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Stem Cells in Cartilage Diseases and Repair 2018View this Special Issue
Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review
Knee osteoarthritis (OA) is a chronic degenerative disorder which could be distinguished by erosion of articular cartilage, pain, stiffness, and crepitus. Not only aging-associated alterations but also the metabolic factors such as hyperglycemia, dyslipidemia, and obesity affect articular tissues and may initiate or exacerbate the OA. The poor self-healing ability of articular cartilage due to limited regeneration in chondrocytes further adversely affects the osteoarthritic microenvironment. Traditional and current surgical treatment procedures for OA are limited and incapable to reverse the damage of articular cartilage. To overcome these limitations, cell-based therapies are currently being employed to repair and regenerate the structure and function of articular tissues. These therapies not only depend upon source and type of stem cells but also on environmental conditions, growth factors, and chemical and mechanical stimuli. Recently, the pluripotent and various multipotent mesenchymal stem cells have been employed for OA therapy, due to their differentiation potential towards chondrogenic lineage. Additionally, the stem cells have also been supplemented with growth factors to achieve higher healing response in osteoarthritic cartilage. In this review, we summarized the current status of stem cell therapies in OA pathophysiology and also highlighted the potential areas of further research needed in regenerative medicine.
Osteoarthritis (OA) is a prevalent debilitating joint disorder characterized by erosion of articular cartilage, excessive stiffness pain, and crepitus [1, 2]. According to the United Nations estimates, till 2050, 130 million people will be affected by OA throughout the world, out of which 40 million will develop severe OA . As a consequence, a huge economic pressure will be imposed in treatment and management of OA leading to stressed and decreased quality of life [1, 4]. OA is classified as primary and secondary OA; primary OA is associated with aging, whereas secondary OA is pertinent to disease or other factors . Further, the degradation of network of collagen and proteoglycan in OA cartilage leads to a loss in tensile strength and shear properties of cartilage . Interestingly, though OA manifests as loss of the articular cartilage, it also includes all tissues of the joint, particularly the subchondral bone [5, 7] Besides aging, the increase in level of accumulation of advanced glycation end products (AGEs), oxidative stress, and senescence-related secretory phenotypes are few reported factors associated with pathogenesis of OA . The elevated senescent phenotypes in OA reduces healing properties of cartilage in an aging individual [9, 10], which might be attributed to oxidative damage and telomere shortening . Aging also severely affects extracellular matrix (ECM) and proteoglycans synthesizing capacity of chondrocytes in OA leading to thinning of the cartilage and decreased water content [11–14]. Synthesis of irregular and small aggrecans disrupts the structural integrity of aging cartilage and reduces the chondrocytes’ response to cytokines .
Currently, the awareness, prevention, diagnosis, and nonpharmacological and pharmacological treatments are used to manage the OA. If these initial nonpharmaceutical interventions fail, the pharmaceutical interventions such as NSAIDs, opioids, and surgery are considered as next level of treatment . However, success of these therapeutic approaches is limited due to related complication and their efficiency. Besides, the autologous chondrocyte implantation (ACI) is one of the most preferred therapeutic approaches for treatment of damaged OA cartilage. Still, the complication related to harvesting chondrocytes had compelled to focus on other cell-based therapies . Recent progresses in tissue engineering have highlighted the regenerative potential of stem cells for therapeutic purposes. The multilineage potential of stem cells, suitable scaffolds, and appropriate chondrogenic agent (chemical and mechanical stimuli) has been implicated to regenerate damaged cartilage [18, 19]. Stem cells could be the unlimited source of chondrocytes and expected to control iatrogenic effects of ACI treatments . Mesenchymal stem cell- (MSC-) based therapy is also emerging as alternative to joint replacement with prostheses, due to its long-lasting effect . The potential of stem cells to differentiate into osteoblasts, chondroblasts, and adipocytes , if stimulated properly, can regenerate cartilage both in vivo and in vitro too . Bone marrow-derived MSC (BMSCs) and the MSCs derived from other cell sources such as synovium, umbilical cord blood, periosteum, peripheral blood, adipose tissue, and muscle have extensively been induced to differentiate into specialized tissues and organs . Moreover, the coculture system of chondrocytes and MSCs have been investigated for cartilage regeneration . Embryonic stem cells (ESCs) are considered as a better source of chondrocytes; however, the ethical concerns and other safety-related complications had impeded the utilization of these cells in regenerative therapy . So, the current researches have more focused towards establishing adult stem cells as therapeutic progenitor for cartilage regeneration. The stem cell-based therapy offers various opportunities such as resurfacing whole joint surface, selection of personalized stem cells, mimicking the environmental conditions to develop the desired phenotype, and increase in level and rate of matrix synthesis, intra-articular stem cell injections, and exogenous wangling of stem cells to regenerate articular cartilage. However, the retention of the chondrogenic phenotype of differentiated stem cells, their integration with native tissue, and mimicking the natural physical strength is posing a challenge to adopt stem cell therapy for OA . Therefore, in this review article, we summarized the current status of stem cell therapies in OA pathophysiology and also discussed the potential areas of further research needed in regenerative medicine.
2. Cartilage Injury and Stem Cells
The proper balance of aggrecan and collagen contents establishes the cartilage homeostasis and develops a characteristic physiochemical structure for distribution of loads and mobility . The proteolytic enzymes are associated with synthesis, restructuring and repair of connective tissues, and any cartilage injury or genetic incongruity in association with irregular loading, which promote imbalance in metabolic activity through enhancing proteolytic activity, resulting in degradation of cartilage [24, 25]. Chondrocytes express these proteins under various stimulations such as mechanical stress, oxidative stress, growth factor response, and aging . The cartilage injury leads to disintegration and degradation of cartilage and finally leads to release of aggrecan fragments, chondroitin sulfate, keratin sulfate, and type II collagen along with other catabolic and anabolic products such as disintegrin, the collagenase matrix metalloproteinase 13 (MMP-13), tumor necrosis factor-inducible gene 6 protein (TSG-6), tissue inhibitor of metalloproteinases-1 (TIMP-1), and activin A . Monoclonal antibodies have also been produced to detect the presence of these compounds in body samples such as sera, urine, and synovial fluids of arthritis patients [28–31]. Cartilage is a nonvascular tissue and eludes vascularization by secreting antiangiogenic compounds (thrombospondin-1, chondromodulin-1, and SPARC (secreted protein acidic and rich in cysteine)), collagen type II derived N-terminal propeptide (PIIBNP), and the type XVIII derived endostatin . Along with these factors, presence of tidemarks and calcific nature of the cartilage also resists vascularization of cartilage . It has been established that injured cartilage activates kinases, resulting in activation of growth factors such as fibroblast growth factor 2 (FGF-2) [34, 35] and expression of chemokines and cytokines . FGF-2 plays a critical role in degradation and protection of cartilage depending on its interaction with FGF receptor (FGFR)-1 or FGFR-3, respectively . Molecular signaling pathways such as WNT and BMP have been reported for their role in promoting cartilage repair . It has been reported that cartilage regeneration in OA is promoted by an increase in matrix synthesis and cellular growth, where chondrocytes clumps are generated in middle and deep zones of the cartilage [38, 39]. However, these processes are not capable enough to fully regenerate damaged cartilage .
Multilineage potential of stem cells is progressively exploited to regenerate cartilage and to provide cellular therapy for other related arthritis disorders. The current developments in tissue engineering have been made feasible to mimic the process of cartilage synthesis both in vivo and in vitro. Embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), bone marrow-derived stem cells (BMSCs), adipose-derived stem cells (ADSCs), and synovium-derived stem cells (SMSCs) have been widely explored for regenerating cartilage (Figure 1). In the further section of this article, we will discuss the various stem cells for cartilage regeneration for the treatment of OA.
3. MSCs and Cartilage Regeneration
Owing to multipotency and less problematic with regard to ethical issues, the adult MSCs are the natural choice for cartilage regeneration (Figure 2). The bone marrow, adipose tissues, peripheral blood, umbilical cord blood (UCB), synovium, and skeletal and cardiac muscles are well-known sources of MSCs . Notably, the low concentration of MSCs in bone marrow (BM) aspirate made it compulsory to isolate MSCs which is primarily done by Ficoll gradient centrifugation and further expanded to acquire the sufficient number for quicker recovery of injury after transplantation [42, 43]. The isolated stem cells reduce the chance of cross-contamination and increase the efficacy of stem cell-based therapy. However, the isolation and expansion of MSCs need expertise and also make regenerative therapy expensive. Hence, if the isolation and expansion steps are skipped, it will save significant amount of cost and time in providing cell-based regenerative therapy at less equipped hospitals . To accomplish this goal, volume of BM may be reduced by closed centrifuge to achieve higher concentration of MSCs as compared to Ficoll gradient, which seems a prospective method to provide instant stem cell therapy. Further, the adipose tissue, synovial fluid, and Wharton’s jelly of the umbilical cord are considered as potential source of MSCs for cartilage regeneration; however, the source of MSCs depends upon the factors such as feasibility in harvesting, expansion potential, hypoimmunogenicity, and establish procedures . These MSCs are positive for CD73, CD 90, and CD 105 cell markers, whereas they do not express hematopoietic markers such as CD11b, CD14, CD19, CD34, CD45, and HLA-DR [21, 41]. Further, various studies have been carried out to evaluate the potential of human and animal MSCs to regenerate cartilage tissue in vitro  with reduced immunogenic response [47, 48], thus making feasibility of allogenic MSC transplantation without HLA matching . The other approach for chondrocyte differentiation and cartilage regeneration includes coculturing of MSCs with chondron or other chondrogenesis-promoting cells. Coculturing provides more natural environment and biomechanical stress to promote cartilage regeneration [50, 51]. Various studies have also established an improved chondrogenesis and ECM synthesis when MSCs were cocultured with chondrocytes [52–54].
