believe that iPSC-derived RPCs hold great potential to be used as seed cells for personalized treatment in regenerative medicine.
IPSCs culture
Undifferentiated iPSCs were routinely cultured and expanded on mitotically inactivated MEFs (50,000 cells/cm2) in six-well culture plates with mES medium: DMEM supplemented with 15 % FBS, l-glutamine, nonessential amino acids, β-mercaptoethanol (Gibco), and 1000 U/ml LIF (Millipore). The iPS cell line used in the present study was purchased from SiDanSai Biotechnology (Shanghai, China). The sequence of gfp gene, for tracing the iPSCs and iPSC-derived cells, was inserted into the chromosome of iPSCs. iPSCs transduced with this sequence showed robust expression of GFP.
Renal differentiation of murine iPSCs
iPSCs were differentiated through embryoid body (EB) formation in EB medium (DMEM supplemented with 15 % FBS, l-glutamine, nonessential amino acids, and β-mercaptoethanol). On day 3 of differentiation, the EBs were transferred to gelatin-coated culture dishes at a density of 10 EBs per 1 ml of medium. The cells in the control group were maintained in EB medium for 5 days, and the medium was changed every 2 days. The cells in the induction group were exposed to a nephrogenic cocktail of factors, including 0.1 μM RA (Sigma), 10 ng/ml activin-A (PeproTech), and 50 ng/ml BMP7 (PeproTech), in the EB medium for 5 days. The induced cells were then cultured in the EB medium alone (RAB group) or in Renal Epithelial Cell Growth Medium (RAB + REGM group) for another 5 days and harvested for further analyses.
Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR)
The total RNA from cells or tissues was extracted using the TRIzol reagent according to the protocol delineated by the manufacturer (Invitrogen-Life Technologies). One microgram of total RNA was reverse transcribed into cDNA with oligo-dT primers and reverse transcriptase (Invitrogen-Life Technologies). Real-time quantitative PCR was performed using SYBR Green (Toyobo Co, Japan). The primers used in the amplification reaction are shown in Table 1.
Table 1 Primers used for quantitative reverse-transcriptase polymerase chain reaction (RT-PCR)
The differentiated cells were detached from the flask using accutase (Invitrogen-Life Technologies). The single cells were fixed with 4 % paraformaldehyde (Sigma) for 15 min, permeabilized with 0.5 % Triton x-100 (Sigma), and blocked with 3 % BSA (Gibco) for 30 min at room temperature. The cells were then incubated with the following primary antibodies for 1 h: Pax2 (1:100; Abcam), Bry (1:100; Abcam), E-cadherin (1:100; Cell Signaling Technology), CD24 (1:200; BD Biosciences), and WT1 (1:50; Santa Cruz Biotechnology Inc). After washing three times, the cells were incubated with the secondary antibody conjugated to Alexa Fluor 594 (1:200; Invitrogen-Life Technologies). The cells were washed to remove any unbound antibody and then analyzed using a flow cytometer (Millipore).
Preparation of hydrogel and cell mixture for injection
Hydrogels belong to a class of biological materials and produce a nanoscale environment similar that of the native extracellular matrix [27–30]. A hydrogel consists of 1 % self-assembling peptides (w/v) and 99 % water (w/v). The detailed constituents and properties and the detailed preparation of the hydrogel used in this study are detailed by the manufacturer (Beaver Nano Technologies, China). Briefly, the hydrogel (1 %) was sonicated for 30 min before use. The cells were suspended with 50 µl of 10 % sucrose solution, and 50 µl of the cell suspension was rapidly and carefully mixed with 50 µl of 1 % hydrogel. Then, 100 μl of PBS (Corning) was carefully added to the top of the cell and hydrogel mixture for instantaneous gelation. The 1 % hydrogel (50 µl) diluted with 150 μl of PBS was used as a control.
Rat renal IR model and injection of RPCs
The renal IR model was generated in 8-week-old male Sprague–Dawley as described previously [16]. Briefly, thirty rats (3–3.5 kg) were anesthetized with chloral hydrate (0.2 mg/g, Sigma), and this step was followed by exposure of the abdomen. For induction of total ischemia in the kidney, the left renal artery was clamped with a small vascular clamp for 45 min. Reperfusion was initiated by removal of the clamp. The right kidney was removed simultaneously. Thirty-four rats survived the IR surgery and no rats died in the following experiments. Then, the hydrogel (200 μl; denoted "IR-control" group) or the suspension of iPSC-derived RPCs (1 × 105 cells in 200 μl of 0.25 % hydrogel per rat; denoted "IR-transplantation" group) was respectively injected into the renal parenchyma of rats (seventeen rats per group). The rats were injected with the immunosuppressant cyclosporine A (Sigma) at a dose of 5 mg/kg per day. Six sham-operated animals underwent similar operative procedures but without clamping of the left renal artery and right kidney nephrectomy. At the indicated time, the blood was collected to measure the levels of blood urea nitrogen (BUN) and serum creatinine (Scr). The rats were killed at the indicated days for the collection of kidney tissue samples. All care and handling of animals was performed with the approval of the Ethical Review Board of Shanghai Six People's Hospital Affiliated to Shanghai Jiaotong University. The animals were raised in a specific pathogen-free (SPF) environment.
Histological analysis and tubular injury score
For the histological analysis, the kidney tissues were fixed with 4 % paraformaldehyde overnight and embedded in paraffin. The paraffin sections (4 μm) were stained with hematoxylin and eosin (H&E, Sigma). The quantitative analysis of the renal tubular injury used the grading scores proposed in a previous study [22]. The sections were evaluated by assessing 10 randomly selected high-power fields (40 × objective), and higher scores represented more severe damage: tubular epithelial cell flattening (1 point), brush border loss (1 point), cell membrane bleb formation (1 or 2 points), interstitial edema (1 point), cytoplasmic vacuolization (1 point), cell necrosis (1 or 2 points), and tubular lumen obstruction (1 or 2 points).
Immunohistochemical staining was performed with mouse anti-GFP antibody (1:100; Cell Signaling Technology) and mouse anti-proliferating cell nuclear antigen (PCNA, 1:200; Abcam). Briefly, paraffin sections of the kidneys were deparaffinized with xylene and rehydrated in an alcohol series and water. The kidney sections were subjected to antigen retrieval and blocked with a peroxidase-blocking reagent. The sections were incubated with the primary antibody overnight at 4 °C. After washing, the kidney sections were incubated with horseradish peroxidase-conjugated secondary antibody (ZSJQ-BIO, China) for 1 h at room temperature. The sections were visualized with 3,3′-diaminobenzidine (DAB, ZSGQ-BIO) and counterstained with hematoxylin. The number of positive cells was evaluated by counting the stained cells per high-power field in at least 20 randomly selected fields. The apoptotic cells in the kidney were detected by terminal deoxynucleotidyl transferase (TdT)-mediated digoxigenin deoxyuridine nick-end labeling (TUNEL, Promega) staining according to the protocol delineated by the manufacturer. The TUNEL-negative controls were stained without TdT enzyme.
All of the experiments were performed at least three times. The data are shown as the mean ± SEM. Differences were analyzed using one-way analysis of variance (ANOVA). Values of P < 0.05 were considered statistically significant.
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YW and NSW conceived the idea, designed the experiments, and provided their funds to the study. SFT, YG and SCG participated in the experiments of Cell-culture and animal experiments. XN and BH were responsible for Data collection and analysis. QL and SFT contributed to Manuscript writing. All authors read and approved the final manuscript.
This work was financially supported by the National Natural Science Foundation of China (No: 81170640, 30960385).
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
Qing Li, Xin Niu, Bin Hu, Shang-chun Guo & Yang Wang
Department Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
Shou-fu Tian & Nian-song Wang
Department of Integration of Traditional Chinese and Western Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
Shou-fu Tian
Department of Neurosurgery, Shandong Jining No. 1 People's Hospital, Jining, 272011, China
Ye Guo
Qing Li
Xin Niu
Bin Hu
Shang-chun Guo
Nian-song Wang
Yang Wang
Correspondence to Nian-song Wang or Yang Wang.
Qing Li and Shou-fu Tian contributed equally to this work
Additional file
Additional file 1:
Figure S1. Schematic representation and representative bright-field image during the differentiation of mouse iPSCs towards renal progenitor cells. EB, embryoid body. RAB, RA, activin-A and BMP7 in the EB medium. REGM, Renal Epithelial Cell Growth Medium. Scale bar: 100 μm.
Li, Q., Tian, Sf., Guo, Y. et al. Transplantation of induced pluripotent stem cell-derived renal stem cells improved acute kidney injury. Cell Biosci 5, 45 (2015). https://doi.org/10.1186/s13578-015-0040-z
iPSC-derived RPCs
Renal ischemia–reperfusion injury


