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The potential and limitations of induced pluripotent stem cells to achieve wound healing
Jolanta Gorecka1,
Valentyna Kostiuk1,
Arash Fereydooni1,
Luis Gonzalez1,
Jiesi Luo2,
Biraja Dash3,
Toshihiko Isaji1,
Shun Ono1,
Shirley Liu1,
Shin Rong Lee1,
Jianbiao Xu1,
Jia Liu1,
Ryosuke Taniguchi1,
Bogdan Yastula1,
Henry C. Hsia3,
Yibing Qyang2,4,5,6 &
Alan Dardik1
Stem Cell Research & Therapy volume 10, Article number: 87 (2019) Cite this article
Wound healing is the physiologic response to a disruption in normal skin architecture and requires both spatial and temporal coordination of multiple cell types and cytokines. This complex process is prone to dysregulation secondary to local and systemic factors such as ischemia and diabetes that frequently lead to chronic wounds. Chronic wounds such as diabetic foot ulcers are epidemic with great cost to the healthcare system as they heal poorly and recur frequently, creating an urgent need for new and advanced therapies. Stem cell therapy is emerging as a potential treatment for chronic wounds, and adult-derived stem cells are currently employed in several commercially available products; however, stem cell therapy is limited by the need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo. Induced pluripotent stem cells (iPSC) are an exciting cell type with enhanced therapeutic and translational potential. iPSC are derived from adult cells by in vitro induction of pluripotency, obviating the ethical dilemmas surrounding the use of embryonic stem cells; they are harvested non-invasively and can be transplanted autologously, reducing immune rejection; and iPSC are the only cell type capable of being differentiated into all of the cell types in healthy skin. This review focuses on the use of iPSC in animal models of wound healing including limb ischemia, as well as their limitations and methods aimed at improving iPSC safety profile in an effort to hasten translation to human studies.
Wound healing is a complex physiological response to the disruption in the normal architecture of the protective skin barrier. It involves the spatial and temporal coordination of various cell types and cytokines and is divided into three distinct phases: inflammation, proliferation, and remodeling [1, 2]. This complex and delicate process is prone to dysregulation secondary to local and systemic factors that can lead to failure of healing and progression to chronicity.
Immediately post-wounding, hemostasis is achieved by platelet aggregation and initiation of the coagulation cascade. Chemotactic signals including platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) are released and attract macrophages, neutrophils, and fibroblasts to the wound bed. Neutrophils and macrophages clear the wound of any bacteria and debris and elaborate further cytokines including interleukin 1 (IL-1), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-α), all of which promote cellular recruitment and proliferation. A provisional matrix composed of fibronectin and hyaluronic acid (HA) is synthesized and secreted, upon which epithelialization occurs with the aid of stem cells from hair follicles and adjacent epidermis. Eventually, fibroblasts convert fibronectin-based microfibrils into collagen-enriched fibers. During these events, angiogenesis results in re-vascularization of the wound [3,4,5,6].
Chronic cutaneous wounds, such as those seen in diabetic foot ulcers (DFU) and pressure ulcers, contribute significantly to patient morbidity and mortality. They affect over six million Americans annually and cost upwards of $25 billion [7]. Nearly every stage of wound healing becomes dysregulated in diabetic wounds, contributing to the poor healing of DFU. Diabetic individuals suffer from impaired growth factor production, decreased angiogenesis, depressed macrophage function and collagen accumulation, poor keratinocyte and fibroblast migration and proliferation, and impaired stem cell homing [1, 8,9,10,11].
The gold standard of chronic wound management involves careful diagnosis of etiology, control of infection, optimization of vascular inflow to reduce ischemia, debridement of nonviable tissue, and offloading of pressure. Despite optimal care, only 50% of DFU heal within 12–20 weeks and 50% recur within 18 months. As such, novel and improved methods of wound healing are urgently needed [12,13,14,15,16].
Stem cell therapy has emerged as an exciting potential therapy for wound healing. When transplanted into a wound, stem cells act in a direct and paracrine manner to promote cell recruitment, immunomodulation, extracellular matrix remodeling, and angiogenesis by secretion of cytokines and growth factors [17,18,19]. Adult-derived cells, such as mesenchymal stem cells (MSC), have shown potential in accelerating healing of chronic wounds, particularly in the diabetic population where populations of MSC are deficient [20,21,22,23,24]. MSC have shown efficacy in multiple clinical trials of DFU healing and are currently included in several commercially available topical products including Grafix and Stravix [25,26,27]. Embryonic stem cell (ESC)-derived MSC are superior to adult-derived MSC, as they retain their potency, show a high proliferative ability, and display a consistent phenotype [28]. However, use of these cells is limited by the ethical issues associated with the use of embryonic stem cells, need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo [29].
Induced pluripotent stem cells in chronic wound healing
Induced pluripotent stem cells (iPSC) represent a groundbreaking innovation for adult-derived stem cells that carry enhanced therapeutic and translational potential. First developed in 2006, iPSC are pluripotent stem cells derived from adult somatic cells. They are reprogrammed into a pluripotent state in vitro by induced expression of four transcription factors including Oct4/Sox2/c-Myc/KLF4 or Oct4/Sox2/NANOG/LIN28 [30,31,32]. Although their initial derivation required retroviral transfection, recent progress in stem cell techniques allows for their generation with the use of non-integrative techniques, improving their safety profile (Table 1) [33,34,35].
Table 1 Current methods for generating induced pluripotent stem cells
Similar to embryonic stem cells, iPSC are pluripotent, have the potential for self-renewal, and can differentiate into any adult cell type. iPSC have certain advantages over other stem cell types in models of regenerative medicine and wound healing. Because they are derived from adult somatic cells, and not embryos, iPSC are not associated with the ethical dilemmas surrounding the use of embryonic stem cells. They are easily harvested from cutaneous sources such as skin fibroblasts, obviating the need for invasive harvesting procedures such as bone marrow or adipose tissue biopsies. iPSC are pluripotent and can therefore be differentiated into any adult cell type, enhancing their potential in models of various disease processes. Since iPSC can be derived in principle from any adult tissue including skin, the potential pool of source cells is many orders of magnitude greater than other stem cell types. Lastly, iPSC can be transplanted in an autologous fashion to avoid immunogenicity, enhancing their in vivo survival [36, 37].
iPSC are currently being evaluated in pre-clinical studies of three-dimensional (3D) organ printing, wound healing, and angiogenesis [38]. Although much remains to be learned about their safety and generation methods prior to use in humans, iPSC are already being investigated in clinical trials of disease modeling including cardiomyopathy, autism spectrum disorder, coronary artery disease, oncology, and cystic fibrosis [38].
Because they can differentiate into descendants of all three germ layers, iPSC-derived terminally differentiated cells have the potential to enhance each of the phases of diabetic wound healing through their paracrine and direct cellular effects (Table 2) [38]. During the inflammatory phase, iPSC-derived cells can secrete growth factors and cytokines, counteracting the suppressed cytokine secretion profile seen in diabetic patients [39, 40]. This results in recruitment of macrophages as well as proliferative cells including fibroblasts and keratinocytes, which are known to be deficient in chronic wounds [41,42,43,44]. Direct application of stem cells into the wound bed also mitigates the impaired homing potential of progenitor cells into diabetic wounds [45]. In the proliferative phase, potential iPSC-derived cells include endothelial cells, smooth muscle cells, fibroblasts, pericytes, keratinocytes, or MSC [46, 47], subsequently promoting angiogenesis [43] and increasing collagen deposition [42]. Because the remodeling phase is highly dependent on functional myofibroblasts, their recruitment during the proliferative phase is essential to the last stage of wound healing. Finally, unlike MSC, iPSC retain the ability to differentiate into keratinocytes [46].
Table 2 Dysregulation of wound healing in diabetic wounds
The following sections review the use of iPSC in animal preclinical studies of non-ischemic and ischemic wound healing and the limitations that need to be overcome prior to clinical use. Major findings of studies relating to cutaneous wound healing in a murine model are outlined in Table 3.
Table 3 Induced pluripotent stem cells in wound healing
Human-induced pluripotent stem cell-derived endothelial cells
Angiogenesis is a vital component of wound healing, as it reestablishes perfusion to injured tissues and delivers key nutrients. Unfortunately, angiogenesis is diminished in the hypoxic environment of chronic wounds. Additionally, diabetic patients have reduced homing potential of endothelial progenitor cells to sites of injury, further suppressing their angiogenic potential. Endothelial cells are critical for vessel formation and upregulation of VEGF expression. As such, delivery of human-induced pluripotent stem cell-derived endothelial cells (hiPSC-EC) holds great promise for accelerating diabetic wound healing [8, 9].
Several mechanisms by which hiPSC-EC improve wound healing have been identified thus far. Increases in wound perfusion and vessel density may be seen within the first 4 days following treatment in hiPSC-EC-treated wounds in a murine model [42]. hiPSC-EC-treated wounds have increased collagen deposition and macrophage number. Angiogenic gene expression, including endothelial cell adhesion molecule and VEGF, are also significantly upregulated. Cooperation of hiPSC-EC and human-induced pluripotent stem cell-derived smooth muscle cells (hiPSC-SMC) may also be important for neovascularization in dermal wounds. In vitro, hiPSC-EC elaborate more VEGF, epidermal growth factor (EGF), and FGF-4 compared to primary cells and are able to promote the chemotactic migration of smooth muscle cells [43]; in vivo, co-implantation of hiPSC-EC and hiPSC-SMC leads to greater vascular perfusion, significantly smaller open wound areas, and greater arteriole density compared with mice treated with hiPSC-EC alone [43].
The optimal delivery platform for iPSC and enhancement of their in vivo survival in chronic wounds is currently under investigation, with several biomimetic materials showing promise [48, 49]. The use of hyaluronic-acid (HA) hydrogel constructs containing hiPSC, endothelial progenitor, and early vascular cells has been shown to be an effective method of stem cell delivery [48]. These vascular constructs containing hiPSC derived from both healthy and type I diabetic patients accelerated the recruitment of host macrophages to the matrix and rapidly integrated into wound bed neovessels. Neovessels and macrophages in turn increased angiogenic factors, leading to increased angiogenesis and rapid wound closure.
One study showed there was no significant difference between healing in wounds treated with hiPSC derived from healthy versus type I diabetic donors in terms of both healing rate and time to reach maximum rate [48]. Although these findings need to be confirmed with cells from type II diabetics, these results hold promise for autologous transplant in diabetic patients. In murine models, iPSC-EC from obesity-induced diabetic mice showed defective function compared to iPSC-EC from healthy controls [50], suggesting further studies comparing iPSC derived from healthy and diabetic sources.
As with many stem cell approaches, the low rate of in vivo cell survival has been a major limitation in wound healing. The in vivo lifetime of hiPSC-EC increased by culturing them on electrospun polycaprolactone (PCL)/gelatin scaffolds; this mode of cell delivery also increased blood perfusion and arteriole density in the tissue surrounding hiPSC-EC-seeded scaffolds compared to controls [49]. Similar to observations by Shen et al. [48], the local immune response involving macrophages was increased by twofold in the presence of a scaffold alone, and this was further enhanced by the addition of hiPSC-EC, although macrophage subtype was not evaluated.
Together, these studies confirm that hiPSC-EC not only accelerate wound healing via increased angiogenesis, but have potential to do so to a greater extent than primary cells. Although equivocal in animal-derived iPSC, some studies examining hiPSC derived from diabetic humans suggest that they are not inferior to those from healthy donors, potentially allowing diabetic patients to undergo autologous transplant of their own cells with equal regenerative potential. This finding broadens the scope of hiPSC translational potential. Although the optimal delivery vehicle and hiPSC niche are yet to be elucidated, early studies show promising results at increasing cell survival in vivo, while advances in hiPSC-EC differentiation are becoming more efficient and rapid [51, 52].
Human-induced pluripotent-derived fibroblasts
During wound healing, fibroblasts are responsible for the production of collagen, fibronectin, and proteoglycans, which form the extracellular matrix on which re-epithelialization and healing occur [53]. Fibroblasts isolated from DFU have decreased proliferation potential in response to growth factors [54], leading to delayed wound healing. As such, reconstitution of a healthy fibroblast population in DFU wounds can promote wound closure.
Kashpur et al. [55] found that hiPSC-derived fibroblasts from DFU are better at facilitating wound closure compared to primary DFU fibroblasts. hiPSC-derived cells from diabetic and healthy patients are more similar to each other than the cell lines from which they were derived and have similar gene expression. Gene ontology showed that hiPSC differ compared to primary cells in genes responsible for cell migration, cell proliferation, extracellular matrix organization, response to endogenous stimuli, developmental processes, and cell adhesion [55]. In functional assays, hiPSC-derived cells showed improved migratory properties in two-dimensional culture, although proliferation was unchanged [55].
In vivo, self-assembled 3D extracellular matrix tissues from hiPSC-derived fibroblasts improved re-epithelialization in a diabetic mouse model, when applied topically [55]. Tissues constructed from primary healthy foot fibroblasts significantly improved wound healing compared with primary fibroblasts of DFU origin. hiPSC derived from healthy and diabetic fibroblasts also accelerated wound healing to a greater extent than primary DFU-derived fibroblasts [55]. Therefore, hiPSC fibroblasts from diabetic subjects appear to have similar wound healing potential as those derived from healthy donors, suggesting their translational potential.
Human-induced pluripotent-derived mesenchymal stem cells
MSC are multipotent stem cells that promote cutaneous healing by homing to wounds and differentiating into myogenic, chondrogenic, osteogenic, and adipogenic derivatives. MSC also produce growth hormones that drive angiogenesis and re-epithelialization, while mobilizing the resident stem cell niche and contributing to favorable immunomodulation [21]. However, MSC derived from diabetic rats appear to have impaired proliferation, differentiation, and expression of pro-angiogenic factors, and lack of ischemic wound healing potential [56]. Thus, repopulating chronic wounds with human-induced pluripotent stem cell-derived MSC (hiPSC-MSC) may have better potential to accelerate healing.
Nakayama et al. [57] successfully established hiPSC-MSC from keratinocytes of healthy individuals and patients with epidermolysis bullosa and studied their wound healing potential in a nude mouse model [57]. With subcutaneous and intravenous delivery, hiPSC-MSC successfully secreted human type VII collagen at the dermal-epidermal junction. Intravenous injection of cells led to increased wound healing as measured by epithelialization. However, cells were eliminated from the wounds by 2 weeks.
Human-induced pluripotent stem cell-derived extracellular vesicles
Although pluripotent iPSC hold tremendous promise in wound healing and regenerative medicine, their use in clinical trials is currently limited due to their teratogenic potential. Although teratoma formation after topical transplantation has not yet been studied, subcutaneous injection of differentiated iPSC led to teratoma formation [58]. Thus, harnessing hiPSC potential independent of cellular transfer may prove to be safer. Nano-sized extracellular vesicles containing protein, mRNA, and miRNA (previously known as exosomes) accelerate chronic wound healing similar to hiPSC, but eliminate the risks of teratoma formation as they are devoid of nuclei and therefore incapable of dividing, making them a new and exciting candidate among potential wound healing therapies.
Extracellular vesicles released from hiPSC-MSC facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis [59, 60]. Specifically, hiPSC-MSC extracellular vesicle treatment promotes greater wound closure, faster re-epithelialization, decreased scar width, and higher density of blood vessels in treated animals including diabetic wound models [59, 60]. In vitro, human fibroblasts show greater proliferation, migration, and expression of fibronectin, collagen type I and III, and elastin in the presence of hiPSC-MSC-extracellular vesicles. Similarly, human umbilical vein endothelial cell (HUVEC) exhibit increased migration, proliferation, tubule formation, and branching with hiPSC-MSC-extracellular vesicle treatment [59].
The primary hurdle to overcome before clinical application of hiPSC-derived cells is the elimination of their tumorigenic potential. The aforementioned studies were able to harness the therapeutic potential of hiPSC without obvious negative side effects, a major step in furthering these cells' translational potential.
Human-induced pluripotent stem cells in ischemic wounds
In addition to their therapeutic potential in cutaneous wound healing, iPSC are currently being investigated in multiple disease models of ischemia, including peripheral arterial disease, myocardial infarction, osteonecrosis, and retinopathy. Consistent with findings from cutaneous wound healing studies, the primary driver of iPSC healing in the majority of these models is their pro-angiogenic potential [61]. Although iPSC have thus far been examined in models of peripheral arterial disease, these models have not yet evaluated wound healing in chronically ischemic limbs.
iPSC ameliorate ischemia in models of peripheral arterial disease by reducing inflammation, promoting angiogenesis, and reconstituting viable cellular populations such as endothelial cells. In a nude mouse hind limb ischemia model, hiPSC-EC in conjunction with VEGF reduce inflammation and promote muscular regeneration [62]. hiPSC-EC also improved blood flow to ischemic limbs by increasing the total number of capillaries as well as angiogenic cytokines and growth factors [63]. Compared to induced endothelial cells generated from fibroblasts, hiPSC-EC show similar perfusion recovery, although capillary density in the ischemic muscle was only increased in the induced endothelial cell group [64]. Furthermore, hiPSC-EC enhanced angiogenesis via paracrine signaling in ischemic tissue [65].
In a similar model, when compared to bone marrow-derived MSC, hiPSC-MSC reduced muscle fibrosis, improved ambulatory impairment and tissue loss, and enhanced perfusion [66]. hiPSC-MSC extracellular vesicles also enhance microvessel density and blood perfusion in limb ischemia models. In vitro, these extracellular vesicles activated angiogenesis-related protein expression and promoted HUVEC migration, proliferation, and tubule formation [67]. Similarly, hiPSC-derived pericytes injected into ischemic murine limbs increased the reperfusion of limbs by approximately fourfold by incorporating not only into host vasculature, but also into muscle [68]. This observation demonstrates their potential for differentiation and regeneration of multiple types of ischemic tissue.
The majority of studies employing iPSC in models of peripheral arterial disease have delivered cells or extracellular vesicles via intramuscular (IM) injection with cells suspended in buffer or culture medium [61, 63,64,65,66,67,68,69]. Cell survival was increased when the cells were suspended in a recombinant hydrogel, which may prevent cell membrane damage from the shear stress of injection [70]. Similarly, delivery of cells in a shear-thinning hydrogel for injectable encapsulation and long-term delivery (SHIELD) found that cells were not only protected from syringe shear stress resulting in higher acute cell survival, but had enhanced in vivo retention [70]. Similar to studies of iPSC in cutaneous wound healing, the optimal delivery method for cells in models of peripheral arterial disease remains to be perfected.
Induced pluripotent stem cells and teratoma formation
Despite their great promise, the use of pluripotent stem cells whether induced or embryonic is limited by their tumorigenic potential [71,72,73]. Because iPSC and human embryonic cells are capable of differentiating into cells from any of the three germ layers, they also carry the potential to form teratomas in the undifferentiated state. For example, in vivo teratoma formation in immunodeficient mice is frequently used as an assay for defining pluripotency [74,75,76]. Because hiPSC and their behavior are complex, the latency, efficiency, and tissue composition of their resultant tumors vary greatly with the number of transplanted cells, site of injection, cell line, and mode of hiPSC derivation. Even among ten commercially available hiPSC cell lines derived in a similar fashion, there were variations in tumor incidence, formation latency, and tumor volumes; these differences may be attributed to different viral insertion sites, as well as acquired mutations [69].
Numerous strategies are currently under investigation aimed at eliminating iPSC teratogenic potential, in addition to the use of extracellular vesicles mentioned above. Cellular differentiation prior to cell transplantation is one approach to decreasing the risk of teratoma formation. For example, cellular-based therapies, such as those used in some wound healing studies, use terminally differentiated cells. This strategy, however, does not eliminate the risk of inadvertent transplantation of residual undifferentiated cells. In fact, multiple studies using neural and chondrogenic derivatives have shown persistent teratoma formation [58, 77, 78]. Further, gene expression patterns from hiPSC-MSC overlap with those from cancer cells, but not corresponding primary cells [79].
Several methods are currently employed for generating iPSC, with the oncogenic safety profile of some superior to others (Table 1). Retroviral vectors were the first to be described, including Moloney murine leukemia virus (MMLV) and lentivirus. However, these viruses integrate into the host genome and require the use of harmful viral particles expressing oncogenes. They are also prone to insertional mutagenesis and are therefore not safe for clinical application. The piggyback transposon, although still integrative, can be excised. Adenovirus, Sendai virus, and plasmid delivered vectors do not integrate into the host genome, but are less efficient and difficult to clear from host cells. Plasmids, small plasmids, and episomes are safer than viral vectors, but some genome integration has been observed. By far, the safest reprogramming methods are those which employ the use of RNA, protein, and small particle chemical delivery, all of which are transgene-free. Unfortunately, these methods are the least efficient and slowest; nonetheless, they are being employed with greater frequency [34, 35].
Other modes of eliminating iPSC oncogenic potential are being investigated. Cells are now successfully reprogrammed without the use of c-Myc, the most oncogenic Yamanaka factor [80]. Small molecules including quercetin and YM155, which target anti-apoptotic signals such as survivin, have been successfully used to eliminate the undifferentiated cells in a mixed population in vitro [81]. Similarly, inhibitors of lysine-specific demethylase 1, deregulated in teratogenic cells, prevent tumor formation [82]. Pluripotent cell-specific inhibitors (PluriSIns), including oleic acid synthesis inhibitors, are now commercially available for the prevention of teratoma formation after the use of undifferentiated cells [83]. Undifferentiated cells capable of teratoma formation can also be distinguished morphologically from their differentiated counterparts to select for differentiated cells only [84]. Brentuximab vedotin, which targets CD30 on undifferentiated cells and induces apoptosis, has been used to eliminate the teratogenic potential of iPSC-derived cardiomyocytes [85]. Together, these techniques have the potential to produce iPSC in safer and more efficient ways, hastening their entry into clinical trials.
iPSC are an innovative and exciting new cell type with potential to revolutionize the fields of regenerative medicine, inherited genetic disease, and drug therapy. hiPSC hold great promise to accelerate chronic wound healing, with increased healing and reperfusion following wounding or ischemia in rodent preclinical models. Although much has been learned about iPSC generation and optimization in the short time since their development, their safety profile, particularly in relation to tumorigenic potential, remains to be understood in sufficient detail to allow clinical translation. In addition, hiPSC can be derived from patients with chronic diseases and reprogrammed into cells functionally resembling those derived from healthy individuals. However, iPSC-EC derived from obesity-induced diabetic mice showed decreased healing and angiogenic capacity, and thus, further studies will be required to understand the differences between hiPSC derived from diseased and healthy donors.
Major hurdles must be overcome before iPSC use in humans becomes possible. Methods for generating hiPSC with non-integrative technology, preferably by protein and small particle transfer, must become more efficient and speedier. Standardized protocols for teratoma formation assays as proof of pluripotency must be developed in order to derive meaningful conclusions about cell lines. The optimal platform for delivery of hiPSC into a wound, including the ideal niche to prolong cell survival and intracellular signaling, needs to be determined. New methods for eliminating undifferentiated cells capable of tumorigenic potential prior to cellular transplant are necessary. Although studies have examined the tumorigenic potential of cells injected directly into murine tissues, no study to date has examined this potential after cutaneous application of hiPSC. Thus, further animal studies to evaluate the safety and efficacy of iPSC are crucial prior to their translation into humans, including large animal models that more closely mimic human skin [86]. Lastly, since the therapeutic potential of hiPSC appears to be mainly driven by their paracrine effects, the role of extracellular vesicles, which entirely eliminate tumorigenic potential, should be understood.
DFU:
EGF:
FGF:
HA:
hiPSC-EC:
Human-induced pluripotent stem cell-derived endothelial cell
hiPSC-MSC:
Human-induced pluripotent stem cell-derived mesenchymal stem cell
hiPSC-SMC:
Human-induced pluripotent stem cell-derived smooth muscle cell
HUVEC:
Human umbilical vein endothelial cell
IL-1:
Interleukin 1
Intramuscular
MMLV:
Moloney murine leukemia virus
PCL:
Polycaprolactone
PDGF:
Shear-thinning hydrogel for injectable encapsulation and long-term delivery
Tumor necrosis factor alpha
VEGF:
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Shen YI, Cho H, Papa AE, Burke JA, Chan XY, Duh EJ, et al. Engineered human vascularized constructs accelerate diabetic wound healing. Biomaterials. 2016;102:107–19.
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Gu M, Mordwinkin NM, Kooreman NG, Lee J, Wu H, Hu S, et al. Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism. Eur Heart J. 2015;36(13):806–16.
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Loots MAM, Kenter SB, Au FL, van Galen WJM, Middelkoop E, Bos JD, et al. Fibroblasts derived from chronic diabetic ulcers differ in their response to stimulation with EGF, IGF-I, bFGF and PDGF-AB compared to controls. Eur J Cell Biol. 2002;81(3):153–60.
Kashpur O, Smith A, Gerami-Naini B, Maione AG, Calabrese R, Tellechea A, et al. Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes. FASEB J. 2018. https://doi.org/10.1096/fj.201801059.
Kim H, Han JW, Lee JY, Choi YJ, Sohn Y-D, Song M, et al. Diabetic mesenchymal stem cells are ineffective for improving limb ischemia due to their impaired angiogenic capability. Cell Transplant. 2015;24(8):1571–84.
Nakayama C, Fujita Y, Matsumura W, Ujiie I, Takashima S, Shinkuma S, et al. The development of induced pluripotent stem cell-derived mesenchymal stem/stromal cells from normal human and RDEB epidermal keratinocytes. J Dermatol Sci. 2018;91(3):301–10.
Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. Functional engraftment of human ES cell–derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 2006;12:1259.
Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015;13:49.
Kobayashi H, Ebisawa K, Kambe M, Kasai T, Suga H, Nakamura K, et al. Editors' Choice Effects of exosomes derived from the induced pluripotent stem cells on skin wound healing. Nagoya J Med Sci 2018;80(2):141–153.
Lai W-H, Ho JCY, Chan Y-C, Ng JHL, Au K-W, Wong L-Y, et al. Attenuation of hind-limb ischemia in mice with endothelial-like cells derived from different sources of human stem cells. PloS One. 2013;8(3):e57876.
Mulyasasmita W, Cai L, Dewi RE, Jha A, Ullmann SD, Luong RH, et al. Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J Control Release. 2014;191:71–81.
Rufaihah AJ, Huang NF, Jame S, Lee JC, Nguyen HN, Byers B, et al. Endothelial cells derived from human iPSCS increase capillary density and improve perfusion in a mouse model of peripheral arterial disease. Arterioscler Thromb Vasc Biol. 2011;31(11):e72–9.
Clayton ZE, Yuen GS, Sadeghipour S, Hywood JD, Wong JW, Huang NF, et al. A comparison of the pro-angiogenic potential of human induced pluripotent stem cell derived endothelial cells and induced endothelial cells in a murine model of peripheral arterial disease. Int J Cardiol. 2017;234:81–9.
Yoo CH, Na H-J, Lee D-S, Heo SC, An Y, Cha J, et al. Endothelial progenitor cells from human dental pulp-derived iPS cells as a therapeutic target for ischemic vascular diseases. Biomaterials. 2013;34(33):8149–60.
Lian Q, Zhang Y, Zhang J, Zhang HK, Wu X, Zhang Y, et al. Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation. 2010;121(9):1113–23.
Hu GW, Li Q, Niu X, Hu B, Liu J, Zhou SM, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res Ther. 2015;6:10.
Dar A, Domev H, Ben-Yosef O, Tzukerman M, Zeevi-Levin N, Novak A, et al. Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation. 2012;125(1):87–99.
Yasuda S, Kusakawa S, Kuroda T, Miura T, Tano K, Takada N, et al. Tumorigenicity-associated characteristics of human iPS cell lines. PLoS One. 2018;13(10):e0205022.
Foster AA. Protein-engineered hydrogels enhance the survival of induced pluripotent stem cell-derived endothelial cells for treatment of peripheral arterial disease. Biomater Sci. 2018;6(3):614–22.
Gutierrez-Aranda I, Ramos-Mejia V, Bueno C, Munoz-Lopez M, Real PJ, Macia A, et al. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem Cells. 2010;28(9):1568–70.
Zhang Y, Wang D, Chen M, Yang B, Zhang F, Cao K. Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. PLoS One. 2011;6(4):e19012.
Gerami-Naini B, Smith A, Maione AG, Kashpur O, Carpinito G, Veves A, et al. Generation of induced pluripotent stem cells from diabetic foot ulcer fibroblasts using a nonintegrative Sendai virus. Cell Reprogram. 2016;18(4):214–23.
Przyborski SA. Differentiation of human embryonic stem cells after transplantation in immune-deficient mice. Stem Cells. 2005;23(9):1242–50.
Prokhorova TA, Harkness LM, Frandsen U, Ditzel N, Schrøder HD, Burns JS, et al. Teratoma formation by human embryonic stem cells is site dependent and enhanced by the presence of Matrigel. Stem Cells Dev. 2009;18(1):47–54.
Cooke MJ, Stojkovic M, Przyborski DSA. Growth of teratomas derived from human pluripotent stem cells is influenced by the graft site. Stem Cells Dev. 2006;15(2):254–9.
Wernig M, Benninger F, Schmandt T, Rade M, Tucker KL, Büssow H, et al. Functional integration of embryonic stem cell-derived neurons <em>in vivo</em&gt. J Neurosci. 2004;24(22):5258.
Saito T, Yano F, Mori D, Kawata M, Hoshi K, Takato T, et al. Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells. Biomed Res. 2015;36(3):179–86.
Zhao Q, Gregory CA, Lee RH, Reger RL, Qin L, Hai B, et al. MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs. Proc Natl Acad Sci U S A. 2015;112(2):530–5.
Wernig M, Meissner A, Cassady JP, Jaenisch R. C-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell. 2008;2(1):10–2.
Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, Shim SH, et al. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A. 2013;110(35):E3281–90.
Osada N, Kikuchi J, Umehara T, Sato S, Urabe M, Abe T, et al. Lysine-specific demethylase 1 inhibitors prevent teratoma development from human induced pluripotent stem cells. Oncotarget. 2018;9(5):6450–62.
Ben-David U, Gan Q-F, Golan-Lev T, Arora P, Yanuka O, Oren Yifat S, et al. Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell. 2013;12(2):167–79.
Nishimori M, Yakushiji H, Mori M, Miyamoto T, Yaguchi T, Ohno S, et al. Tumorigenesis in cells derived from induced pluripotent stem cells. Hum Cell. 2014;27(1):29–35.
Sougawa N, Miyagawa S, Fukushima S, Kawamura A, Yokoyama J, Ito E, et al. Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy. Sci Rep. 2018;8(1):3726.
Grada A, Mervis J, Falanga V. Research techniques made simple: animal models of wound healing. J Invest Dermatol. 2018;138(10):2095–105.e1.
This work was supported by the Association of VA Surgeons Resident Research Award [J.G.], the National Institutes of Health R01-HL128406 [A.D.], R01HL116705 and R01HL132130, DOD 11959515, and Connecticut's Regenerative Medicine Research Fund [Y.Q.], the Yale Department of Surgery Ohse fund [H.C.H.], as well as with the resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, CT.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Vascular Biology and Therapeutics Program and the Department of Surgery, Yale School of Medicine, Yale University, 10 Amistad Street, Room 437, PO Box 208089, New Haven, CT, 06520-8089, USA
Jolanta Gorecka
, Valentyna Kostiuk
, Arash Fereydooni
, Luis Gonzalez
, Toshihiko Isaji
, Shun Ono
, Shirley Liu
, Shin Rong Lee
, Jianbiao Xu
, Jia Liu
, Ryosuke Taniguchi
, Bogdan Yastula
& Alan Dardik
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale School of Medicine, 300 George Street, Ste 773A, New Haven, CT, 06511, USA
Jiesi Luo
& Yibing Qyang
Section of Plastic Surgery, Department of Surgery, Yale School of Medicine, Yale University, PO Box 208062, New Haven, CT, 06520-8062, USA
Biraja Dash
& Henry C. Hsia
Yale Stem Cell Center, Yale University, New Haven, USA
Yibing Qyang
Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, USA
Department of Pathology, Yale University, New Haven, USA
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JG conceived the manuscript; collected, analyzed, and interpreted the data; and wrote the manuscript. VK collected, analyzed, and interpreted the data. AF and LG interpreted the data and wrote the manuscript. BD, TI, SO, SL, SRL, JX, JL, RT, and BY wrote the manuscript. AD, HCH, and YQ analyzed, interpreted, and wrote the manuscript. All authors read and approved the final manuscript.
Correspondence to Alan Dardik.
Gorecka, J., Kostiuk, V., Fereydooni, A. et al. The potential and limitations of induced pluripotent stem cells to achieve wound healing. Stem Cell Res Ther 10, 87 (2019) doi:10.1186/s13287-019-1185-1
Chronic wounds