Cellular contact, secretion of signals (growth factors, cytokines, etc.), and mechanical stress are factors demonstrated to promote cartilage formation and increase in ECM content [55, 56]. Chondrocytes and MSCs in ratio of 1 : 1 and 1 : 4 have been used to explore the advantage of coculture for development of functional cartilage [53, 55, 57]. However, in a study, the coculture of human infrapatellar fat pad-derived stem cells (IPF-ASCs) and chondrons was unable to promote chondrogenic differentiation . BMSCs and articular chondrocytes were cocultured in 1 : 1 ratio in different models and injected in OA-induced rats; as a consequence, the reduced vascularization and hypertrophy along with increased expression of chondrogenic gene was found . Further, in an interesting study, the suspension coculture of hMSCs and hACs was used, which yielded 4.74-fold increase in 3-dimensional aggregates of chondrocytes till 16 days . On the other hand, the hypoxia and transactivation of stable hypoxia-inducible factors (HIF) also promote chondrogenesis . It has also been reported that the proper concentration of hyaluronic acid (HA) also boosts chondrogenesis . Furthermore, the factors including TGF-β and insulin growth factor- (IGF-) 1 have been reported to regulate MSC proliferation and chondrocyte differentiation, whereas BMP controls the development of skeletal muscle [63, 64]. Taken together, the MSC-based OA treatment procedures seem promising which has also been shown in various clinical studies (Figure 3). However, some obstacle like control of differentiation, characterization of MSC, and lack of established procedures for chondrogenesis hinders the progress in the therapeutic exploitation of MSCs .
4. Rejuvenating Cartilage through ADSCs
Stromal vascular fraction (SVF) of adipose tissue contains stem cells, known as adipose-derived stem cells (ADSCs), has the potential to differentiate into chondrocytes, adipocyte, osteoblasts, and myocytes [66, 67]. Currently, the ADSCs are considered as a promising source of chondrocytes due to ease of harvest, their abundance in adipose tissue, and low morbidity rate and side effect, as well as a noninvasive procedure. Various studies have already implicated the significance of ADSC in cartilage regeneration for the treatment of OA [68–71]. Specifically, the intra-articular and surgical implantations of ADSCs combined with biomaterials have been carried out to assess the magnitude of cartilage regeneration in OA-induced animal models . Additionally, the autologous platelet-rich plasma induces cartilage regeneration by secreting growth factors such as TGF-β, epidermal growth factor (EGF), and fibroblast growth factor (FGF) to promote the growth and differentiation of stem cells and their adherence to cartilage lesions . In an important study by Tang et al., the intra-articularly injected subcutaneous ADSCs were found to be more effective than visceral ADSC in a rat model of OA . The paracrine effect of ADSCs is considered as one of the paramount factors for cartilage regeneration in OA . Further, the scaffolds seeded with ADSCs in presence of growth factors, stimuli, and compressive stress promote regeneration of cartilage ex vivo. A 3-dimensional scaffold of collagen type I was developed to study the effect of PRP and human recombinant insulin on differentiation of ADSCs into chondrocytes and osteocytes . The study showed that through this approach, it promoted ADSC-mediated chondro- and osteogenesis, and the PRP/insulin-induced differentiation was independent of IGF-1R signaling. In another study, it was reported that xanthan gum significantly improved the chondrogenic potential of intra-articularly implanted ADSC in a rat OA model . Based on the above evidence, ADSC seems highly promising for therapeutic treatment of OA; however, limited knowledge of differentiation mechanism and lack of established procedures are hindering the progress of this therapy to exploit clinically. Issues related to the safety of ADSC-based therapy have been addressed in various clinical trials [75–79]. A report including 70 systematic studies documented that approximately 20% patients developed antibodies during allogeneic cellular therapy, and one case of breast cancer out of 121 patients was also found . Therefore, though the clinical trials indicate the potential of ADSCs in cell-based therapy of OA, further extensive clinical studies are needed to identify potential risks.
5. Revitalization of Cartilage by BMSCs
MSCs derived from bone marrow (BMSCs) are capable enough to differentiate into tissues such as bone and cartilage [80, 81] and mobilize at an injured cartilage site in knee joints thereby assisting in cartilage regeneration in OA . In a study, the intra-articularly transplanted BMSC successfully regenerated injured cartilage in a rabbit model of OA and also improved osteoarthritic symptoms in humans without any major side effect even in the long-term . This study demonstrated the possibility of intra-articular injection of MSCs for the treatment of injured articular tissue including anterior cruciate ligament, meniscus, or cartilage. Therefore, if this treatment option is well-established, it may be minimally invasive procedure compared to conventional surgeries. In a very interesting study, out of the alginate, fibrin-alginate (FA), agarose hydrogel 3D culture, and cell pellet systems, the FA hydrogels and cell pellet promoted chondrogenic differentiation of equine BMSCs, whereas no effect was found in agarose group . However, FA seems a better option than pellet culture system, as the pellets require large amount of chondrocytes. Another study established an agarose hydrogel-based model for cartilage regeneration from human BMSCs in presence of TGF-β3, where the level of chondrogenesis in agarose gel was dependent on the initial density of cells . Furthermore, a scaffold-free human BMSCs-derived cartilage-like sheet matrix has also been developed in presence of FGF-2 and its efficacy was assessed by transplanting it into an OA rat model. This approach though improved OA condition, the cellular density was decreased significantly within 12 months . Further, in a report by Peng et al., limited proliferation ability of the primary BMSCs was overcomed by immortalizing them by using human papillomavirus- (HPV-) 16 E6/E7 genes, which showed enhanced chondrogenic potential and long-term survival both in in vitro and in vivo OA mice model . A recent study identified both the promoting as well as the inhibitory role of miR-29b factor in BMSC-based regulation of collagen expression and cartilage regeneration in OA model . Further, the chondrogenically primed BMSCs have also demonstrated to promote cartilage regeneration under hypoxia in a sheep model of OA . However, the effect of oxygen tension was not consistent during ex vivo cartilage regeneration. On the other hand, BMSC also showed enhanced chondrogenesis when seeded on chondrogenic fibrin/hyaluronic hydrogel with improved mechanical strength by adding methacrylic anhydride. Hence, it can also be considered as a promising delivery method for cartilage regeneration in OA therapy . Besides, the intra-articular injection of MSCs may also be applied via microfracture through the cartilage and subchondral bone . In a clinical trial (phase I/II), the intra-articularly injected BMSCs among OA patients showed a significant improvement; however, to assess all the clinical parameters, clinical phase III study was required . In another clinical study, human BMSCs demonstrated that the optimum level of cell dose (25 million) improved the OA without any major adverse effects . However, at higher doses, the knee pain and swelling were among observed as adverse effects, which suggested that more clinical studies are required to establish the therapeutic role of human BMSCs in OA treatment.
6. SMSCs and Cartilage Regeneration
SMSCs have been considered more efficient for chondrocyte differentiation than ADSCs or BMSCs . Notwithstanding, in the recent years, only few human-based studies using SMSCs have been conducted compared to ADSCs and BMSC for the treatments for OA. SMSCs are also isolated from hip joints; however, those isolated from knee joints have shown a better chondrogenic potential . These MSCs can also be preserved in complete human serum at 4 or 13°C without significantly affecting their viability and chondrogenic potential . In an interesting research, the exosomes derived from SMSC-140s promoted chondrogenesis without affecting the quality of ECM . SMSCs isolated from OA patients have also shown to be an effective alternative cell source for tissue engineering construct-based therapy for chondral defects . Besides, the pretreatment of SMSCs with IL-1β also enhances the chondrogenic potential of SMSCs .
In a rat knee OA model, the periodically injected SMSCs migrated into the synovium and retained their undifferentiated SMSC properties with an increased genetic expression of chondroprotective proteins such as BMP-2 and an anti-inflammatory gene, TSG-6 . This suggests that SMSCs not only retain their MSC characteristics but might also inhibit the advancement of OA through genetic machinery. Further, SMSCs have demonstrated the ability to enhance the repair of longitudinally torn menisci in avascular areas in a miniature pig model . In 2014, Hatsushika et al. further demonstrated that intra-articularly injected MSCs in pig knee joint regenerated cartilage in resected medial meniscus . Based on these abovementioned evidence, it could be concluded that the regenerative chondrogenic capabilities of SMSCs catapulted them to the forefront of cell-based OA therapy.
7. Infrapatellar Fat Pad- (IFP-) Derived Stem Cells in Cartilage Regeneration