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Gardner-Webb University (GWU) is a private, Christian university in Boiling Springs, North Carolina. It is a Carnegie-classified Doctoral/Professional University, and in 2021, U.S. News & World Report ranked the university 284th among national universities.
In 1905, the Boiling Springs High School was chartered by the Kings Mountain Baptist Association and the Sandy Run Baptist Association. Boiling Springs Baptist Church offered its old church house for the site of the school. Boiling Springs High School's charter was accepted in December 1905 by the school's trustees. The town, Boiling Springs, is named after the natural springs that have provided clean water for the school since 1907.
In 1928, the school became Boiling Springs Junior College. Following WWII, years of physical growth and academic development occurred. For instance, in 1971, the institution achieved full accreditation as a senior college. The Graduate School at the school began in 1980. Gardner-Webb officially became a university in 1993.
Academics & Campus
The 225-acre campus is situated in the foothills of the Blue Ridge Mountains. There is also a satellite campus in Charlotte. Gardner-Webb comprises several residential opportunities such as nine residence halls, seven apartment buildings, and three suite-style buildings. GWU has six professional schools and 13 academic departments.
The university offers eight degree programs as well as 80 undergraduate and graduate major fields of study. It is accredited by the Commission on Colleges of the Southern Association of Colleges and Schools. Roughly 4,000 students attend Gardner-Webb University, including online students. The student body represents 23 foreign countries and 43 states.
GWU provides a wide array of organizations such as the arts, culture, politics, performance, service, spirituality, and sports. Additionally, there are academic honor societies: Alpha Chi, Beta Beta Beta, Sigma Tau Delta, and nationally recognized chapters: College Democrats, College Republicans, and Fellowship of Christian Athletes.
For more information, visit: gardner-webb.edu. The campus is located at: 110 S Main St, Boiling Springs, NC 28017, United States.
Athletics – Runnin' Bulldogs
The sports teams play in NCAA Division I in the Big South Conference. The wrestling team belongs to the Southern Conference. The men's and women's swim teams belong to the Coastal Collegiate Swim Association.
The Runnin' Bulldogs athletic teams include:
Women: basketball, cheerleading, cross country, golf, lacrosse, soccer, softball, swimming, tennis, track & field, and volleyball.
Men: baseball, basketball, cheerleading, cross country, football, golf, lacrosse, soccer, softball, swimming, tennis, track & field, volleyball, and wrestling.
The men's basketball team has had notable success and has been featured on ESPN against teams like Duke, UNC, Virginia Tech, and Oklahoma. In 2005-06, the track and field team won the A-Sun conference championship. Go Scarlet & Black!
Show your school spirit and represent your school! You're one step away from getting your school gear. We've got everything you need for school pride like officially licensed sweatshirts, hats, men's t-shirts, women's tanks, and more. Shop now!
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Read more about GWU Gardner Webb University Runnin' Bulldogs Apparel – Official Team Gear

redpajama_set_name: RedPajamaCommonCrawl


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Q: Freeswitch Invalid profile [External]: 2002 I installed Freeswitch and fusionPbx using docker. here is the docker file:
FROM ubuntu:20.04

#ARG DEBIAN_FRONTEND=noninteractive
ENV TZ=Asia/Tehran
RUN ln -snf /usr/share/zoneinfo/$TZ /etc/localtime && echo $TZ > /etc/timezone

# Install Required Dependencies
RUN apt-get update \
    && apt-get upgrade -y \
    && apt-get install -y wget
RUN wget -O - https://raw.githubusercontent.com/fusionpbx/fusionpbx-install.sh/master/ubuntu/pre-install.sh | sh \
 && cd /usr/src/fusionpbx-install.sh/ubuntu && ./install.sh
#RUN wget -O - https://raw.githubusercontent.com/fusionpbx/fusionpbx-install.sh/master/debian/pre-install.sh | sh \
#&& cd /usr/src/fusionpbx-install.sh/ && ./install.sh
USER root
COPY supervisord.conf /etc/supervisor/conf.d/supervisord.conf
COPY start-freeswitch.sh /usr/bin/start-freeswitch.sh
VOLUME ["/var/lib/postgresql", "/etc/freeswitch", "/var/lib/freeswitch", "/usr/share/freeswitch", "/var/www/fusionpbx"]
CMD /usr/bin/supervisord -n

the docker is working fine and running. and is running using below command:
docker run -dit -name fus5 -p 80:80 -p 443:443 -p 5060:5060 -p 5080:5080 fus_ew:0.5

Problem:
the problem is that when trying to connect to an external sip gateway, give the below error when I hit the start button:
Freeswitch Invalid profile [External]: 2002
Appreciate it if anyone can help.
Regards

redpajama_set_name: RedPajamaStackExchange


Maunsel Canal Centre: Take a trip along the picturesque Bridgwater and Taunton Canal. You will experience exciting passage through a working lock and enjoy the Somerset countryside. No matter what the weather is doing, the Maunsel Canal boat trips are an excellent way to spend a day out. Don't worry because the Maunsel Lady Trip Boat has all weather cover, keeping you warm and dry!
These journeys take place on the weekend and on bank holidays from Easter to October. However during school holidays these trips may also take place on weekdays. You can book in advance or just turn up on the day, booking guarantees your place.