The Cincinnati EnquirerMichael Gallagher, now a Saugatuck newspaper editor, appears in court in 1998 during a phone-hacking case against him.
An Ohio judge recently expunged the phone-hacking conviction of a West Michigan newspaper editor who was the force behind a 1998 Cincinnati Enquirer series that alleged crimes and worker abuse at Chiquita Brands International.
Michael Gallagher, who leads the Local Observer weekly in Saugatuck and once was the Enquirer's high-profile investigative reporter, now has no criminal record tied to illegally intercepting executives' messages at the banana producing giant, his former newspaper reported this week.
Gallagher did not return a message seeking comment left by The Press.
The 54-year-old journalist worked for a year with another Enquirer reporter to write an 18-page, 21-story series that accused the Cincinnati-based fruit firm of illegal business practices, the paper reported. Chiquita denied all claims in the report.
He stole voice messages during the investigation and the crimes led to his guilty plea and five-year probationary sentence that he successfully complete in 2003.
Gallagher requested his record be sealed and a judge signed off on the legal move that is often granted in non-violent offenses, according to the Enquirer.
The paper fired Gallagher and retracted the series while issuing three front-page apologies. The Gannett-owned paper reportedly paid Chiquita a $14 million settlement.
Gallagher moved to Saugatuck in Allegan County shortly after being dismissed from the paper. He has been with the Local Observer for years.
The Gallagher case has been brought up in multiple reports surrounding phone-hacking by reporters at Rupert Murdoch's now-defunct News of the World.