Knee joints are surrounded by extrasynovial adipose tissue known as IFP, which not only provides energy but also releases cytokines/adipokines . IFP is considered as an alternative source of autologous stem cells. MSCs isolated from these tissues of knee joints have superior chondrogenic properties than BMSCs or ADSCs . The characterization of IFP-MSCs is based on the presence of cell markers such as CD9, CD10, CD13, CD29, CD44, CD49e, CD59, CD105, CD106, and CD166 . These cells are also capable to differentiate in trilineages (adipo-, chondro-, and osteogenic) [104–107]. In a recent study, ADSCs were isolated from both the human suprapatellar and IFP and differentiated into trilineage cells. However, the suprapatellar-derived ASCs were found to be more effective in reducing OA symptoms, including knee inflammation and cartilage degeneration in a mouse model . Besides, the IFP-MSCs have been demonstrated with higher rate of expansion compared to synovial fluid- (SF-) MSCs . However, both cells can be exploited to treat the cartilage injury in OA. Further, it was reported that platelet-rich plasma and hyaluronic acid-treated IFP adipocytes promote chondrogenesis and inhibit adipocyte-mediated inflammation . IFP is also a rich source of perivascular stem cells (PSCs) and homeostasis regulating the progenitor MSCs. IFP-PSCs maintain their characteristic and adherent growth properties even after multiple expansion due to their ability to retain the structural integrity of telomere . Interestingly, the PSCs isolated from IFP have shown superior chondrogenic activity as compared to those derived from subcutaneous adipose tissues. In another study, the improved chondrogenic efficiency of coculture of chondrocytes and IFP-MSCs in the presence of chitosan/hyaluronic acid nanoparticles was revealed, which implied that coculture approach in presence of proper stimuli could assist in cartilage regeneration in an osteoarthritic knee . The IFP-PSCs can also be engineered by manipulating the oxygen gradients and mechanical environment of hydrogels to obtain cartilage structurally and functionally similar to a natural one . Though the IFP-derived stem cells appear to be a prospective alternative, further extensive studies are needed to prove their clinical efficacy towards cartilage regeneration for the treatment of OA.
8. Regeneration of Cartilage Using ESCs
ESCs are derived from inner cell mass of the blastocyst and could be indefinitely expanded and differentiated into any of the three embryonic germ cell lines including ectoderm, endoderm, and mesoderm . The perpetual self-renewal potential of ESCs makes it unlimited source of stem cells and chondrocytes for cartilage regeneration. However, the major bottleneck to utilize ESCs for cartilage matrix is ethical complexity and poor survival rate of human ESCs after the disintegration of cell mass . Additionally, the differentiation of ESCs into chondrocytes and regeneration of cartilage is complex as it requires complicated microenvironment along with 3-dimensional structure and specific mechanotransduction signal . In a seminal study, McKee et al. showed that under compressive stress, ESCs combined with polydimethylsiloxane (PDMS) scaffolds promoted the initial expression of chondrogenic markers Sox9 and Acan, which further enhanced the expression of collagen type 2 (cartilage-specific marker) and reduced Oct4 (pluripotent marker). However, it did not promote differentiation of hypertrophic cells . This study showed that a proper model is still needed to established ESC-mediated chondrogenesis. An in vitro study used embryoid bodies to assess the chondrogenic potential of ESCs and demonstrated that ESCs could develop into hypertrophic and calcifying cells . In another study, ESC also revealed chondrogenic activity when stimulated with bone morphogenetic protein 4 (BMP-4). Further, the accumulation of cartilaginous matrix and type II collagen was recorded in the presence of transforming growth factor- (TGF-) β3. , and this chondrogenic activity was further promoted by the platelet-derived growth factor- (PDGF-) BB. The higher concentration of BMP-2 with other cofactors, the TGF-β-1, insulin, and ascorbic acid, also promotes the chondrogenic ability of ESC under controlled environmental conditions . Transforming growth factor-β1, BMP-2, and BMP-4 have been reported to induce differentiation of mice ESCs into chondrocytes [115–120].
Besides, the exosomes have been reported to mediate cellular communication between stem cells and chondrocytes, and understanding this interaction is crucial in developing an effective protocol to regenerate the cartilage . Exosomes are extracellular vesicle primarily secreted by MSCs and assist in maintaining homeostasis, repair and regeneration, and tissue function . In a seminal study, Wang et al. isolated exosomes from culture media of ESC-MSCs and evaluated their effect in OA mice model. This study showed that exosomes exerted protective and regenerative effecst in the injured cartilage . Likewise, various studies have established the chondroregenerative potential of ESCs; however, the major bottlenecks to utilize ESCs for cartilage matrix regeneration are ethical concerns involving the destruction of embryo and poor survival rate of human ESCs after disintegration of cell mass [115, 123].
9. iPSCs and Cartilage Regeneration
iPSCs are the reprogrammed somatic cells similar to ESCs, which seems to be a promising alternative to the ESCs . Oct 4, c-Myc, Klf4, Nanog, Esrrb, Lin28, and Sox2 are some of the transcription factors which have been used to reprogram these somatic cells [125–128]. Other approaches like viral transfection and genetic engineering are used to develop iPSCs. Vector characteristics and related promoters are critical factors in gene delivery to differentiate iPSCs into specific cells. Adenoviral, adeno-associated viral, retroviral, and lentiviral vectors have been considered suitable for delivery of target genes in iPSCs . Moreover, the differentiation of patient-specific somatic cell to iPSCs reduces the risk cross-reactivity and immunogenicity [130, 131]. Chondrogenesis has been induced in iPSC-derived embryonic body of mice by using growth factors such as TGF-β3, transretinoic acid, and BMP-2 [132, 133]. Another study demonstrated that human iPSCs (hiPSCs) differentiated into chondrocytes and expressed type II collagen and aggrecan similar to cartilage . Zhu et al. induced embryonic body formation from hiPSCs, which were further differentiated to chondrocytes and transplanted in an OA rat to regenerate cartilage . They have also shown that MSCs derived from induced pluripotent cells (iMSCs) were able to secrete exosomes which were superior to exosomes of synovial membrane MSCs (SMMSC) in regenerating cartilage in OA rat . Besides, both with and without scaffold-based cartilage regeneration approaches have been explored for differentiating hiPSCs into chondrocyte for the treatment of cartilage injury [122, 137–142]. The utilization of iPSCs cannot be limited up to regeneration of cartilage but also in the discovery of agents promoting chondrogenesis or inhibiting cartilage degeneration . These studies showed the immense potential of iPSCs to regenerate cartilage in OA. However, the low efficiency and variations in requirement of transcription factors in somatic cells are the major limitation for iPSC generation. Moreover, the undifferentiated iPSC contaminates differentiated MSCs causing tumorigenicity, which limits the use of heterogeneous-differentiated MSCs in cell-based regenerative therapy . Furthermore, over and unregulated expression of Oct4, Sox2, Klf4, and c–Myc develops cell dysplasia, serrated polyps and mucinous colon carcinomas, breast tumors, and cancers, respectively [145–150]. Moreover, the clinical application is limited due to lack of a proper model for large-scale and economic differentiation of iPSCs.
10. Conclusion and Future Prospects
The self-renewing and multidifferentiation abilities have rendered stem cells, an attractive alternative for the treatment of osteoarthritic pathology. Considering the complexity and efficiency of currently available therapies in long-term, the cell-based regenerative therapy has widely been explored to treat the OA and proven to hold a promising future. The MSCs obtained from adults offer a considerable therapeutic approach in translational medicine. The therapeutic efficacy of stem cells can also be magnified through supplementing growth factors. One of the major limitations of therapies for cartilage repair is that they employ autologous cells and therefore, the development of a universal donor cell is still lacking.
Current reprogrammable approaches to induce stem cell differentiation into cartilage tissues seem inefficient. Further, it seems that genetic modification and gene editing techniques will assist to overcome the current limitations of stem cell-based therapy. The localized delivery of gene therapeutic agents provides more effective and safe recovery in OA. Recombinant adeno-associated viral vector (rAAV) is also used as a genetic vector to deliver genetic sequence in situ to promote the cartilage regeneration . Various animal model studies and clinical trials were carried to out to develop a comprehensive approach for effective gene therapy and encourage to extended clinical trial to develop gene transfer technique to regenerate injured cartilage in situ . microRNAs (miRNAs) such as miR-29a, miR-140-3p, miR-140-5p, miR-145, miR-146a, miR146b, miR-193b, miR-194, miR-221, miR-495 are known to be involved in the differentiation of stem cells into chondrocytes; and their regulated expression enhance chondrogenesis and thus repair cartilage injury [153, 154]. Besides, the development of gene editing technique, the CRISPR/Cas 9 seems promising to regulate chondrogenesis . This technique was exploited in the development of stem cells that controlled interleukin-1 (IL-1) and tumor necrosis factor-α- (TNF-α-) mediated inflammatory response . Further, the 3-dimensional scaffold promotes the development of cartilage tissue structurally similar to native cartilage by providing conducive microenvironment and essential mechanical stimuli [152, 157]. The recent advances in 3D printing will also improve the scaffold design, which might support chondrocytic growth to overcome osteoarthritic symptoms . It is of note that though multiple studies have sorted out the most effective stem cells, scaffold materials, genetic approach, and other procedures for cartilage regeneration in OA knee and the rigorous randomized and blinded trials, with large sample sizes and long-term follow-up, is needed to reach a consensus.
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper.
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domain: literature