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Philip Schofield voted Britain's favourite breakfast smoothie
Silver-tongued, silver-haired Philip Schofield has won the battle of the presenters to be crowned Britain's favourite breakfast smoothie by UK women. Philip topped the poll which was commissioned by Cancer Research UK in support of Britain's Biggest Breakfast, a fundraising campaign taking place throughout March to raise awareness of the links between diet and cancer and to raise vital funds for research into the disease.
In the survey of 1,000 women, nearly a quarter (24 per cent) put Philip in first place as the most charming and charismatic of all the male breakfast presenters, with thousands of women watching him every day on This Morning. Irish charmer Terry Wogan took second place, winning 15 per cent of the votes for his smooth tones on Radio 2's breakfast show. Third position went to Ben Shepherd for his role on GMTV, and Radio 1's outspoken "saviour of morning radio" Chris Moyles came in fourth.
Heart FM's Jamie Theakston was the favourite London radio station breakfast presenter – beating Capital FM's Johnny Vaughan, who received only two per cent of the vote and came in last.
Each year, Britain's Biggest Breakfast aims to raise awareness of how eating a healthy breakfast as part of a balanced diet, including plenty of fruit and vegetables, can help reduce your risk of cancer. Experts believe that about a quarter of all cancer deaths are caused by unhealthy diets and obesity. The campaign aims to raise £200,000 for research into cancer by asking people to hold fundraising breakfast parties.
You can hold a Britain's Biggest Breakfast party at anytime throughout March. For further information on Britain's Biggest Breakfast or to order a fundraising pack, click here or call 08701 60 20 40.
Philip Schofield – This Morning
Terry Wogan – Radio 2
Ben Shepherd – GMTV
Chris Moyles – Radio 1
Dermot Murnaghan – BBC Breakfast
Bill Turnbull – BBC Breakfast
Eamonn Holmes – Sky
Jamie Theakston – Heart FM
Andrew Castle – GMTV
Johnny Vaughan – Capital FM
For further media information contact Kim Edwards in the Cancer Research UK Press Office on 020 7061 8320 email [email protected]
About Cancer Research UK
Together with its partners and supporters, Cancer Research UK's vision is to beat cancer.
Cancer Research UK carries out world-class research to improve understanding of the disease and find out how to prevent, diagnose and treat different kinds of cancer.
Cancer Research UK ensures that its findings are used to improve the lives of all cancer patients.
Cancer Research UK helps people to understand cancer, the progress that is being made and the choices each person can make.
Cancer Research UK works in partnership with others to achieve the greatest impact in the global fight against cancer.
For further information about Cancer Research UK's work or to find out how to support the charity, please call 020 7009 8820 or visit our homepage.
Preventing cancer Lifestyle Diet People Sex Women


Rosacea is known to affect around 16 million Americans however, a survey by the National Rosacea Society found that 95 percent of rosacea patients had known little or nothing about its signs and symptoms prior to their diagnosis. Papulopustular rosacea is a skin disease causing inflammatory lesions (papules and pustules) on the nose, cheeks, chin and forehead.
Recently, Bayer HealthCare Pharmaceuticals Inc. announced the US Food and Drug Administration approval of its product Finecea Foam (azelaic acid) 15% for the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.
The FDA approval of Finacea® Foam is the result of several years of research and development. Not only does it add to our current product line, it also demonstrates Bayer's continued commitment to addressing the needs of patients with mild to moderate rosacea.
he severity of a subject's rosacea was based on scoring from an IGA scale as well as a count of the inflammatory lesions. The clinical trials revealed that the use of Finacea resulted in a higher success rate in the reduction in the mean nominal change of inflammatory lesion count from baseline to the end of the 12-week treatment period.
Finacea gel is usually applied twice daily, in the morning and at bedtime. This treatment will soon be available by prescription only beginning in September 2015.


Heroes of Normandie - Sainte-Mère Eglise is a new scenario pack that adds new tiles, units, and scenarios.
June 6, 1944 : The scattered units of the 82nd and 101st Airborne have taken position in the most famous village in Normandy to have been liberated by American paratroopers. Relive this battle, which John Steele was able to watch from the tall spire of the Saint-Mère church, suspended from his parachute, feet dangling in the air. From the Drop Zones to the resistance at La Fière manor, lead your paratroopers to victory!
Check out a preview of all the tiles here!
- Rules for night combats, street lamps, sleeping units, dominant position and large buildings, gliders, etc.


The most glamorous downtown Austin wedding at Hotel Ella. Laura, an amazing makeup artist, wore a stunning Galia Lahav gown with a convertible skirt that fit the occasion perfectly. Dinner included a surprise mariachi band, which was a major hit with Jae's Korean family!