John Paine is a founder and director of TBK Capital. He is highly experienced in both debt and equity funding. He has spent nearly 40 years in the financial securities industry – 16 of those with Fay Richwhite & Company. He has a wealth of investment banking experience; including arranging loan finance, project analysis, structuring offers for the most effective proportions of debt and equity, and the marketing of those offers to qualified private investors. John holds a B.Sc. and Dip BIA from Auckland University.
Alex Smith is a founder and director of TBK Capital. His background includes 6 years in financial services where he specialised in capital raising and 4 years in consulting & professional services. He has also been involved in numerous market viability studies and new enterprise and product launches including finance companies, import and distribution ventures, and health and nutrition businesses. Alex holds a BA (Hons) from the University of Lincolnshire and Humberside and a BBS from Auckland University of Technology.
Murray Yeates is a founder of TBK Capital. He has been an owner of numerous businesses himself and over the last 10 years worked with hundreds of New Zealand privately owned companies offering advice, services and consultation on business valuation, divestment and acquisition. Murray holds an array of business and management qualifications including a Post Graduate Diploma from Waikato University and an Advanced Professional Certificate on Business Valuation from the University of Western Sydney.
Sandy Hay is a Chartered Accountant and an Associate of TBK Capital. He arranges both debt & equity funding - specialising in the Bay of Plenty & Waikato regions. Sandy has been a successful business owner and operator for nearly 35 years. He has experience in Supermarkets, Service Stations, Multi-Franchised Motor Vehicle Dealerships, Importation, Distribution & Horticulture.