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New Addition Sonogram Photo Frame - $14.99
Baby > Gifts > Keepsakes
Home Decor > Frames > Picture Frames
Home Decor > Frames > Special Occasion Frames
Wall Decor > Frames > Picture Frames
Wall Decor > Frames > Special Occasion Frames
Capture your first look at your child with this wonderful black wood photo frame. It holds 4" x 5" sonogram photo and a 4" X 6" photo, and is engraved with the words "When they placed you in my arms you slipped into my heart." Wall hooks included. Measures 9 1/4" H x 13" W x 1 1/4" D.

domain: artistic


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Emergency services this afternoon responded to an overturned catamaran in Somerset Long Bay. According to a spokesman for the Department of Marine and Ports Services, a member of the public alerted Harbour Radio to the incident at about 4pm. A police rescue vessel was dispatched and righted the catamaran after attempts by other. ..
Tue Nov 10 , 2015

domain: news


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A SENIOR care worker has described to jurors how he was told one of his staff was abusing patients.
Care assistant Tammy Knox, 23, is alleged to have tormented six extremely elderly and vulnerable patients while working at a Dovecot nursing home.
She is alleged to have pushed, hit and flicked food in the face of residents being cared for at Unit 1, the highest dependency ward at Finch Manor nursing home, Finch Lea Drive.
Knox, of Clieves Road, Kirkby, denies eight counts of ill-treatment of a person who lacks capacity between February and August, 2008.
At Liverpool crown court yesterday, senior care worker Kevin Allen described being told of concerns over Knox’s behaviour in July 2008, by fellow care assistant Sharon Gamble. He said: “I was very shocked. Sharon was very upset. She said if I was to say anything she would deny it, she was frightened, when she was telling me she was shocked.
“She just said it had been going on for a few months and if I was to say anything she would deny it. It was an allegation that had to be reported.”
Mr Allen told how later that night he rang the manager of the nursing home, Diane Hollingsworth, who asked him to make a report of the allegations.
Mr Allen said the concerns were raised after he questioned staff over a bruise on the face of 85-year-old Eileen Carter after returning from a few days holiday.
He said: “During the day I asked all the staff if they knew what had happened. They still said no.
“At 5.15pm, a member of staff [Sharon Gamble] asked if a private word was possible with me. It was tea-time so it wasn’t possible to talk. At 6.45pm I spoke to the member of staff. It was brought to my attention about the client’s welfare, about a concern they had about a member of staff.”
In his report filed later that night, the witness wrote: “It has been brought to my attention that a certain member of staff has been rough to a client, not just on one occasion, but on several other times.
“The staff member has told me other incidents have occurred and gave me names of some of the clients.”
He described how the allegations related to Knox pushing Sarah Warren, 88, who was later diagnosed with a fractured leg, causing bruising on the face of 79-year-old Frank Hengler, and slapping Mrs Carter in the face. (Proceeding)


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How To Make Homemade Potato Chips With Flavors
Commercial Potato Chips: Are They Worth It?
Potato chips are one of the most popular snacks nowadays. Many brands offer their version and they can be found literally everywhere. No matter if you prefer them simply salted, with oregano, paprika, chili or other flavors, chips are an excellent addition to movie watching nights and are children favorites, too.
However, everyone knows it is not exactly the healthiest choice of snack, especially for children who cannot control themselves when allowed to have some and who tend to ignore important facts, such as dietary information and the ingredients of the product.
Commercially found potato chips are packed with calories and additives; most of them are not reflected on the ingredients tag with a recognizable way. Though potato chips really come from potatoes, they do not carry any useful nutrient with them to the final product due to being fried in low quality oils and processed with artificial flavorings and other additives.
Potato Chips And Calories Intake
What is reflected on the tag, though, is the calories intake which cannot be hidden; commonly, it is extremely high regardless of the fact that potato, as food is not really fatty. The problem actually lies within the oils and fats used. Those oils are actually the worse kind of fat someone could have in his diet, since most are trans fats, known to cause increasingly popular health conditions, for example high cholesterol and the effects that typically come with it, such as high blood pressure and others. It is actually well known that potato chips are not healthy snack, but none of us can resist them, right?
That's when you might find this article useful; simply because, you can cook your own potato chips, at the comfort of your home and right when you need them, in a matter of minutes and with ingredients you will choose.
A Potato Peeler
Homemade Chips: What You Will Need
The items you will need to cook your own potato chips at home are:
- Potatoes, the larger the better
- Vegetable peeler that allows very thin slices
- Spices and herbs for flavoring: possible choices are salt, pepper, paprika powder, curry powder, rosemary, thyme, oregano, crushed cumin
- Oil for frying
- Towel or paper to remove excess oil after frying
- Optionally: your preferred dip sauce for serving
- Choose your potatoes carefully - big ones will be easier to turn into chips. Also check for possible areas with spots or discoloration, you would like to remove those parts.
- Peel the skin off the potatoes until all is gone and wash.
- Use the peeler, same as you did when you were peeling the skin off, but this time do it on the potato flesh. The peeler is able to produce very thin slices of potato which will turn into great potato chips. If you choose to do it with knife, there is no way you can make it as thin.
- Place the slices on a towel to absorb the water.
- Add your cooking oil in a large pan. The chips will be crunchier and more tasty if you choose a high quality oil, such as olive oil. However, any oil suitable for frying will do.
- Heat the cooking oil in high heat until ready. Try it by dropping inside it a potato slice; it should start frying at once. If it does not, remove and get rid of the slice and let the oil heat more.
- When oil is done, drop inside some potato slices but be careful not to put too many inside. You would like each frying batch to contain 10-15 chips and not more, because they could stick to each other and get fried only from one side.
- Lightly stir the chips until their color is golden brown. It does not take much time until they are ready, because they are just too thin.
- When done, remove from the pan and place on a tray with much paper, to allow it to absorb excess oils. Add the next batch for frying.
- Now is the time you would like to add your spices, because the chips are still hot and the spices will stick on them.
- Keep frying and spice each batch, until all slices are fried.
- Serve in large bowls at once (along the dip sauce, if you have one) and eat as soon as possible, because after some time they will not be as crunchy anymore.
Consume As Soon As Possible
Generally, homemade potato chips will not last crunchy for long, so it is not very convenient to fry them unless you are ready to consume them almost immediately. On the other hand, you will be satisfied because you made tasty, delicious potato chips with ingredients you chose yourself for a snack as healthy as possible.
You Can Bake Them Too!
If you do not want to fry the potato chips, you will have a similar result but with less "oily" taste if you bake them in medium heat for 6-7 minutes or until golden colored. Place the chips in a shallow baking pan or on special (silicone usually) baking sheet, sprinkle them (or spray if you can) with few olive oil and your spices and let bake until ready.
Other Versions Of Chips
You might be surprised to find out that with the previous method you can make other kinds of chips, rather unusual but still tasty. Serving such "special" chips to your visitors you will impress them and make them wonder what your initial ingredient was. Possible ingredients are:
- Banana, very common in Asian cuisine
For all these ingredients you simply follow the same procedure. Some of them could require, for better result, cutting with knife. Banana chips, for example, tend to be a bit thicker.
You Might Like These, Too!
- Barbecue Or Meat Grill: Instructions For A Successful BBQ Meal
As days start to heat up, what's better idea than grilling outside, with friends or family? Find out how you can turn every BBQ into a worthy experience.
- Traditional Greek Recipe From Crete: Pork In Yoghurt Gravy With Rosemary
A really simple dish to make but with mouth-watering, astonishing results. Pork and rosemary get combined with a thick sauce based on Greek yoghurt.
- Traditional Greek Recipe: How To Make The Perfect Greek Village Salad (Horiatiki Salata)
Greek village salad is en exceptional dish of fresh vegetables, tasty feta cheese and healthy olive oil, easy to make in no time.