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REGULAR CONVOCATION
An address by the ME Pro First Grand Principal Peter Lowndes
I am delighted to report that the Royal Arch Masons Bicentenary Appeal for the Royal College of Surgeons, launched last November, is progressing well. I am informed that very nearly two hundred thousand pounds has been donated to date. Thank you to those who have generously donated. As we move towards the bicentenary in 2013, I encourage you, in your fund raising endeavours, to continue to request presentations from a Royal College team for example, at your annual Provincial meetings so that the Companions in your Province can fully understand the important research work that the Research Fellows can undertake as a result of our continued support.
The First Grand Principal summed this up with great clarity when he wrote, "This campaign gives us an excellent opportunity to contribute further towards something that is helping to save lives and improve the quality of life for us, our children and grandchildren".
Your Provincial Appeal co-ordinators know the procedure for requesting these presentations and for ordering donation leaflets for distribution when those presentations take place. I also remind you that the information for donating to the Appeal is on the Grand Charity website. As a minimum target we are aiming for one million pounds and as I said a moment ago, we are well on our way.
The Appeal is a highly visible external contribution from the Royal Arch. However, there are other internal areas that we all ought, as members of the Order, to be looking at to give the Royal Arch a higher profile.
The first is encouragement by you, to bring in new members for exaltation, understanding that this will be for them the completion of their pure ancient Masonry that they have discovered during the ceremonies of initiation, passing and raising in the craft – most particularly the latter. Companions, I like to use the analogy of a four part TV drama. What is the point of watching the first three episodes and then ignoring the fourth when all is revealed.
This is not just about keeping member numbers up, it is also about making sure you have enough work at each meeting to keep the members' skills honed. Remember, of course, to share the work out as much as possible so as to achieve the maximum involvement of the Companions in your Chapter. That way Companions will become far more interested in the beauty of the ceremonies as well as keeping up their interest. I note that we had three thousand nine hundred and thirty exaltations last year.
Companions, I have mentioned before that I, along with many other companions, find the lay out of the current ritual books to be confusing and difficult to follow. A new lay out with the new version, currently known as the "permissive" version, as the main text and the former version printed separately at the back. The ritual organisations are updating the books and it is likely that all the major rituals will be reprinted in the next eighteen months to two years.
Secondly, we have two important weapons in our 'communication armoury'. Our house magazine, Freemasonry Today and the new members' website launched in September. The strap line refers to the magazine as the official journal of the United Grand Lodge of England but Companions, the editorial policy is predominantly to cover stories and news about both the Craft and the Royal Arch. This is also the case with the website which will be timely in getting news to you. I know the Editor of Freemasonry Today is keen to receive more stories for consideration and possible inclusion on the Royal Arch. The Provincial Information Officers have a key role to play here and are well briefed on the process for submission for both the magazine and the website.
For your interest, we are now starting to work on the new website for the Royal Arch, to bring the current one both up-to-date and in line with all the other communications initiatives we have recently launched.
Many of you will know that Grand Scribe Ezra, as Grand Secretary, is chairing a working party on mentoring in the Craft with the aim of seeing what elements of this are relevant to import to the Royal Arch. We already have Royal Arch representatives in many of our Lodges and one of the key decisions, as I am sure you can all appreciate from your experience, is when is the right time to brief the newly joined Mason on the Royal Arch – to have him understand the importance of the Royal Arch in the completion of pure ancient Masonry. For example there are questions such as, is it best after they have been raised, how does their mentor brief them, and how does the mentor or Royal Arch representative gain the right level of knowledge to correctly brief them in the first place? These are some of the conundrums that the working party are grappling with and I look forward to briefing you on their suggestions early next year. I am sure, however, that many of you have been debating these issues for some time! Fundamental is establishing the relevance, to prospective candidates, of the Order all of us who have been exalted so enjoy.
Since the beginning of the year we have installed six new Grand Superintendants in our Provinces and I have also installed the new Grand Superintendant for North Island New Zealand. This is, together, of course, with the South Island, the furthest of our Districts and our visit was seen as both supportive and a real sign of our commitment. We also met the Grand Superintendent from South Island who explained the continued havoc in Christchurch. Much of the damage from the devastating earthquakes of 2010 and 2011 and the multitude of aftershocks had come from liquefaction, when the soils are shaken and turn into a liquid form, undermining buildings and other structures. There is little chance of buildings being replaced in Christchurch as a result. What brought it home for us was when we learnt that the Hotel we stayed in for District's 150th Anniversary, at the end of 2010 had crashed to the ground, not that long after we had left. Aftershocks continue to this day, illustrated by the fact that Christchurch was rocked by a 5.5 aftershock last Friday – the biggest they had had since June. Our continued sympathy and support goes out to our Companions in these tough conditions.
It is good top see so many of you here today and it is also appropriate that I take this opportunity to remind you that all Companions are eligible to attend this Supreme Grand Chapter meeting.
Published in Speeches
Pro First Grand Principal's address - April 2011
ROYAL ARCH INVESTITURE
I know that you would want me to congratulate the Grand Officers whom I have invested on behalf of the Most Excellent the First Grand Principal. At the same time I remind them that their new ranks are not the culmination of their Chapter careers. In accepting appointment or promotion, they have committed themselves to increased activity in the Royal Arch, especially with regard to recruitment and retention.
At this investiture meeting last year I announced that as part of the Royal Arch celebrations in 2013 it had been decided that a donation be made to the Royal College of Surgeons. The Royal Arch Masons 2013 Bicentenary Appeal was launched at the November Convocation of Supreme Grand Chapter. Our donation will help to fund the College's successful surgical research fellowship scheme, which supports surgeons to undertake a surgical research project.
Freemasonry has had a long and close association with the College and we are their major benefactor. We were pleased to have several surgeons - who had been beneficiaries - come and present to us at the November Convocation. Although I was unable to be at that meeting, I have heard from many Companions how fascinating it was to hear about their research in surgical care for current and future generations. The Grand Scribe Ezra has written to all Grand Superintendents informing them how to request similar presentations from the College in their Provinces.
The information for donating to the Royal Arch Masons 2013 Bicentenary Appeal is on the Grand Charity website and donation leaflets are available by request. We are grateful to those who have already donated.
Companions, as you are well aware changes were made to the general practice of the Royal Arch in 2004 affecting the ritual, together with certain permitted ritual alternatives. As a result, I wonder how many of you are like me and get thoroughly confused when deciding which version of the ritual to use. With this in mind, it is proposed to use 2013 as the catalyst to publish new ritual books, which would have the permitted alternatives as the main version and the original version printed out separately. For clarity, this is not a change to the ritual. It is intended to be helpful to Chapters by simplifying the printed material and to avoid any confusion the 2004 changes may have caused.
The aim is also to encourage those Chapters who have not yet made the change to the alternative form, to more easily adapt what is already widely practised and enjoyed. This alternative ritual involves more companions in the ceremony and I believe encourages greater delegation of the work. Interestingly, the 2013 Committee is proposing that a demonstration of the alternative exaltation ceremony form part of the bi-centenary celebrations, to be performed by the Metropolitan Grand Stewards demonstration Team in the Grand Temple on the morning of the special celebration Convocation in October 2013.
Finally, Companions, I must on your behalf and mine, thank the Grand Director of Ceremonies and his Deputies for conducting today's proceedings so successfully and the Grand Scribe E and his staff for all the arrangements for this important day. Most of you will be aware that the Grand Scribe E and his Secretary were working here on Monday to ensure the smooth running of yesterday and today.
UGLE's Grand Master, The Duke of Kent, unveils Victoria Cross Remembrance Stone at Freemasons' Hall
In honour of all English Freemasons awarded the prestigious Victoria Cross (VC), the United Grand…


Rhinoplasty is one of the most popular cosmetic surgeries available, but many of those who are unsure about the surgery seek answers to their questions about the procedure. Do you have questions about rhinoplasty? These questions and answers may ease some of your fears.
How long does recovery from rhinoplasty take?
Rhinoplasty has some side effects that can last months, but they are minimal and include only light swelling. Most of the recovery occurs within the initial weeks of the surgery. For the first few days, the patient will wear a splint over the nose to ensure proper healing. Most patients are able to return to work after the first week, but patients should not resume any strenuous activities until approved by a doctor.
Typically, side effects of rhinoplasty include pain, discomfort, and some swelling of the face. Most side effects do not persist for longer than several days. If they do, you must speak with your doctor and ensure that nothing is wrong.
Does rhinoplasty require follow-up surgeries?
Rhinoplasty can become complicated under certain circumstances. For this reason, some patients may come in for follow-up surgeries to ensure that they achieve the perfect look they desire.
The risks of rhinoplasty include infection, bloody noses, and numbness. In rare cases, a patient may experience collapse of the nose or visible scarring. If you experience strange side effects following your surgery, it is essential that you contact your doctor right away.
Can you have rhinoplasty to fix birth defects?
Yes. Many people seek out a nose surgery to change the shape of the nose for this reason.
What is the best way to prepare for rhinoplasty?
First, you should always start out with realistic expectations for your surgery. Your surgeon will ask you questions to ensure that you have a healthy attitude toward cosmetic surgery and that you are a good candidate for the procedure.
You should avoid taking medication that prevents blood clotting or that may influence the way blood flows during and after the procedure. These include ibuprofen and even aspirin. You should also avoid smoking in the month before your surgery.
Rhinoplasty is not typically available for those who are still growing. For this reason, doctors often will not operate on teenagers or children without a medical reason.
Rhinoplasty may be considered safe, but it still comes with its own set of risks. It is important to ask your cosmetic surgeon any questions still lingering in your mind so that you can go into surgery with confidence. Contact a professional such as William M. Parell, MD, PSC for more information.