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The New York Times highlights the emotional aspect of news gathering
SPOTTED: The insight behind the ads
The New York Times has launched a campaign that depicts the intense process of producing good quality journalism. To assuage anxieties about media trustworthiness, the ad shows how good reporting can be both factual and gripping, rather than emotionally exploitative. We explore the insights behind the ad and understand how the campaign is rallying against misinformation.
Produced by creative agency Droga5, the 'Truth is Worth It' campaign comprises a series of videos detailing the editorial process at the Times. From reporter Caitlin Dickerson's piece on migrant children being separated from their parents at the US border to David Barstow, Susanne Craig and Ross Buettner's investigation into President Trump's tax schemes, the spots underline the publication's diligent and meticulous journalistic process.
News publications are fighting to re-establish their value
New York Times| YouTube (2018) ©
The New York Times' campaign addresses people's complicated relationship with truth and the media. In the wake of the fake news epidemic and the ensuing trust implosion, news publications have been fighting to re-establish their value. The Times' ads take an interesting approach to this. While they explicitly emphasize the value of truth, facts, and informational integrity – both in the name of the campaign and in the journalistic process – the videos highlight the emotional aspect of news gathering. In doing so, the newspaper recognizes that truth alone might not be compelling enough to push people past a paywall, showing prospective readers that they can have good journalism and content that resonates with them emotionally.
Mira Kopolovic is a behavioural analyst at Canvas8, which specialises in behavioural insights and consumer research. She has a Master's degree in creative industries, which focused on artist-brand collaborations, and spends her spare time poring over dystopian literature.
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If Faisal Islam, Ralph Keyes and the New York Times are to be believed, the Trump candidacy and the vote for Brexit show we've entered a post-truth era – a world where emotion and populism win out over facts and experts. But is it true? And do emotional appeals really trump facts and figures?
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Hotel Sale Deals
Our visit to Blists Hill Victorian Town – Review
We have visited Beamish in the North East of England and St Fagan's in Wales but were curious to see what Blists Hill offered that was different and with children in mind.
We arrived around 11am and parked in an overflow car park. There was a £3 all day parking charge, however, Blists Hill is also a charity. There was a slight queue to gain entry for people purchasing annual tickets but there was a separate till area with no queue for people who just wanted to buy a day pass to Blists Hill.
You head straight from reception into a room with information boards and screens which were informative of life in a working class mining town known as Blists Hill around 1900. We explained to the children they were going to travel back in time to around 1900 and visit a working class Victorian town.
As we walked out of the train station into the Victorian town the girls couldn't believe that they were suddenly back in time as they saw the old fashioned streets, houses and shop fronts.
Our first visit was to Lloyds Bank, where we had to change our modern day decimal money into old money in the form of farthings, halfpennies, pennies, silver threepenny bits and sixpences which we could use to spend around the town of Blists Hill. The bank manager was really engaging with us explaining about the money and how it relates to today's money.
The girls thought this was amazing as they left the bank with their pounds and shillings from the £5.00 each that they changed. There was also a guide to help you convert to the modern money equivalent.
You could use the money to buy goods from the shops in the town.
The 52-acre site is crammed full of the sights, sounds and smells of Industrial England and is much more than a museum, you are truly immersed into the reality of how it would have been to life back in 1900.
There was lots of activities for children to take part in and the girls loved dipping their own candle.
What I really liked about Blists Hill was the amount of interaction that the girls could have with the characters in the town and from the purchases they could make from the many shops in the town.
They bought bread from the bakers, a hand made leather bracelet from the ironmongers and pies, pasties and sausage rolls from the butcher.
At the plasterer they liked spending the time learning how the products were made before choosing their plaster ornaments which we took home to paint to paint.
The activities and produce sold in the town were very reasonable and ranged from 20p to around a few pounds. What the children made or bought have made lovely unique keep sakes and memories.
In the post office the postmaster explained to us how the post office would have operated over 100 years ago and the clothes store was really popular with the girls. They loved trying on the hats before buying handkerchiefs and a lavender scented bag.
The girls, as you may have guessed, loved the sweet shop and enjoyed queuing up and asking the shopkeeper to weigh out 1 and ½ penny worth of sweets (60p). When we were in the shop a pretend policeman and dog came into the shop to solve a crime. It's these little touches which add to the realism to your visit and especially for the girls who thought that were in a town from yesteryear.
The town was very busy during our visit and queues for the fish and chip shop and bakers were extremely long, but I can understand why as the smell from the fish and chip shop was just amazing. We did go back to the bakers later on in the day and purchased some wonderfully tasting fresh bread.
My youngest daughter loved the wood turner's workshop. The craftsman was extremely friendly and interesting and made hand carved wooden birds for both the girls to take home.
A few of the places we visited were the doctors surgery, candle makers, iron mongers, blacksmiths, chemist, printers, post office, grocers and the village pub.
Holly loved getting to smooth Casey the shire horse.
There were many buildings and houses to explore all offering different learning experiences such as the squatter's cottage. Going inside this house was really interesting as it showed the difficult living conditions that the residents faced during this period of our history.
What caught the girls attention was the sign in the bedroom, which said "Children should be seen and not heard" which brought on lots of questions from them asking why and how..
We visited the school in the town which at various times of the day ran Victorian school lessons that you could take part in.
To explore other historic industrial areas of Blists Hill such as the blast furnaces you can ride on the incline railway or take the train into the mine shaft.
The Victorian funfair was brilliant and the girls had so much fun on the chair'o'plane ride. The member of staff who was running the ride was brilliant with the children telling them to kick their legs and flap their arms to go faster and higher which just added to their excitement. They enjoyed this attraction more than a theme park that we had visited the day before.
Blists Hill is not a traditional museum, but a very accurate representation of what life would have been like in Victorian times. Finding a historic attraction that has the ability to engage and educate children is fantastic.
As soon we stepped through the door of the old train station it felt like we were transported back in time and we had such a fantastic day out. As the majority of the attraction is outside do make sure you dress for the weather but we thoroughly recommend a family visit to Blists Hill.
After our visit to Blists Hill we managed to fit in a visit to the UNESCO World Heritage Site of Ironbridge (England's first such structure, cast in nearby Coalbrookdale in 1779) that gives the town its name.
The village is very quaint with chocolate box type of buildings and lovely tea rooms. We enjoyed a late afternoon snack here and a wander through some of the lovely unique shops.
Blists Hills is part of Ironbridge Gorge, a collection of ten varied museums all set close together by the original Ironbridge. We bought an annual passport ticket at a cost of £68 (using our Tesco Clubcard vouchers) for a family of four which provided unlimited access to any of the 10 museums at Ironbridge which I think is really great value
I'm told that Enginuity is amazing too and the kids would have loved the hands-on science learning there, but we ran out of time during our visit. We plan to visit this beautiful area of the country again soon to make the use of our annual pass so we can visit some of the other attractions available at the Ironbridge Gorge musuems.
The Belfry Hotel Review
Our visit to Brunel's SS Great Britain - Review
Lauren November 9, 2016
Exploring Edinburgh Castle with Children
Lauren May 1, 2017
St Fagans National History Museum Cardiff
Lauren November 18, 2016
Our visit to Brunel's SS Great Britain – Review