domain: food


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Polkton black single women
History of polkton, two state federated clubs are present in town - the polkton literary club (inactive) and the polkton women’s service club. Health of black or african american non-hispanic population birth rate for unmarried women: 424 births per 1,000 unmarried women aged 15-44. Matchcom, the leading online dating resource for singles search through thousands of personals and photos go ahead, it's free to look. Black and white singles interracial dating for sincere black and white men and women, interracial personals.
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domain: sociology


Olayiwola Gabriel , otherwise known as Granite , is an upwardly mobile entertainer with a penchant for success. A native of Osun State, The multi-talented fast rising artiste/songwriter signed to MANDILAS RECORDS, premieres the VIDEO to his debut single, WOMAN.
The song was produced by DAIHARD BEATZ , & currently enjoying massive airplay online/offline.
The video was shot by smokkyfilmz & it is the first video with a story line that the Director will ever shoot.
Watch the official video for “Woman” by Granite below


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Schneider Bipartisan Resolution Opposing Global BDS Movement, Supporting Two-State Solution Passes House
Today, Congressman Brad Schneider (D-IL) issued the below statement following the passage of his bipartisan resolution H.Res.246 by a vote of 398-17. The legislation had more than 350 co-sponsors, including three-quarters of the members of both parties:
“Today’s strong bipartisan vote sends a clear message that Congress continues to be united in support of the Jewish, democratic state of Israel and a two-state solution as the path to peace for both Israelis and Palestinians. At the same time, we condemn the Global Boycott, Divestment, and Sanctions (BDS) Movement that seeks to delegitimize Israel and block that path to peace.
“The Global BDS Movement denies the Jewish people’s connection to the land of Israel, refuses to accept the basic idea of a Jewish state and seeks to delegitimize Israel in international forums, on college campuses, and in global commerce.
“Our resolution does not infringe on any American’s right to protest, and it explicitly recognizes that boycotts have a long and important history in our country, including during the Civil Rights movement and efforts to end apartheid in South Africa. However, not all boycotts seek just ends. Our objection is to the fundamental aim of the Global BDS Movement: the delegitimization of Israel and the destruction of the Jewish state.
“It’s been our country’s long-held policy that the best path to assuring Israel’s long-term security as a democratic and Jewish state, and realizing the Palestinian people’s aspirations for a state of their own, is through a negotiated two-state solution. I appreciate the resounding support of my colleagues for this resolution to reaffirm that truth and stand against efforts, like the Global BDS Movement, that stand in the way.”
Schneider discussed the resolution on an interview with CNN – Link
Schneider spoke on the House Floor during debate on the resolution - Link


While certainly not a new initiative, electronification has been gaining momentum following the severe liquidity and payment flow challenges since September 11, 2001. A new emphasis has been placed on building greater disaster tolerance into global payments processes, payment flow, and settlements between parties. The shift toward electronification is being driven by regulatory requirements such as the USA PATRIOT Act, the Uniform Electronic Transaction Act and the pending Check 21 Act. Even governing bodies such as the Bank for International Settlements (BIS) and the European Central Bank (ECB) have publicly mandated the implementation of secure real-time settlement systems.
To help accelerate the adoption of electronification of payment systems around the world, a new storage solution has been developed to improve the manageability and resiliency of a company's information assets.
Despite the operational cost advantages of electronification, many companies are still reluctant to fully embrace it. A recent study by the New York Clearing House found that only 14 percent of U.S. business-to-business payments are electronic.
The study also shows that a primary barrier to real-time settlement is the absence of corresponding remittance information within most payment transactions.
This is largely a result of the limited integration between the multiple software applications used to control payables, receivables and cash management processes. And, because so many companies lack the technology necessary to change, the velocity of electronic payments has appeared to be no faster than paper checks.
A new storage solution, known as automated networked storage, has been designed to address these issues and allow for the consolidation of disparate heterogeneous storage resources.
The Solution To the Problem
Automated networked storage offers companies a way to efficiently manage, protect and share information assets with the creation of a logically centralized data repository. As client demands for integrated real-time payment information increases, so has the emergence of online banking services via the Internet.
By attaching network-addressable storage resources directly to existing public and private IP-based networks, a company has the ability to leverage sophisticated storage software that automates and controls the management and continuity of stored information.
Automated networked storage has emerged as the most comprehensive solution by combining intelligent software and services with the benefits of storage area network (SAN) for applications like data warehousing and OLTP; network attached storage (NAS) for file sharing and collaboration); and content addressed storage (CAS) for fixed content assets through integrated content management applications.
These networking technologies not only address the need for better utilization, less support requirements, increased recoverability and so on-but can open the door for companies looking to painlessly integrate their remittance information within payment transactions, thereby facilitating real-time settlement.
Mission-critical payment solutions such as payment image archives depend on a continuously available automated networked storage solution. An automated networked storage solution enables increased server consolidation, a rise in storage utilization rates, and enhanced business continuity through instant restore and automated backup capabilities.
A company can then make multiple backup copies of their payment data ensuring that the data is continually available, and will not interfere with other transaction applications.
In addition, companies can leverage the mirrored data to automatically detect unauthorized or potentially fraudulent transactions before the payment is committed.
In fact, a recent survey by the Association for Finance Professionals found that the most dominant concern of more than 67 percent of the respondents was fraud-detection capabilities in electronic payment initiatives.
Another unique feature of automated networked storage is its ability to leverage content addressed storage, or CAS, capabilities. CAS is the newest networking technology that provides performance, manageability and scalability.
CAS offers several key benefits for financial companies and global payment companies: assured content integrity (guaranteeing that all data will remain unchanged over a long period of time), plug-and-play scalability (automatically recognizes additional capacity as it is added), cost savings (eliminate the costs of storing the same file or image multiple times), and online information availability (making it possible to retrieve data from anywhere on the network at any time). Never before has data stored on traditional media such as film, tape, and optical been accessible at Internet-speeds.
Finally, automated networked storage enables companies to combine their many diverse servers, applications, and operating systems into a single information storage infrastructure so they can manage and consolidate the explosive growth of file-based data (such as e-mail, Web content, and user directories filled with documents), and preserve data that can never change such as check images, monthly billing statements, mortgage notes, and many other financial-based assets.
Philip Faulkner is director of the financial services group at EMC Corporation, in Hopkinton, Mass. He can be reached at (508) 435-1000.