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No priests, no doctors, just film: Eye & Ear Clinic's weekly screenings
By Simon Hunt April 1, 2006 Uncategorized
by Simon Hunt
Jodie Mack, Buki Bodunrin and I are packed into a tiny room in the photo department. Jodie is measuring spoonfuls of coffee into a developing tank and talking about the Eye and Ear Clinic. They are using the coffee to hand-process film, part of a Super 8 demonstration they're preparing for, and I'm in the way.
To clarify, this isn't the Haiti-based ministry Eye & Ear Clinic, or the medical facility in Belfast. It is the student group that runs a free bi-weekly film screening in MacLean Center's 13th floor screening room. They present films and videos through the year, showcasing faculty work as well as curating presentations of material from the Flaxman Library 16mm archive, and rented tapes and prints.
Buki turns out the lights so they can load the film into the tank, and I listen to their disembodied voices talk about some of the difficulties of running the series. Returning a film to the Flaxman before it closes at 6:00 p.m. on Friday is a challenge. "It took a while to figure out how to get money," says Jodie, before they discovered that the student government awards grants to student groups.
Despite the challenge to their wallets, the two hope to continue presentations throughout the summer, and are looking at alternative venues like the Hideout, Busker Space, The Ice Factory, and even a public pool.
The screenings take place in MI1307, and the schedule for the rest of the semester is as follows:
Thursday, March 30, 4:30 p.m.
"Super 8 Extravaganza!"
Friday, April 7, 4:30 p.m.
"Critical Clown"
Thursday, April 14, 4:30 p.m.
Michele Mahoney's "The Undergrad"
Friday, April 21, 4:30 p.m.
Friday, May 5, 4:30 p.m.
"[FRAY]," Scott Bartlett's "Off/On," and other New Media work
Uncategorized No priests, no doctors, just film: Eye & Ear Clinic's weekly screenings
Racism in popular media: How much is too much?
At Home World Wide: Where style and collaboration collide
Waxing Philosophic
Hearing Weird Stories From Your Friends…
My Delicious Trip To Devon Avenue
127 Hours: CHICAGO


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Home	Blog	South Africa vs Finland: Education System Showdown
South Africa vs Finland: Education System Showdown
Finland has a pretty good reputation when it comes to education. So what lessons can we as South Africans take from the Finns to improve our own education system?
The South African and Finnish education systems are extremely different. The current Finnish education system has been in place for the last 40 years and they've done it by breaking the education-mold that almost every other education system in the world follows. If it works so well, why aren't we all doing it?
South Africa vs Finland
Before we try to think about the differences between our education systems, we have to take a look at the differences between the two countries.There are few countries that are more different from one another than these two.
There are many websites that illustrate the differences between countries, such as Find the Data. When comparing Finland to South Africa, the differences between the first and third world become very clear:
South Africa is a much bigger country than Finland, with a population of around 55 million. That's nearly 10 times bigger than Finland's 5.48 million.
South Africa has a lower GDP (gross domestic product) per capita, higher unemployment rate, higher inflation rate and weaker currency.
South Africa also has a much higher GINI index, which is a measure of the economic equality in the country. Finland has GINI index of 27.12, one of the lowest in the world, where South Africa's GINI index is 63.38 – the highest in the world.
We also have a much lower life expectancy and the overall health of our population is much poorer than Finland's.
In Finland, nearly 93% of people use the internet, where in South Africa, only 52% of the population are internet users.
From these statistics alone, it is clear that these countries have very different economies and that we cannot expect the same things from government. Finland is a well-developed country with a thriving economy and very few of the issues that South Africa has to deal with. South Africa has an array of issues to deal with beyond their education system and doesn't have the same freedom to experiment that Finland has.
The Two Education Systems
The Finnish education system is a little unorthodox, but is still consistently ranked as one of the best in the world. It is broken into six main parts:
basic comprehensive school
secondary general academic and vocational training
There are no tuition fees at Finnish schools and full time students are served meals that are fully subsidised by the government. Here is a break down of how the schooling system works:
Daycare and Pre-school
Early childhood education is considered critical in Finland. Children take part in this preparatory phase of education until age seven. This phase is aimed at instilling a culture of learning, as well as teaching the children vital communication and co-operation skills that the child will use throughout their life. This phase of schooling is not mandatory, but it is still widely used. The education is not formally structured, it rather focuses on teaching the children how to learn.
These 9 years (from the ages of 7 to 16) of schooling make up the only phase of schooling that is compulsory. Most of the schools are funded by the Finnish government, but there are some private schools which are usually religion-based. Homeschooling is also allowed, but it is uncommon. The state sets curriculum guidelines, but teachers are given a lot of freedom in terms of how they present the work and what learning material they use. During the first few years of school, grading is mostly verbal and informal. The local government decides when the formal assessments will begin. Students are given progress reports twice a year, but they do not write any high-stakes tests (like final exams in SA).
This phase of education is not compulsory. It typically lasts three to four years and students are able to choose whether they receive vocational training or a more academic education. The vocational training is aimed at getting the student occupation-ready, but they can also choose to study further at a polytechnic institute (which is similar to a university of technology). The academic training (or upper academic school) is designed to prepare students for university studies and to pursue professional degrees, such as law, engineering or medicine. People who have studied at vocational school are not limited to studying at a polytechnic school, but may also apply to study at a university and vice versa.
Upon graduation, students from vocational school are awarded a vocational school certificate. Whereas students at academic school receive a secondary school certificate and undergo a matriculation exam.
Tertiary education is split into two main sections: traditional universities and universities of applied sciences. Traditional universities are more research focused and give a theoretical education, and many of their programmes are combined undergraduate and Masters programmes.
Universities of applied sciences are more focused on producing industry-ready individuals and give an education more focused on the skills needed in the world of work, kind of like universities of technology in SA.
FYI: Finland have decided to change things up by replacing traditional subject learning (i.e. learning physics, math and geography) with "Phenomenon-Based Learning".
Basically instead of learning subjects because the system says so, students will choose a modern, real-life topic (phenomenon) to study; with only relevant subjects included to help them excel in that topic. Example: If someone chooses "The African Union" as their field of study, subjects such as economics, languages, geography and history of African countries would make up their learning areas.
Finland's plan is to have this approach completely implemented by 2020.
The South African education system is controlled by two departments:
The Department of Basic Education (DBE)
Department of Higher Education and Training (DHET).
The DBE controls two bands of basic education. Namely grades 1 to 9 (General Education and Training (GET) phase), and the Further Education and Training (FET) phase. South Africa's basic education is subsidised by the government, but students from higher income areas are expected to pay some fees if they have the financial means.
General Education and Training Phase
The GET phase is further split into three groups: foundation phase, intermediate phase and senior phase. This is the only phase of education that is compulsory for all students. It begins in pre-primary at the age of 6.
The foundation phase of education is from pre-primary to grade 3, and this is where students learn basic reading, writing and numeracy skills.
The intermediate phase, grades 4 to 6, is when the education becomes slightly more formal. Students are introduced to formal subjects and begin writing exams.
The senior phase, or grades 7 to 9, is the final part of compulsory schooling for South Africans. In these grades, students study 10 subjects and are expected to write formal exams in these subjects twice a year. After completing grade 9, most students continue to pursue further education, either by continuing to matric at their high school, or in the form of a vocational qualification.
Further Education and Training Phase
This phase consists of two streams: academic and vocational qualifications. If a student chooses the academic stream, (traditionally grades 10 to 12), they will be expected to take seven subjects – four of which are prescribed by the government. The four compulsory subjects are English, a second language, Mathematics or Mathematical Literacy and Life Orientation. The student is then free to choose the remaining three subjects from whatever is available at their school and according to what will be most useful to them in their future. At the end of grade 12, students are expected to write a series of standardised exams in each of their subjects and are awarded a national senior certificate upon passing these exams.
The vocational stream consists of occupation-orientated subjects that will give the students the skills that they need to enter into the workplace. Both of these streams can qualify a student to pursue tertiary education, either at a university or university of technology.
SA has a wide range of tertiary institutions, with traditional universities and universities of technology. Traditional universities offer academic and professional degrees, where universities of technology offer vocational diplomas or technical degrees.
To enter into a university to university of technology, a student will need to have received a national senior certificate. On top of this, higher education institutions set other academic requirements that the student must meet.
What lessons can we learn from the Finnish education system?
As we can see, the two education systems have a similar structure — a compulsory phase of general education. This is followed by an optional phase during which a student can choose between a vocational or academic stream.
However, the rules of assessment are very different.
In South Africa assessment is more formal, with high-stakes examinations written twice a year, where in Finland's assessment is more continuous with few high-stakes tests. The problem with the South African education system is not in its structure. The frame is there for South Africa to have a thriving and competitive education system. South Africa's problem lies in the implementation of the system.
In this regard, there is one vital difference between Finland and South Africa. In Finland, teachers are respected professionals who earn a good salary. One is not allowed to become a teacher without a master's degree — entrance into an education degree is extremely competitive. In SA, teachers are paid relatively low salaries and most talented students leaving high school are often not keen on the idea of becoming a teacher.
This is where we can learn from Finland. Teachers are the people who mold young students' minds and have a huge influence on the next generation. They should be treated (and paid) as professionals. This will encourage talented students with a passion for teaching to enter into the education system and give the South African education system the people it needs to become great.
If you are interested in making a significant difference in South Africa and have a passion for it, you should definitely consider becoming a teacher. Educating the next generation is the most effective way to have a positive impact on the next generation. If becoming a teacher is an idea that interests you, then take a look at this article.
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I hope everyone survived the record heat... I know that I'm very happy with our decision a few years ago to add an air conditioner when we replaced the furnace. We had to be out and about in the heat some, but it was nice to come home to a relatively cool house (still way too hot for me, though).
anonymoushubby finally came down with the plague, almost 2 weeks after I did. I'm not actually sure that it was the same thing, but he was pretty sick for a few days. Since we didn't want the rest of us to get sick again, he got quarantined to the bonus room with a can of Lysol and hand sanitizer (and a window a/c unit, thanks Grandpa!). He's feeling much better now so he got to come back downstairs and go to work today.
Between the heat and being anonymoushubby sick, we didn't get out as much as we'd planned. The girls and I made a fun trip over to my folks, though, complete with (kiddie) swimming pool and dinner! They had a great time splashing and playing in the water and stayed in the pool for a long time because of the hot weather.
We did get a bit of cleaning and organizing done this weekend. Not nearly as much as we need to do, but anything is good!
We missed out on going to the Ren Faire but, happily, it runs for two more weekends. That is particularly handy as the Pierce County Fair is this coming weekend. widgetsworld was very excited to see a couple of rides driving down the road this morning. Have I mentioned how much I love fairs?
This week is the start of new classes for the kids. widgetsworld is taking swimming a class again and sprocketsspace will be taking one, too (though she has to have one of us with her). widgetsworld is also going to try out gymnastics. It will be interesting to see what she thinks of that since she's been so excited about doing summersaults and walking on the balance beam by herself.
I'm just glad that it's not as hot anymore.