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Rumold von Konstanz (1051 erstmals erwähnt; † 4. November 1069) war von 1051 bis 1069 Bischof von Konstanz.

Leben und Wirken

Rumolds Geburtsdatum und seine familiäre Herkunft sind unbekannt. Frühneuzeitlichen Überlieferungen zufolge soll er zunächst Mönch im Kloster Einsiedeln gewesen sein. Er gehörte der königlichen Hofkapelle an und wurde von Heinrich III. zum ersten Propst des Stifts St. Simon und Juda in Goslar ernannt, bevor er 1051 den Konstanzer Bischofsstuhl bestieg.

Bischof Rumold starb am 4. November 1069 und fand im Konstanzer Münster seine letzte Ruhestätte.

Nähe zu den Herrschern
Bischof Rumold stand nicht nur Kaiser Heinrich III., sondern auch dessen ältestem Sohn und Amtsnachfolger Heinrich IV. besonders nahe. Sein enges Verhältnis zu den Herrschern zeigt sich nicht nur daran, dass er sich häufig in deren Umgebung aufhielt, sondern auch an dem besonderen Vertrauen, das Kaiserin Agnes dem Konstanzer Bischof entgegenbrachte, indem sie ihre Tochter Mathilde zur Erziehung in seine Obhut gab.