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Numerical Investigation of Over Fire Air (OFA) Effect on Flow Characteristics, NOx Combustion and Emission in a 600 Mw Tangentially Fired Pulverized Coal Boiler
One of the coal-fired air emissions in boilers is NOx, which has a significant impact on the environment and could cause acid rain, ozone formation, visual impairment and health problems in humans. There are several technologies to reduce and control the formation of NOx emissions, which one of these technologies is the use of over-fire air (OFA). In this research will observe the effect of overfire air (OFA) usage and analyze by numerical 3D modeling method using computational fluid dynamics (CFD) in Paiton 9 power plant boiler and analyzed for 5 (five) OFA damper opening variations, i.e 0%, 25%, 50 %, 75% and 100%. This research will analyze several factors that have significant influence on NOx emission formation, that are: the temperature distribution of the boiler during the combustion process, the distribution of nitrogen oxide (NO) and carbon dioxide (CO2), direction of flue gas flow and trajectory of coal particles and residence time indicating the length of time of burning. The results showed that the lower the flame temperature, the smaller the formation of NOx; the smaller the oxygen content in the combustion process, the smaller the formation of NOx; the shorter the residence time of combustion products in the high temperature zone the smaller the formation of NOx, and the smaller the nitrogen content in coal, the smaller the formation of NOx.
N. Hachenberg, “Prediction of NOx emissions in pulverized coal combustion,” Louisville, 2014.
Y. A. Zeldovich, D. F. Kamenetskii dan P. Sadovnikov, The oxidation of nitrogen in combustion and explosions, USSR: Publishing House of the Academy of Sciences of USSR, 1947.
B. Sudarmanta, R. M. Wijayanto, A. Syaifudin dan G. Nugroho, “Studi numerik pengaruh diameter bed material terhadap karakteristik fluidisasi pada circulating fluidized bed boiler beban 28,6 MW,” dalam Seminar Nasional Teknik Mesin 12, Surabaya, 2017.
F. Winter, C. Wartha, G. Loffler dan H. Hofbauer, “The NO and N2O formation mechanism during devolatilization and char combustion under fluidized-bed conditions,” dalam Symposium (International) on Combustion, Vienna, 1996.
B. Sudarmanta, R. M. Wijayanto, G. Nugroho, A. Syaifudin, A. Setiyawan dan J. B. Ariateja, “Numerical study effect of fluidizing air to erosion pattern in circulating fluidized bed boiler,” The International Journal of Mechanical Engineering and Sciences, vol. 1, no. Institut Teknologi Sepuluh Nopember Surabaya, pp. 17-26, 2017.
R. M. Wijayanto, B. Sudarmanta, A. Syaifudin dan G. Nugroho, “CFD simulation of circulating fluidized bed boiler 30MW: Effect of primary and secondary air distribution on fluidization behavior,” dalam AIP Conference Proceedings, Surabaya, 2018
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The Fine Line (Between Worlds) (Volume 1), Ed: 2
by Tracee Ford
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Amazon.com Product Description (ISBN 0692413596, Paperback)There is a fine line between the world of the living and the world of the dead, and Robin Hillard and her handsome husband Dr. Matthew Gregory are about to cross it. After the two meet in the ER of the local hospital, Robin and Matt begin a whirlwind romance. Matt surprises Robin when he proposes to her in the midst of the beautiful Pikeview Manor, the home that Matt has just purchased for them to begin their lives together. What the newlyweds are unaware of is that by walking through the front door they have walked between the worlds. The couple begins to hear strange noises, find objects moved, and they see the shadows once hidden within the majestic house. Robin has dreams of the past, while Matt struggles with the line between science and the world of the unseen. Matt’s young daughter Olivia begins speaking of the little girl that she plays with in her room, and of the darkness lurking within every board, nail, brick, and tile of the house. The family’s love and strength is tested as they realize that terror is not imagined…its real!
(retrieved from Amazon Mon, 06 Jul 2015 11:42:36 -0400)
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domain: library


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Posted by Titch on October 09, 2003 at 13:08:17:
In Reply to: Re: Halloween Games posted by MM on October 08, 2003 at 12:56:57:
Thanks, I'll check it out.
I'm in my 20s, so looking for games that involve both adults and kids. Have to get into the Halloween spirit!

domain: entertainment


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Everyones favourite time traveller returns to do battle with his greatest foes. Years after his peremptory departure from Totters Lane (see the first ever story Doctor Who: An Unearthly Child) the Doctor (Sylvester Mc...
When the Doctor and the recently regenerated Romana arrive on a radioactive planet, the Time Lord has the strangest feeling that he has been there before. Exploring the ruins of an old city, it is not long before they discover the disturbing truth. The TARDIS has materialised on Skaro - original home to the evil Daleks. But who are the mysterious Movellans and what terrible treasure are the Daleks
You certainly wouldnt want to miss this Doctor Who walking tour if youre a long-term fan of the Doctor and friends, because this is your chance to walk in their footsteps. On top of seeing some of the stunning city of London, youll see and learn about many filming locations for the series; a friendly guide will be happy to point out where the Daleks had a battle, the stairwells of the Earth Prison
Cluedo Doctor Who - Missy, formerly the master, escaped from Gallifrey when the Doctors freed the planet from the Time War in The Day of The Doctor. Now, only she knows its whereabouts. But as she watched the Doctor and Clara on their adventures through season 8, she left a vital clue to its whereabouts somewhere in space and time and one of the doctors enemies has found it. Can you figure out
Poor Plop! Baby owls are meant to love darkness but hes terrified of it. How can he overcome his nerves and become a true night owl? Slowly, with the help of the other night creatures, he learns that dark is exciting, dark is gentle, dark is mysterious and dark is kind A wonderful look at the unseen side of things, and at all the positive things that night and dark can be, this is a funny and
We have Doctor Who Socks – socks are cool! These timey-wimey, cottony-wottony socks come as a pack of three pairs, featuring the Doctor’s Tardis logo, a dramatic Dalek design and the face of one of the Cybermen.Because they are soft and cotton rich, our Doctor Who mens socks will not exterminate your feet – in fact, they’re rather comfortable! Join the Doctor on his
Doctor Who, Gallifrey, the TARDIS, K-9, Tom Bakers crazy stare. Its what being a Time Lord is all about. Not official merchandise.Mug design reads: TimelordOur ceramic mugs are all white barring the printed design and are a standard mug size.
Create fun Doctor Who-inspired costumes for 18 inch dolls with this paper pattern from Simplicity. Following the step-by-step instructions you can create four costumes with accessories. The pattern includes bodice, skirt, overskirt, boot cover in two styles, trousers, shirts, jacket, coat, suspenders and neckwear.
The Man Who Cycled the World. On 15 February 2008, Mark Beaumont pedalled through the Arc de Triomphe in Paris. 194 days and 17 hours previously, he had begun his attempt to circumnavigate the world in record time. Mark smashed the Guinness World Record by an astonishing 81 days. He had travelled more than 18,000 miles on his own through some of the harshest conditions one man and his bicycle can
Who? Don't Fear the Reaper T-ShirtCheck out these new threads for summer '15, fresh from the guys atWho? clothingWho? Don't Fear The Reaper Crewneck teeHand screen printed in United Kingdom.200gsm 100% CottonDouble stitched hemsRegular fit (unisex)S - (18W x 28L)M - (20W x 29L)L - (22W x 30L)XL - (24W x 31L)
doctor who remembrance of the daleks on other UK sites
50 years after its only UK broadcast on BBC One, one of Doctor Whos most celebrated, lost adventures is regenerated, with a brand new hand-drawn black and white animation, synchronised with a digitally remastered recording of the original 1966 audio. The six-part adventure takes place immediately after the first regeneration, as the Time Lord and his companions, Polly (Anneke Wills) and Ben
For all of you sci-fi fanatics out there, we present this officially licensed Doctor Who The Daleks Coffee Mug. One look at the powerful Dalek featured on the face of this yellow mug and you won't even need that coffee. The mug features and embrossed image of a Dalek on the outside with the words 'The Daleks' and the famous 'Exterminate' Phrase on the inside of the mug.
The Doctors multipurpose tool is a Gallifreyan device, with numerous settings, easily controlled at the press of his thumb. The Doctor has had many sonic screwdrivers of different designs throughout his life. This is the Fifth Doctors Sonic Screwdriver.Dimensions (cm): 3.7 x 7.0 x 25.0WARNING: CHOKING HAZARD - Not suitable for children under 36 months. Choking hazard (small parts).
Get festival season ready with The Who. ; Slim-fit tri-blend tee sports a vintage graphic at front. ; Rib crew neck and short sleeves. ; Straight hemline. ; 50% polyester, 38% cotton, 12% rayon. ; Machine wash cold, tumble dry low. ; Made in the U.S.A. and Imported. Measurements: ; Length: 29 in ; Product measurements were taken using size MD. Please note that measurements may vary by size.
If youve got a wild side then these are the Crown Joules for you. Featuring a whole host of animals from stags to horses and dogs to pigs. Crafted from super soft cotton that contains a little stretch for a lot of comfort.
\26in Tall, 4 legs covered in sisal, Sisal provides alternate scratching texture your cat will love, Hole in bottom so your cat can climb inside for a cozy home, Poly whiskers provide hours of entertainment for your cat, High quality materials, Excellent craftsmanship. Molly is a unique cat toy that is a favorite among cats and their owners. High quality materials and craftsmanship alone make
This medium (2.5), easy to clean rubber ball whistles in flight; adding another fun element to an what would otherwise be an ordinary game of fetch! Whistler ball is compatible will all Chuckit! Medium ball launchers.