text:
Judge: Feds failed to study how delta pumping affects salmon
By Paul Elias
San Francisco, California (AP) 4-08
A federal judge ruled that water regulators failed to consider the effects of global warming and other environmental issues related to the decline of California salmon populations when they approved increased pumping from the Sacramento-San Joaquin Delta.
U.S. District Judge Oliver Wanger said a 2004 study prepared by federal regulators to support the increased water exports was scientifically inadequate.
"There is no analysis of adverse effect on critical habitat," Wanger wrote about winter-run chinook salmon.
The judge also ruled that there was a "total failure to address, adequately explain, and analyze the effects of global climate change on the species."
The study had concluded that more water could be taken from California's Central Valley to quench residential and agricultural thirsts throughout the state. The new pumping plan was already on hold because of a similar ruling the judge made about the Bush administration's failure to address its effects on a threatened fish species called the Delta smelt.
The U.S. Bureau of Reclamation and the National Marine Fisheries Service, the agencies that prepared the study at issue, plan to submit a new study by the end of the year, said NMFS spokesman Jim Milbury.
"I'm sure they will look at the judge's opinion in developing it," he said.
Wanger scheduled a hearing April 25 to begin determining how the delta should be managed until the new study is published.
A group of environmentalists, fishermen and American Indians sued the two federal agencies in 2005.
"This is a historic decision," said Mike Sherwood, an Earthjustice lawyer who represents the environmentalists. "It may well be the turning point to reverse the decline toward extinction of these fish."
Scientists have pointed to increased water exports from the delta as one possible cause for an unprecedented decline in the number of chinook salmon returning to spawn in the Sacramento River and its tributaries last fall.
Earlier this month, federal fishery regulators voted to ban salmon fishing along the California coast and most of Oregon to protect California's shrinking salmon stocks.


text:
Dean of Libraries & Belk Distinguished Professor for Library & Information Studies - Appalachian State University
The University seeks an experienced, energetic, and strategically minded library leader and engaging library advocate. Successful candidates will have demonstrated interests in and commitment to equity, diversity, and inclusion; the values and skills to support collaborative and collegial governance within and beyond the Libraries; and the vision and abilities to balance traditional library values and services with the fast-moving innovations and transformations of university libraries in the 21st century. The Dean leads a large and highly accomplished library faculty and staff committed to service, teaching, and scholarship, and serves the broader university and community as a member of the Dean's Council and Provost's Council.
Qualifications: ALA-accredited master's degree in library or information science or its international equivalent. Significant and progressive academic library management and leadership experience. A demonstrated and steadfast interest in and commitment to equity, diversity, and inclusion. A record of scholarly activity meeting requirements for the rank of full professor.
Library Jobs in North Carolina
Tuesday, Dec 15, 2020 4:04 PM to Thursday, Jul 15, 2021 5:00 PM
218 College St.
Boone, NC 28608
For More Information/To Apply
Jeff Vahlbusch, Dean of The Honors College
vahlbuschjb@appstate.edu