Konflikte
Rumolds Regierungszeit war überschattet von langwierigen Konflikten mit dem Kloster Reichenau und dem Kloster St. Gallen.

Ulrich I., Abt des Klosters Reichenau, bestand auf die erneute Bestätigung des 998 von Papst Gregor V. verliehenen und 1031 von Papst Johannes XIX. erneuerten und erweiterten Privilegs der Reichenauer Äbte, die Abtsweihe unmittelbar vom Papst entgegenzunehmen und die Messe mit Dalmatica und Sandalen, also zwei Ornatsstücken, die eigentlich nur Bischöfen zustanden, zu feiern, obwohl dieses bereits von Bischof Warmann aufgehoben wurde.

Der Konflikt mit Nortpert, dem amtierenden Abt des Klosters St. Gallen, verlief jedoch weitaus problematischer und artete zu einer Fehde aus, die auf beiden Seiten Opfer forderte und enorme Schäden anrichtete.

Bau- und Weihetätigkeit
Bischof Rumold nahm während seiner Amtszeit zahlreiche Kirchweihen vor. 1052 weihte er die Marienkirche in Eichstetten am Kaiserstuhl und 1064 die Klosterkirche von Muri sowie die des Klosters Allerheiligen in Schaffhausen.

Nachdem das dreischiffige Langhaus des Konstanzer Münsters bereits 1052 eingestürzt war, veranlasste Rumold 1054 den Wiederaufbau des Langhauses, der jedoch erst 1089 abgeschlossen werden konnte. Die Weihe des bereits 1065 fertiggestellten Petrusaltars im rechten Arm des Querschiffes nahm er jedoch noch selbst vor.

Literatur
 Helmut Maurer: Die Konstanzer Bischöfe vom Ende des 6. Jahrhunderts bis 1206 (= Germania sacra. NF 42,1; Die Bistümer der Kirchenprovinz Mainz. Das Bistum Konstanz. 5). Walter de Gruyter, Berlin/ New York 2003, ISBN 3-11-017664-5, S. 193–199. (Digitalisat)

Weblinks

Einzelnachweise

Bischof von Konstanz
Römisch-katholischer Bischof (11. Jahrhundert)
Person (Konstanz)
Historische Person (Baden-Württemberg)
Geboren im 10. oder 11. Jahrhundert
Gestorben 1069
Mann

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Home Pop Watch: Stanaj releases Powerful new song "Love Me"
Watch: Stanaj releases Powerful new song "Love Me"
Vocal powerhouse Stanaj releases his new track and video "Love Me" today via LAVA/Republic Records.
"Love Me" is an inspirational anthem promoting the importance of self-love, showcasing the singer's incredible vocal range. The track and video premiered earlier today on Billboard with the outlet calling it "an empowering anthem that exemplifies Stanaj's bone-chilling falsetto and pure heart."
An insane journey brought New York-born and Los Angeles-based Albanian-American singer, songwriter, and producer Stanaj to the doorstep of superstardom. He landed a deal on the heels of extensive social media praise by numerous celebrities including Drake, Chris Brown, and Kim Kardashian West. His first hit came in the form of "Romantic" (NOTD Remix), which racked up nearly 120 million Spotify streams and counting to date. Stanaj's first two EPs—The Preview and From a Distance—hit the Top 10 of the iTunes Top Pop Albums Chart. As a result, he canvassed the globe on tour alongside JoJo and Jessie J and shared the stage with other superstars like Dua Lipa .
Not to mention, he made his late-night television debut on The Tonight Show Starring Jimmy Fallon, and the night's guest Justin Timberlake gave a coveted co-sign. 2018 saw him drop the slick and seductive "Dirty Mind" [feat. Ty Dolla $ign] and lend his voice to Gryffin's "You Remind Me," which he performed on Jimmy Kimmel LIVE! In the summertime, he hit the studio with the likes of Tommy Brown [Ariana Grande] and d.a. doman [Kodak Black, Chris Brown, Tyga] and ultimately honed his signature style as evidenced by his slick and show-stopping song "Sweat," which came out earlier this year.
https://www.facebook.com/StanajOfficial/
Albanian-American
STANAJ
Stanaj Love Me
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A hydrogen powered calculator!? Amazing stuff. This product is eco-friendly, provides free energy and has a replaceable H2O cell.
The great thing about a H20 battery is that each component is recyclable unlike conventional dry cell batteries. Usually the recycling of such dry cell batteries is not just expensive, it is incomplete which results in pollution and damage to our environment.


Are you looking to buy a new Android phone? If yes, you can ponder upon the latest OnePlus 5.
The fabulous OnePlus 5 is truly the best Android device available in the market and it is also the cheapest high-end phone. Starting at $479, it's a bit costly than previous versions of the OnePlus line but still knowingly cheaper than its nearby competitors, such as the Samsung Galaxy S8 ($574), HTC U11 ($649), and Google Pixel ($649).
In terms of performance, this phone is just awesome.
From design perspective, OnePlus 5 is incredibly stunning. Its matte aluminum body is elegant and sleek. The edges are curved so that it fits firmly in your hand. It features a fingerprint scanner built into the home button (not on the back like so many other Android phones). The screen is big and bright and colorful.
Its fingerprint scanner is quick and flanked by two capacitive keys. There's an option to have them backlit in the settings, but they're just tiny dim dots.
The software of OnePlus 5 is not much different from stock Android. Popularly known as OxygenOS, it is pretty much smooth to work on.
Though you can replace your launcher, the OnePlus Launcher is what's available by default here. It's a basic, yet relatively customizable launcher with a fluid swipe-up motion to bring up the app drawer.
If you swipe over to the left, you'll find the "Shelf", which is essentially a place to put widgets and other shortcuts.
With the latest and advanced Qualcomm Snapdragon 835, the OnePlus 5 is amazingly quick. Not only that, it either has 6GB or 8GB of RAM depending on which model you get. That's great overstatement for a phone, but it also future-proofs the device thoroughly.
Featuring a 3,300mAh battery, the OnePlus 5 gets better-than-average battery life, but it's not unmatched. With simple usage you can manage for two days, but with medium-to-heavy usage, you'll probably just make it one day.
Is OnePlus 5 the best choice?
Of course! This is the Android phone that can really take on the iPhone 7. It's just as fine, if not better, than all the other premium devices out there — and it's a best deal grabber. You won't find better value than the OnePlus 5.
However, if you can manage without a water-resistant phone, OnePlus 5 is indeed the best bet.


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Register to list your shows or get our weekly email of shows in your area.
Andrew Bird - Fourth Presbyterian Church of Chicago
126 E Chestnut St Chicago,IL
12/12/2019 8:00 PM - 12/12/2019 10:00 PM
2019-12-12 20:00:00 2019-12-12 22:00:00 America/Detroit Andrew Bird Fourth Presbyterian Church of Chicago info@wamza.com
Andrew Bird announces the reprise of his annual "Gezelligheid" concerts this winter with a five-night residency at Chicago's Fourth Presbyterian Church. The intimate performances arrive on the heels of Bird's worldwide tour in support of his latest full-length record, "My Finest Work Yet." Appropriating a Dutch term that loosely translates to "cozy," the Gezelligheid performances concentrate mainly on instrumental violin pieces amplified only by Bird's signature giant Victrola horns. Special guest Madison Cunningham to join.
Andrew Bird is an internationally acclaimed musician, songwriter and composer who has released fifteen records to date. Recording and touring extensively, Bird has performed around the world at festivals and renowned institutions including Carnegie Hall, Sydney Opera House and Walt Disney Concert Hall. In addition to being a TED Talks presenter, a New Yorker Festival guest, and an op-ed contributor for the New York Times, Bird was recently cast in FX's critically-acclaimed, Emmy Award-winning limited series, Fargo. The series begins production in Chicago this fall and will air on FX in 2020.
Fourth Presbyterian Church is located at 126 East Chestnut Street, on the corner of Michigan Avenue and Delaware Place (across from the John Hancock Center).
- Des Moines, IA
All Events +
Stevie Stone Live at Lefty's
Lefty's Live Music Read More +
Mobile Deathcamp Live at Lefty's
Haunted Hallows & Deadline String Band
Palace Theatre - St. Paul/Minneapolis Read More +
The Standby Live at Lefty's
Ragland LIVE at Lefty's W / The DM Project & Joshua Sinclair
King Princess
Coldsaint on the Come Up
Sleep Signals ~ Young Medicine ~ What Lies Within
VRSTY | So Soon, The Truth
Calexico and Iron & Wine
Wicked Ways Burlesque Redux
Been Better / Display Case & Friends
Bodysnatcher Live at Lefty's
The Toasters - 4 Decades in Ska Tour
Vaudeville Mews Read More +
Blacktop Mojo w / Hollowpoint
Big Head Todd And The Monsters
Another Lost Year w / Cold Kingdom, Enemies Closer
The Motion Mosaic Live at Lefty's
Chicago Farmer & the Fieldnotes w/ Dan Tedesco
Cryptic Wisdom Live at Lefty's
Mac Lethal Live at Lefty's
Wamza is a space for local bands, venues, and promoters to create a free profile (Click the register link above) and list their upcoming shows. Privacy Policy


text:
Q: Azure Traffic Logs - see geography of requests Is there any way to see, on an Azure Website, a log of all the requests divided by geographic area / IP?
Today we experienced a lot of requests (4 times than the average) and I'd like to know if is some kind of DDoS or similar.
Thanks
Marco