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Background & Experience
Mark R. Dycio, President of the Law Office of Mark R. Dycio, P.C. (dba Dycio & Biggs) was born in Biddeford, Maine on April 11, 1962. Mr. Dycio is the principal of the firm bearing his name, consisting of six lawyers in Fairfax, Virginia. Mark has handled numerous cases in the state of Virginia as well as the United States at both the state and federal levels from inception through trial, inclusive of appeals in both federal and state courts. Mr. Dycio’s areas of concentration lie in civil and criminal litigation and expand to include corporate law, arbitration, tobacco advisement and alcoholic beverage control representation.
Mr. Dycio was admitted to the bar in 1990 through the Virginia and U.S. Court of Appeals, Fourth Circuit and has been recognized for his achievements and vast legal abilities by his peers. Mr. Dycio appears before the judiciary on a regular basis. Mr. Dycio has represented clients throughout the United States and has been admitted Pro Hac Vice in multiple jurisdictions. Previous representations include national corporations, law firms, various departments of the United States, and the office of the Independent Counsel. In addition, he has represented parties involved in Alcoholic Beverage Control “ABC” matters at all levels, both civilly and criminally, from manufacturing to sale, franchise to independent, distribution to retail, and the drafting of proposed legislation.
Mr. Dycio’s firm has achieved the honor of representing individual attorneys and law firms evidencing the respect of his peers.

domain: law


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‘I’m Not Just White, I’m French’
Constant Assertions of Individuality are Akin to ‘White Lives Matter’
In the last few years, I’ve encountered an interesting response from certain white people when discussions of race and racism are broached: the clarification of specific European culture. In other words, when racism becomes a topic of conversation, some white people deflect the conversation by referring to the country in Europe from which their ancestors originated. This operates as more than casual conversation, shifting the topic from the all-important political and economic relevance of ‘whiteness’ and collective oppression to individual experiences, which results in avoidance of the original topic, white privilege. White supremacy’s long-standing, highly-entrenched reality was the direct, desired result of European dominance worldwide; this fact requires we focus on collective behaviors rather than switching topic to ‘individuality,’ which always favors white people since they are the only ones considered truly individual. As such, when white people respond to discussions about structural racism and white supremacy with statements about their own personal background, they engage in a form of distraction and gas-lighting which replicates their privilege by avoiding the discussion.
When discussions about white supremacy and racism ensue, the ‘liberal’ options are to discuss these issues in a cogent, honest fashion regardless of who may or may not feel guilt or to avoid the topic with a distractor, lie, or — if all else fails — -outright denial. When the denial includes oneself, it is politely called ‘white ignorance’ to spare white people any sort of active responsibility for these conclusions. When white people respond to discussions about racism with the statement, “I’m not just white, I’m from [fill in the blank with European country]” they paraphrase “White Lives Matter.” This is problematic because white lives have always mattered in the last 500 years or so: white people have always been granted individuality, the ‘right’ to be the backdrop against which all others are compared (and rendered, inevitably, inferior), and the ‘right’ to look down on others while simultaneously denying that they are doing so, AKA white ‘ignorance.’ As a result, statements specifying one’s cultural background, at least in the context of discussions about racism and equality, function to distract from the discussion point: white supremacy and the advantage that all white people have, collectively, in a white supremacist culture. As a result, these statements support white supremacy by reorienting the discussion away from collective reality.
Discussions about racism and white supremacy are discussions about POWER, not culture. White supremacy was invented for one reason only: so that a minority of human beings could have power to dominate, oppress, and subordinate the majority. This establishment, active for 500 or so years, continues. Therefore, any discussions about racism and white supremacy must focus on power and the way in which this egregious invention has, while falsely elevating a minority, greatly oppressed the majority worldwide, for about half an era. This discussion point is necessary because it is the heart of white supremacy: power and dominance on a social level, in a collective context. When white people shift the conversation to individuality — that is, their individual background — they distract from the acknowledgement of collective responsibility that all WHITE people have, regardless of their native country. As a result, this ‘I’m not just white, I’m [so-and-such individual]’ type of response simply shirks collective responsibility. In the context of power, being white is not a ‘just,’ it is a massive advantage. Avoiding this reality, and the discussion that must ensue to eliminate white supremacy, is a form of denial.
In this act, the white person deflecting the conversation point — -power and the way in which resources are distributed in society, not just in the US but worldwide, as a direct result of white supremacy — is actively avoiding the conversation which must take place in order to move forward. The necessary conversation in this context includes collective accountability, and avoiding it comprises active racism because it supports a racist status quo. Robin DiAngelo, in White Fragility, underlines the types of responses that many white people have when faced with the reality of their privilege: “I will be the judge of whether racism has occurred, and “How I am perceived by others is the most important issue.” (p121.) In addition, she reasserts that a focus on individuality denies the historical context of slavery and, as a result, denies dominant culture and white privilege.
In a white supremacist society, individualism is only available to one group: white people. All white people. Whether or not that white person is from France, England, Sweden, or Poland is irrelevant when it comes to discussions of current realities and historical power: all white people have it. There were a few groups of white people who, for two generations or so, were considered ‘not white.’ This period was relatively brief — perhaps two generations — and is discussed with inordinate focus. Other groups of people have NOT entered the realm of white despite multiple generations in this country. Far East Asians, Indians, Middle Easterners, Pakistanis, etc are not treated like white people despite, in some cases, 4+ generations in the US. Europeans are considered white; a brief period of semi-exclusion relative to the 20+ generations of white supremacy is hardly comparable to the experiences of non-Europeans. This fact is another distractor: ultimately, Europeans become white. Others don’t (with the exception of Russians.) Responding to discussions about racism with an assertion of one’s individuality is a form of complicity with white supremacy because it dissolves the collective responsibility that all white people have to address their racial privilege.
This attitude, a product of ‘backlash,’ allows that white person to assert individuality — which he/she/they already have — at the slightest hint of collective responsibility. In other words, the white person, already deemed important enough to be individual on the basis of being white, will not tolerate any erosion of this privilege AND simultaneously cloaks it in the ‘innocent’ statement of ‘culture:’ ‘I’m only talking about my background; why can you talk about couscous and I can’t discuss my culture?’ Because we aren’t talking about couscous when we’re talking about racism: this discussion is about power, and how white people automatically get more of it, permanently, just for being born.
Discussions about racism and white supremacy are discussions about structural realities, collective behaviors, and allowance for continued supremacy through active denial. This active denial is carefully cloaked in the term ‘white ignorance’ which proactively coddles white people by implying that both awareness and intent are lacking without commenting on the impact to POC of this constant, embedded white privilege. Note that, despite multiple efforts for centuries to avail white people of these realities (Douglass, Baldwin, Coates offer examples from a wide range of time), it is still called ‘ignorance.’ How can this be ‘ignorance’ when the truth has been expressed for more than a century? It isn’t: it is, at some level, active denial.
“If politics in the West is ever to return to normal rather than becoming even more polarized, white interests will need to be discussed…In an era of unprecedented white demographic decline it is absolutely vital for it to have a democratic outlet.” Eric Kaufmann
Eric Kauffman, a Canadian white male teaching at a British college, has published a book called Whiteshift which appears to broadly encompass the dictates of backlash and the way in which white people assert their individuality, framing them as victims. He discusses this as if white supremacy is a norm and any erosion of it an unfair deletion of ‘white interests.’ In this quotation, for example, he writes, “If politics in the West is ever to return to normal rather than becoming even more polarized, white interests will need to be discussed…In an era of unprecedented white demographic decline it is absolutely vital for it to have a democratic outlet.” (https://www.newyorker.com/news/q-and-a/a-political-scientist-defends-white-identity-politics-eric-kaufmann-whiteshift-book.)
Here, he illustrates a significant bias in the way he phrases these sentences, focusing on white individuality as if it is the norm. That is, the ‘West’ should ‘return to normal’ implies that the last 500 years of oppression is normal(!); his words imply that polarization comes from nonwhite peoples. His statement re: white interests is framed as if white interests are not being met instead of underlining the fact that white interests are the only ones that have mattered for the last few centuries. He neglects to mention that America’s true ‘normal’ was Native American/Indigenous peoples, and that European occupation was a brutal disruption of this norm.
Kauffman’s opinions are a paean to white fragility: anything which erodes white power must reorient it such that white power is maintained. He does this through a reassertion of white individuality, as if the past was exceptional and any erosion of it must be compensated for by a reminder that, yes of course, white people are overtly individual. The real individuals. Kauffman tells the reader that historical emphasis on the individuality of white people is desirable without any mention for the way in which this stance has oppressed the entire rest of the human race.
“The singularity of whiteness is the main reason Caucasians object to any mention of racism without ‘Not all white people.’ They do not tolerate the collective whiteness that they simultaneously use to excuse mass incarceration, racial profiling, police brutality.” Michael Harriott
Michael Harriott, writing for The Root, states “The singularity of whiteness is the main reason Caucasians object to any mention of racism without ‘Not all white people.’ They do not tolerate the collective whiteness that they simultaneously use to excuse mass incarceration, racial profiling, police brutality.” (https://www.theroot.com/the-privilege-of-white-individuality-1819184476) He hits the nail on the head when he states that white people, as a rule, do not tolerate collective whiteness. They react to this by asserting their individuality as a reminder that they are the real individuals. One way this is done is by referring to individual cultural backgrounds as if this cultural specificity will erase collective privilege. Which, of course, it doesn’t. To acknowledge collective whiteness would be to acknowledge white privilege, oppression, unfair benefit. The only moral response to this acknowledgement would be return of unfairly-obtained resources. It appears that, collectively, most white people will avoid this inevitable humane response even at the cost of self-reflection and self-honesty.
An assertion of one’s individuality in a context in which it already exists is a form of psychological homeostatic maintenance: the individual white person helps to maintain white supremacy by refusing to focus on collective, social realities. Ultimately, this is a refusal to take responsibility for the choice of passivity which continues to maintain this power. Discussions about racism and white supremacy are not about pierogies, tours of the Eiffel Tower, or a visit to Harrod’s for a nice bottle of Penhaligons perfume; they are discussions about power, money, and the way white people collectively have most of it as a result of historical brutality and thievery and current similar behaviors paired with a denial of them. Sidelining these important discussions by channel-shifting the conversation to individuality and culture — much ‘nicer’ topics — only serves to maintain the status quo.
“Chauvinist legitimation narratives that portrayed European-based societies as the progressive vanguard of the human race produced an almost invisible support structure for the collective self-esteem of all those who could claim such a European identity…” Linda Martin Alcoff
Linda Martin Alcoff summarizes this assertion of individuality and its connection to European identity in a few brief sentences: “Chauvinist legitimation narratives that portrayed European-based societies as the progressive vanguard of the human race produced an almost invisible support structure for the collective self-esteem of all those who could claim such a European identity… The “new” or “modern world” legitimation narratives proclaimed that European-based societies led the world in maximizing individualism.” (Visible Identities: Race, Gender, and the Self, p 285; my emphasis). This invisible support structure, a collective advantage to white people worldwide, is clear to POC’s who do not get this support. By denying this collective support exists, white people deny that there is a genuine moral problem in society which gives them benefit while depriving others of it.
By focusing on white individualism in discussions about racism, white people are able to reassert this superiority to maintain the ‘homeostasis’ of white superiority. But this stance actively ignores the derogation which POC’s must tolerate in order for white people to benefit collectively by refusing to acknowledge social realities. By re-centering that white person’s individuality, he/she/they avoid discussing privilege AND reassert their manifest-destiny given right to be the real individuals. So: ‘I’m not just white, I’m (fill in the blank with European background.)’ But in reality, any assertion of individuality which doesn’t include discussion about the derogation of POC which has resulted from white supremacy— simply isn’t comprehensive.
Any assertion of white individuality in the context of discussions about racism is inappropriate when considered comprehensively. The deep-seated need that many white people seem to have to shift the conversation from collective racism to individuality lacks accountability for collective unearned advantage and is ultimately a defense mechanism that upholds the status quo. These advantages come at the expense of a wide range of POC, and in particular, Native/Indigenous Americans and African-Americans. This lack of accountability should be negotiated internally rather than pushed outwards and shoved down the throats of POC’s in the form of fragility, defensiveness, and a reassertion of individuality which, compared to all POC, white people already have in droves. Unfortunately, though, it is not: rather, this attitude is used to defend power.
When white people resort to discussing their specific European background in the context of a discussion on racism, they distract, they gaslight, they avoid, they deny: they use their fragility to avoid dealing with the truth. They do not deal directly with the issue at hand: white privilege, collective white behaviors that maintain unearned benefits of all sorts in white hands, and the way in which their fragility continues to support the status quo and white supremacy.
This denial is no different from active white supremacy and should be negotiated the same way: not as innocence or ‘ignorance,’ but as a very real, passive-aggressive approach to the maintenance of white dominance.