The money was too good to pass up—until it destroyed my body. Here, the dark side of egg donation that you don't usually see.
"Jesus, Jen, you look like hell," Manny told me. He was cooking that day at the restaurant where I worked in Chicago. "You're pale. You should sit down."
I couldn't focus on his face. My vision made me nauseous, alternating between blurry and tilted. I leaned against the wall.
"No, no… I'm fine. I just need…some bread…" My limp body slid down the wall. I woke up on the tile floor a minute later with the crew standing in a circle overhead, peering down at me with worry.
"I should probably go home," I said to nobody in particular as they helped me stand. Manny walked me out to his car and set me inside, then took me back to my Wicker Park apartment. I stumbled up the stairs to the top floor of the three-flat and sat down in my bedroom. And then, as I'd done every day, twice a day, for the past week and a half, I picked up a syringe and stuck it into a vial of clear liquid. I pinched a little bit of fat near my belly button. I closed my eyes, stuck the needle in, and pushed the liquid through—and instantly reeled from the searing pain at the injection site. It was like being burned from the inside out. I threw out the syringe and laid down for a nap.
I wasn't a junkie—I was an egg donor. And my life had turned upside down in a mere six months.
The Number 66 bus was my lifeline in the city, something I rode day in and day out to and from work. And one particular day, I looked up to see it wrapped in a brightly colored ad: "Women under 30, donate your eggs and make $5,000 within a few weeks!"
I was a recent graduate from a pricey art school, drowning in debt and hating my job. Not even five minutes passed before I was on the phone, dialing the number on the ad, calling my savior. Two days later I sat in the donation office taking personality tests, undergoing psychological screening, and giving the staff photos of me to add to the donor binder hopeful parents would browse through.
Within a week I had my first "client." The process was fantastic. Simple to do, no pain aside from the slight pinch of twice-daily shots for several weeks, no nausea, an outpatient harvesting, and quick payment. It was great—at very little inconvenience for me, I had done something wonderful for another person, and been paid handsomely for it.
It was only three weeks before another couple wanted to use my eggs. I jumped on that, too. I was in it now. I was addicted to giving people the eating, burping, pooping bundles of joy they so desperately wanted, for money.
The donation center suggested I wait at least another month to let my body get back into the swing of my normal cycle. But I had student loans piling up into the $100,000s, and I had consulted three separate doctors who told me waiting just a week was more than enough time between donations, so I shrugged it off and signed up.
I spent the next few weeks in my own personal hell, shoving needles into various parts of my body, injecting fluid that felt like pure grain alcohol in an open wound. The doctor I saw throughout the process told me I was likely allergic to the drug, but also said that because my reactions weren't serious, it didn't make sense to stop.
I started fainting on a regular basis.
So I kept at it, even when I started fainting on a regular basis. It was like clockwork: an hour after each injection, I would get woozy and black out. Everything around me spun whenever I stood up. My hearing filtered in and out. I found out later that not only was I allergic, but that my body was responding to the drug in overdrive.
Every egg donation has a 10% risk of ovarian hyperstimulation syndrome, where the ovaries swell from over production of eggs. I didn't suffer the most adverse consequence of the syndrome—death—but my doctor did tell me he'd never seen so many eggs in one extraction. The combination of allergy and overworked ovaries held me captive in a painful, blurry state for the length of the donation process.
I muscled through it, telling myself that it was only a little longer and then it'd all be finished. The day I went in for my extraction, I could practically see the dark cloud of pain and illness lifting from my body.
To extract eggs, the doctor passes a hollow needle up into the ovaries and uses suction to basically vacuum the eggs out of the ovarian follicles. But this time, something went wrong. My doctor slipped. He snagged the wall of my ovary and left a cut that would become thick scar tissue.
Of course, I was too busy to notice, coming out of sedation and praising the nurse for magically knowing I liked Sprite and Animal Crackers.
And then there was yet another mistake. After several hours, I wasn't close to having recovered. I was still sitting in a hospital bed in a daze when they pushed me into a wheelchair and handed me off to my ride home. When two weeks went by and I still couldn't walk up the stairs unaided, I went to the hospital—and they told me there was a problem with the anesthesia. I must have had too much. But the effects would dissipate in their own time. With no other option, I went back to my routine of home, bus, train, work.
The weird cramp blossomed into a fiery stab that spread through my abdomen and I collapsed from the pain.
A month later I was back in the hospital, still no better, finally being told about the scarring on my ovary. I had noticed a strange, tight, tugging feeling in my abdomen not long after the donation, but cramping was a common side effect, so I tried to ignore it. I had gone to a festival and had to be carried out because my energy suddenly drained and I went pale and fell. Back at home, I had reached up to put a utensil on the baker's rack and that tugging feeling suddenly went *snap*. The weird cramp blossomed into a fiery stab that spread through my abdomen and I collapsed from the pain.
A four-hour wait, an internal ultrasound, and a CT scan later, I listened as an emergency-room doctor told me what had happened: I'd had a cyst that formed on top of the scar tissue from the cut, and I collapsed because it burst. I sat quietly as he told me my options: ignore it and expect more cysts, have surgery to remove the tissue (that would probably result in more scarring), or have surgery to remove the ovary altogether.
Either way, my ovary was damaged. Either way, it would be more difficult for me to have children in the long run. Either way, I was screwed.
Ultimately, I chose to ignore it. I still get cysts, oddly about the same time every year. None have been as bad as the first, but it's still a constant reminder of the supposed benevolence that took its toll on my life.
I haven't tried having children yet. I'm too scared. I've seen friends have miscarriages and watched them dissolve into hurt and depression afterwards. Could I willingly latch onto the idea of creating life when I know there's a higher possibility of disaster? I don't know that I can. I'm just not ready to go there yet—which for me is a big problem, because I don't know how much time is left for even the possibility of having children. I could already be past my window.
The stress of not knowing how easy it would be for me to bring a baby to term is like a constant pressure I can't escape from. But that's my burden to bear, and mine alone, as a result of my own decisions. I grapple with that every day.
I see so much positive coverage of egg donation in the media, or hear women scream joyously from rooftops about how simple the process is, and it makes me furious. Even Sofia Vergara and Nick Loeb's frozen embryo legal spectacle twists me down into a rage spiral. It's just not always that easy to go through. It's not always that easy to freeze eggs until you want them. Sometimes, things go wrong.
My only hope is that young women start to think twice about donating. Yes, it's good money and you could potentially make someone else happy—but at what cost to you?


If you would like your remembrance of Frank Calabrese to be included here with the others, please send it in an email to the producer of this website. It is not technically possible for you to post anything directly to this website due to spam control policies. Thank you for your understanding.