A: I ended up enabling diagnostics on the application.
Go on the app, under "Monitoring" select "Diagnostics logs".
Then I enabled every kind of log with storage on the Blob.
After logs have been generated I analyzed them using "Weblog Expert".

redpajama_set_name: RedPajamaStackExchange


text:
Together into 2019: The Year End Results and Plans for the Future
Categories: System News|24 Dec 12:00
Dear friends, we, at WebMoney, wish you a Merry Christmas and a Happy New Year. The days just before these winter holidays are traditionally considered as the time for reflection on the journey made to date, and for sending best wishes. Our wish to you is that you continue to confidently navigate towards your most ambitious goals and aspirations and, of course, that you always have your WebMoney wallets full.
For the past year, we were continuously working on enhancing the convenience of use of the WebMoney electronic wallet, not only for online operations but also in restaurants, cafes and shops. Our WebMoney Keeper mobile applications now have new functions allowing their users to engage in trading at the INDX online exchange, managing a few WMIDs at once and many more.
The WebMoney Events social and business network now has a new section, `Freelancers` and an option for creating personal assistants, bots.
One of the highlights of the year, in the juncture between art and technology, was the ICO for the screening of `Empire V` based on the novel by Victor Pelevin. We are pleased to share with you that the ICO was successfully finalised and, currently, the Bablos tokens can be purchased at the INDX online exchange.
In the past year, we have also supported the Bitcoin Cash hard fork on the 15th of November and credited the relevant volume of notes of the BSV.ECU instrument at INDX.ru to all system participants who were in possession of WMH at the time of the hard fork.
Our fundraising service which was launched at the beginning of 2018 has proved to be very popular among streamers, mainly due to the absence of additional commissions.
Options of adding funds to and withdrawing funds from a WebMoney wallet are now available in dozens of countries where WebMoney has a presence due to newly formed partnerships.
This year we celebrated our 20th birthday and we have no intention of slowing down and can promise you much excitement awaiting ahead, such as the launch of our services in new countries and the delivery of innovative solutions.
Тags: WebMoney Keeper, WebMoney Funding, INDX Exchange, Merry Christmas, Happy New Year, Bablos, 20th birthday, WebMoney Events, fundraising service


"Companies with better Corporate Governance have generally produced a better return for shareholders."
The only question to ask yourself is, how much are you willing to sacrifice to achieve success?
The expert in battle seeks his victory from strategic advantage.
In all realms of life it takes courage to stretch your limits, express your power, and fulfil your potential... it's no different in the financial realm.
Strong, deeply rooted desire is the starting point of all achievement.
Some of us will do our jobs well and some will not, but we will be judged by only one thing. the result.
Winning is not a sometime thing; it's an all time thing. You don't win once in a while, you don't do things right once in a while, you do them right all the time. Winning is habit.
The most important adage and the only adage is, the customer comes first, whatever the business, the customer comes first.
Don't let anyone say you can't do it.
You are surrounded by simple, obvious solutions that can dramatically increase your income, power, influence and success.
The best way to get started is to quit talking and begin doing.
When I'm under the gun and I've got pressure on me, I don't panic. I look for the right solution, and then I go for it.


text:
Q: Use single line functions or repeat code I was writing a Javascript code in which I needed to show and hide some sections of a web. I ended up with functions like these:
function hideBreakPanel() {
  $('section#break-panel').addClass('hide');
}

function hideTimerPanel() {
  $('section#timer-panel').addClass('hide');
}

function showBreakPanel() {
  resetInputValues();
  $('section#break-panel').removeClass('hide');
}

function showTimerPanel() {
  resetInputValues();
  $('section#timer-panel').removeClass('hide');
}

My question is related with code quality and refactoring. When is better to have simple functions like these or invoke a Javascript/jQuery function directly? I suppose that the last approach have a better performance, but in this case performance is not a problem as it is a really simple site.

A: I think you're fine with having functions like these, after all hideBreakPanel might later involve something more than applying a class to an element. The only thing I'd point out is to try to minimize the amount of repeated code in those functions. Don't worry about the fact that you're adding a function call overhead, unless you're doing this in a performance-critical scenario, the runtime interpreter couldn't care less.
One way you could arrange the functions to avoid repeating yourself:
function hidePanel(name) {
  $('section#' + name + '-panel').addClass('hide');
}

function showPanel(name) {
    resetInputValues();
    $('section#' + name + '-panel').removeClass('hide');
}

If you absolutely must have a shorthand, you can then do:
function hideBreakPanel() {
   hidePanel("break");
}

Or even
var hideBreakPanel = hidePanel.bind(hidePanel, "break");

This way you encapsulate common functionality in a function, and you won't have to update all your hide functions to ammend the way hiding is done.

A:
My question is related with code quality and refactoring. When is
  better to have simple functions like these or invoke a
  Javascript/jQuery function directly? I suppose that the last approach
  have a better performance, but in this case performance is not a
  problem as it is a really simple site.

Just from a general standpoint, you can get into a bit of trouble later if you have a lot of one-liner functions and multiple lines of code crammed into one and things like that if the goal is merely syntactical sugar and a very personal definition of clarity (this can be quite transient and change like fashion trends).
It's because the quality that gives code longevity is often, above all, familiarity and, to a lesser extent, centralization (less branches of code to jump through). Being able to recognize and not absolutely loathe code you wrote years later (not finding it bizarre/alien, e.g.) often favors those qualities that reduce the number of concepts in the system, and flow down towards very idiomatic use of languages and libraries. There are human metrics here beyond formal SE metrics like just being motivated to keep maintaining the same code.
But it's a balancing act. If the motivation to seek these shorter and sweeter function calls has more to do with concepts beyond syntax like having a central place to modify and extend and instrument the behavior, to improve safety in otherwise error-prone code, etc., then even a bunch of one-liner functions could start to become of great aid in the future. The key in that case to keep the familiarity is to make sure you (and your team if applicable) have plenty of reuse for such functions, and incorporate it into the daily practices and standards.
Idiomatic code tends to be quite safe here because we tend to be saturated by examples of it, keeping it familiar. Any time you start going deep on the end of establishing proprietary interfaces, we risk losing that quality. Yet proprietary interfaces are definitely needed, so the key is to make them count.
Another kind of esoteric view is that functions that depend on each other tend to age together. An image processing function that just operates on very simple types provided by a language tends to age well. We can find, for example, C functions of this sort that are still relevant and easily-applicable today that date back all the way to the 80s. Such code stays familiar. If it depends on a very exotic pixel and color library and math routines outside of the norm, then it tends to age a lot more quickly (loses the familiarity/applicability), because that image processing routine now ages with everything it depends on. So again, always with an eye towards tightrope-balancing and trade-offs, it can sometimes be useful to avoid the temptation to venture too far outside the norms, and avoid coupling your code to too many exotic interfaces (especially ones that serve little more than sugar). Sometimes the slightly-more verbose form of code that favors reducing the number of concepts and more directly uses what is already available in the system can be preferable.
Yet, as is often the case, it depends. But these might be some less frequently-mentioned qualities to keep in mind when making all of your decisions.

A: If resetInputValues() method returns undefined (meaning returns nothing e.g) or any falsy value, you could refactorize it to:
function togglePanel(type, toHide) {
    $('section#' + type + '-panel').toggleClass('hide', toHide || resetInputValues());
}

Use e.g togglePanel('break'); for showBreakPanel() and togglePanel('break', true) for hideBreakPanel().


text:
{php $diyitem = $diyitem_search}

        <form action="{php echo mobileUrl('goods', array('merchid'=>$page['merch']))}" method="post" class="inner">
            {if !empty($diyitem['params']['leftnav'])}

                    {if $diyitem['params']['leftnav']==1 && !empty($diyitem['params']['leftnavicon'])}

                    {/if}
                    {if $diyitem['params']['leftnav']==2 && !empty($diyitem['params']['leftnavimg'])}

                    {/if}

            {/if}

                <input type="search" value="" placeholder="{$diyitem['params']['placeholder']}" style="color: {$diyitem['style']['searchtextcolor']}; opacity: {$diyitem['style']['opacityinput']}; background: {$diyitem['style']['searchbackground']};" name="keywords" />

            {if !empty($diyitem['params']['rightnav'])}

                    {if $diyitem['params']['rightnav']==1 && !empty($diyitem['params']['rightnavicon'])}

                    {/if}
                    {if $diyitem['params']['rightnav']==2 && !empty($diyitem['params']['rightnavimg'])}

                    {/if}

            {/if}
        </form>

redpajama_set_name: RedPajamaGithub


Whether you're just getting started or already know the basics, our Google Analytics Certification will provide you with all of the tools you'll need to master the tool of the trade—Google Analytics.
Learn how to expertly navigate Google Analytics and create and analyze custom reports to reveal powerful insights into your marketing campaigns. You'll also learn how to maximize your budget by gaining a deep understanding of which channels are producing the most engagement with consumers. It's time to get to the heart of Analytics!