From the design doc, mob files are not involved in the normal HBase compaction process. This means deleted mobs would still take up space and that we never really merge mob files that accrue over time. Currently, MOBs depend on two external tools:
1) A TTL cleaner that removes mobs that have passed their TTL or exceeded minVersions.
2) A 'sweep tool' cleaner that remove mobs that have had their references deleted and merges small files into larger ones.
Today the tools are triggered by admins. The longer term goal would be to integrate them into hbase such that by default mobs are cleaned. The tools will be preserved however so that advanced admins can disable automatic cleanups and manually trigger these compaction like operaitons. #1 would likely be a chore in the master while #2 requires some design work to integrate into hbase.


on 12 February 2016
Johnny Mathis was born on September 30, 1935 in Gilmer, Texas, but raised in San Francisco, California. He was discovered by George Avakian of Columbia Records. He initially recorded as a jazz-styled singer. Columbia A&R executive Mitch Miller switched him to singing pop ballads. Johnny has 53 charted singles on Billboard Hot 100. I have just finished a Complete Singles Discography, and have compiled a total of 132 singles (264 songs, uncharted & uncharted, US & UK) from 1957 to 2003. Amazing feat! He also has 76 charted albums on Billboard 200. In reality, he has released over 100 albums. His label was mainly on Columbia although he founded his own production company, Global Records, for a four-year stay at Mercury Records from 1963 to 1967. On November 17, 2014, a Complete Global Albums Collection box set (13 CDs, covering all 10 previous albums, plus one unreleased and 2 CDs on singles, will be released. As to his vast Columbia album output is another kettle of fish altogether.
This 4 CD set contains 7 complete albums by Johnny Mathis on Columbia, with 104 songs:
01 JOHNNY MATHIS (1956)
02 WONDERFUL WONDERFUL (Columbia 1028)(4/1957)
03 WARM (Columbia 1078)(2/1957)
04 GOOD NIGHT, DEAR LORD (Columbia 1119)(10/1958)
05 SWING SOFTLY (Columbia 1165)(6/1958)
06 MERRY CHRISTMAS (Columbia 1195)(1958)
07 OPEN FIRE, TWO GUITARS (Columbia 1270)(4/1959)
1 It is nice to have 7 early Johnny Mathis albums in one set.
2 The sound is very well remastered, clean with no hiss.
3 All the songs are original versions, no re-recorded versions.
4 The price is reasonable, especially from sellers.
1 There are no bonus tracks. Surely, with a lot of extra space left on the discs, singles of that era (a and b-sides) can be included for added value.
2 There is no booklet, no label & number and chart positions.
3 There are no pictures of album covers.
Real Gone Music, a reputable reissue label from UK, has released 2 Volumes of 7 Classic Albums on Johnny Mathis. (My review of Volume 2 is found elsewhere). Generally, his albums from the 70s and 80s are not available on CDs yet. In this current set, all the albums are familiar to most of us. It is nice to have them all in one set with good sound. If you are a Johnny Mathis fan, this is no brainer. This set is also recommended to all music lovers.