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text:
Original Research Pulmonary Embolism| Volume 134, ISSUE 4, P789-793, October 01, 2008
The Importance of Clinical Probability Assessment in Interpreting a Normal d-Dimer in Patients With Suspected Pulmonary Embolism
Nadine S. Gibson, PhD
Nadine S. Gibson
Correspondence to: Nadine Gibson, PhD, Department of Vascular Medicine, Academical Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Department of Vascular Medicine, Academical Medical Center, Amsterdam, the Netherlands
Maaike Sohne, PhD
Maaike Sohne
Victor E.A. Gerdes, PhD
Victor E.A. Gerdes
Mathilde Nijkeuter, PhD
Mathilde Nijkeuter
Department of General Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
Harry R. Buller, PhD
Harry R. Buller
DOI:https://doi.org/10.1378/chest.08-0344
Previous ArticleExpression of Ig-Like Transcript 4 Inhibitory Receptor in Human Non-small Cell Lung Cancer
Next ArticleAlendronate Once Weekly for the Prevention and Treatment of Bone Loss in Canadian Adult Cystic Fibrosis Patients (CFOS Trial)
The d-dimer test is widely applied in the diagnostic workup of patients with suspected pulmonary embolism (PE). The objective of this study was to investigate how often the d-dimer test fails when clinical probability is not taken into account.
We used data collected in 1,722 consecutive patients with clinically suspected PE to analyze the 3-month venous thromboembolism (VTE) rate in all patients with a normal d-dimer concentration and separately for patients who have a normal d-dimer concentration with an unlikely or likely clinical probability for PE, as assessed by the Wells clinical decision rule.
The 3-month VTE rate in all patients with a normal d-dimer concentration (n = 563) was 2.3% (95% confidence interval [CI], 1.4 to 3.9%). In the patients with an unlikely probability of PE (n = 477), VTE was confirmed in 1.1% of the patients with a normal d-dimer concentration (95% CI, 0.4 to 2.4%). In those patients with a likely clinical probability of PE (n = 86), VTE was confirmed in 9.3% of the patients with a normal d-dimer concentration (95% CI, 4.8 to 17.3%). The difference in VTE incidence between patients with unlikely and likely clinical probabilities of PE was significant (p < 0.001).
Our findings indicate that it is of utmost importance to first examine the patient and assess the clinical probability, after which the d-dimer concentration can be taken into account, in order to prevent physicians from being influenced by a normal d-dimer test result when they evaluate the clinical probability of PE. Patients with a likely clinical probability should undergo further testing, regardless of the d-dimer test outcome.
deep venous thrombosis
CDR (clinical decision rule), CI (confidence interval), DVT (deep venous thrombosis), IQR (interquartile range), LMWH (low-molecular-weight heparin), PE (pulmonary embolism), VTE (venous thromboembolism)


British carmaker Aston Martin developed the Vanquish, a model created to replace the DBS. At a closer look we can see that the design and everything actually reminds us of the DBS, maybe not the name, but the rest look like an improved DBS. Of course, this does not mean the carmaker did not offer several changes to the new model, because it did, starting with the stiffer fourth generation VH bonded aluminum monocoque chassis. In the rear structure Aston Martin used a lot of carbon fiber and hollow-cast aluminum instead of solid cast aluminum at the front end. The front chassis is now 13% lighter than the one used for the DBS. Also, most of the body panels are made of carbon fiber.
The new Aston Martin Vanquish measures 4.720 mm in length, 2067 in width, 1.294 in height and has a 2.740 mm wheelbase. The new Vanquish is powered by a 5.9-liter V12 petrol engine capable of developing 55 extra horsepower and in the end offers an output of 565 horsepower and 620 Nm of torque. This amount of power enables the car to accelerate from 0 to 100 km/h in 4.1 seconds and to reach a top speed of 295 km/h. The DBS reaches a top speed of 305 km/h and it can accelerate from 0 to 100 km/h in 4.3 seconds. All the output is being transferred to the road through a new generation Pirelli P-Zero high-performance tires that hide new 20-inch lightweight alloy wheels. The braking system of the car contains Brembo Carbon Ceramic Matrix brakes.
The carmaker also provides the latest Adaptive Damping System developed by Aston Martin that offers the possibility to choose between three different modes: Normal, Sport and Track. The new Aston Martin Vanquish will be available in either 2+0 or 2+2 seating configuration. The model will be offered in dealerships before the end of this year and the price for the UK customers will start at GBP189.995. The North American customers will have the first possibility to purchase the new model at the beginning of next year for a suggested retail starting price of $279.995.


In larger companies, it is normal to see a wide variety of process and capabilities from division to division and group to group; it is unusual for a top-down project methodology to be followed enterprise-wide. In medium and smaller businesses more consistency can be found, but the specialized disciplines necessary to create and maintain significant common process can be hard to find.
The following table and chart describe a scale of process capability from low to high, and some of the typical characteristics associated with each level. Data has been gathered anecdotally through hundreds of customer interactions in 15 countries. In particular, categories of software are called out and the degree to which each is used is a good indicator of capability for a given division or company. Note that these descriptions are generalizations and a wide variety of deviation may occur. Following the table and chart ore more detailed descriptions of each level.
The largest numbers of companies fall into the low level of common process. Email is the main tool used to manage work in all phases: work planning, task assignments and status reporting. Spreadsheets are generally used in an ad-hoc manner for task and financial management, with common formats or templates used less that 25% of the time. The primary tool used for reporting is presentation software; the content is mostly narrative rather than metrics-based, and templates are used for less than 50% of presentations. In-person meetings are the primary method for communication of responsibilities as well as gathering updates of status. Project scheduling software may be used occasionally for very large projects.
Resources focused on strategic work can often spend more than 30% of normal work hours in meetings, which leads to either lower productivity or lots of overtime and low job satisfaction. As business processes are largely ad-hoc, there tends to be no motivation to capture or analyze process using Business Process Management tools or methodology.
Email remains the core for communication around project work. Spreadsheets are more structured and are used more often for semi-structured tasks lists; templates are now used more for than 1/3 of the spreadsheets. The collaboration portal is sometimes used, generally as a repository for project related documents. This usage of the portal makes a small but perceptible dent in the number and length of required meetings, freeing up more time for productive work.
Although there are relatively few companies at this level of process, it is the most rapidly growing group and therefore the focus of much attention from the work management industry. Use of the collaboration portal has now exceeded the use of email for managing project work. Task lists are maintained there, as well as lists containing other project related data. Project teams come to the portal regularly to understand both their own responsibilities as well as those of the extended team. In many cases reporting, in the form of spreadsheets, charts and even dashboards can be found in the portal, significantly reducing the need for meetings and creating of presentations.
The elusive goal of many Project Management Office managers, this is where a true enterprise project management process and solution are used. The Enterprise Project Portfolio Management portal is the center for strategic decision making, project work management and resource management. Dashboards driven by sophisticated business intelligence capabilities all but eliminate the need for spreadsheets or presentations. In many cases, project work time is collected and used along with task status to understand actual spend, progress and estimate to complete. Predictable deliverable quality, completion schedule and cost become the norm rather than the exception.