Launchpad couldn't import bug #658906 from GNOME Bug Tracker.
The information about this bug in Launchpad is automatically pulled daily from the remote bug. This information was last pulled on 2018-12-03.
When logging in the background wallpaper briefly appears shifted horizontally to the right by around 15 pixels. A grey-ish border is therefore briefly displayed on the left hand side of the desktop.
This occurs under both Compiz and Metacity (compositing on & off).
Does it occur with Unity?
Chris Coulson believes that it is the same bug as bug #804435 for which a patch to GTK is underway.
I still see this bug.. the wallpaper now is shifted vertically when the top panel appears.
I still have this bug.. it is a fresh install with unity 5.0 from staging ppa.


Chicago Bears defensive end Julius Peppers rarely finds himself alone on the edge these days. That's because the perennial All-Pro is normally joined by two or three offensive lineman on almost every repetition.
So this April, when the Bears went out and spent a first-round pick on Boise State defensive end Shea McClellin, the hope was that the selection would pay immediate dividends and lighten the load on Peppers. It's still over a month before McClellin and the Bears have to lace 'em up officially, but two days into padded practices the former Bronco is fighting to make the adjustment to the NFL.
The initial impression of Shea McClellin's play is that he'll need plenty of work if he hopes to establish his own presence on the edge of the Bears 4-3 defense and alleviate any load from Julius Peppers 6'6″ 300 lb. frame. Shea McClellin will tell you just as much.
With Julius Peppers essentially absent from the action, per head coach Lovie Smith's request, McClellin saw reps with virtually every unit, and though he showed occasional flashes, he found himself on the receiving end of a few vicious pancakes.
However, McClellin is still eager to get back out there, put in the time, and earn the experience necessary to impress the coaches.
The extra reps, combined with the adjustment time necessary to adapt to the speed of the NFL game and the rust factor of not having played football since Dec. 22 — when Boise State defeated Arizona State in the Maaco Bowl — seemed to be a toxic combination for McClellin.
"The speed is definitely faster (in the NFL) — the intensity is higher — and when you haven't put the pads on in (seven) months, or whatever, it takes its toll," McClellin said.
McClellin may not have been prepared to be thrust into the furnace of first-team reps, but with Julius Peppers' role already cemented on this team, it may be something he has to get used to quick according the Lovie Smith.
"We're not going to beat (Julius Peppers) up. We pretty much know what he can, so don't monitor his reps. He doesn't even know what they're gonna be," Smith said.
In other words, Smith and his staff will be liberally resting Julius Peppers throughout training camp to keep the Pro Bowler healthy, and it will be feast or famine for the rest of the defensive ends.


text:
Lefkada (eiland) of Lefkas; een Grieks eiland en departement
Lefkada (stad) of Lefkas; de hoofdstad van het gelijknamige Griekse eiland en departement


text:
mapping average Internet download speeds in U.S.
Akamai's publicly filed dataset of observed average Internet download speeds for U.S. network connections is now on Needle. Needle makes it easy to map the reported cities and states according to an average speed threshold. For example, 79 out of the 500 reported cities have average Internet download speed less 2048 kbit/s. Here's a map of states that contain those cities. The map shows that relatively low average Internet download speeds by city are widely dispersed geographically.
To generate a map for an average speed threshold of your own choosing, click on "city" under "every" on the left of the Needle page. Then click on ">>" on the table heading, just to the right of "every city." Then click on "keep only those where…", and then click on "ave speed." Ave speed jumps to the top of the list and a drop-down selection box appears. Select "is less than," and enter a figure (kbit/s) in the box to the right. Then click on next. The screen will change slightly to reflect your choice, and a "done" button will appear. Click on the "done" button. You'll then see a list of the relevant cites. On the upper right, change the drop-down selector from "table" to "map." You'll then see a map with markers for states that contain cities that satisfy your selection criterion. If you change the "group by" drop-down selector from "state" to "city," the map will change to include markers for each city that satisfies your selection criterion. You can similarly map state average speeds by clicking on "state" rather than "city" in the first step. To change your selection criterion, you must start by clicking on "city" or "state" on the left and redo the steps above.
Related post: dispersion of Internet download speeds
Posted on September 5, 2010 By Author Douglas GalbiTags broadband, network connectivity


Creepy-crawlies are making their way up a wall to knock you off. Can you stop their climb, or will you become another faller?
Walls and creatures always make for a nice game and Faller, our program of the month, has both. It takes a bit of imagination, but watch the icky spider climb up the wall towards you. Their goal, of course, is to knock you off and claim the wall for themselves. Like any good hero, you sit at the top and move over the spiders using Z and .. But be quick and knock them off using M to save the day. Just don't be a faller should you miss.


Two Mums is a wonderful story about, you guessed it, two mums and their daughter and how having two mums can be double the fun.
This beautifully illustrated book talks about life with two mums from the perspective of the child and goes through a fun journey about all the things two mums get up to. From rollerblading to baking. Nothing is off limits.
Firstly, I love that the women don't confirm to gender stereotypes. So whilst one mum does baking and art, the other loves more adventurous activities as well as cuddling and reading stories! Secondly, as a gay woman, I love how the women have been illustrated.
Too often, Lesbians are illustrated as 'butch' looking, usually wearing jeans and a t-shirt, boasting rather short hair and maybe a sneaky tattoo. This is not the case in this book. Both mums are incredibly unique and I feel represent the whole spectrum.
This story features a family of two mums and two sons, and doesn't mention the fact that they are a two mum family. The sole purpose of this book is to explore their ever growing family!
Completely different when it comes to illustrations, this more gently illustrated book concentrates on the flow of the story – which has a fun and lively theme – often reading in rhyme.
Again, the illustrations step away from the typical 'Gay stereotype' and even explores a different ethnic background within the family, as well as fits around families who are adoptive – as this story doesn't suggest otherwise!
This is a lovely story and T thoroughly enjoyed identifying all the animals.
Regardless of your family make-up, I would highly recommend adding these gorgeous books to your collection. For us, it was lovely to hear T identify that the parents were two mums – like it was no big deal! It would mean the world to us seeing other children do the same.
We were sent Two Mums & Two Mums and a Menagerie for the purpose of an honest review, however all thoughts, opinions, and images are our own.
Around the World in 18 Raves: A Camp Bestival Rave with Big Fish Little Fish!


text:
Mr (Harry) Henry Basil TURNER, M.A (1905 - 1988)
Place of Birth: Woolwich, New South Wales, Australia
Place of Death: Killara, New South Wales, Australia
Member of the NSW Legislative Assembly 07 Aug 1937 18 Nov 1952 15 years 3 months 12 days
Member for Gordon 07 Aug 1937 24 Feb 1938 6 months 18 days
Member for Gordon 26 Mar 1938 25 Aug 1938 5 months
Member for Gordon 24 Sep 1938 18 Apr 1941 2 years 6 months 26 days
Member for Gordon 10 May 1941 24 Apr 1944 2 years 11 months 15 days
Member for Gordon 27 May 1944 29 Mar 1947 2 years 10 months 3 days
Member for Gordon 03 May 1947 22 May 1950 3 years 20 days
Member for Gordon 17 Jun 1950 18 Nov 1952 2 years 5 months 2 days
United Australia Party. Secretary of Killara branch and delegate to council. Liberal Party.
Lawyer (barrister). Educated at Malvern School, Hunters Hill, Sydney., University of Sydney. BA 1927 and Queens College, Cambridge, MA Canterbury; called to Bar (Inner Temple) in 1930; travelled extensively in Europe; practised in New South Wales 1931 - 1937. Delegate to United Nations general assembly 1963, and 1969; member of parliamentary delegation to East Asia in 1965; delegate to 7th general assembly in Asian Parliamentary Union, Cambodia in 1971, leader of Australian delegation to Commonwealth Parliamentary Association conference, Malawi in 1972; Australian representative in Malawi republic celebrations.
Served in 2nd Australian Imperial Forces 1940 -1944, 2/3rd Australian Infantry Battalion, 6th Division; Greece, Syria, New Guinea, lieutenant.
Member of the Parliament of the Commonwealth of Australia. Member of the House of Representatives for Bradfield 1952 - 1974.
Son of Basil William Turner, metallurgist, and Mabel Lily Breillat. Married Mildred Mary Raymond at Mosman on 4 July 1931 and they had 3 daughters and 1 son.