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Clinical and Translational Medicine
Review | Open | Published: 18 August 2016
Therapeutic use of stem cells for cardiovascular disease
Whitney Faiella1 &
Rony Atoui ORCID: orcid.org/0000-0001-8711-21091
Clinical and Translational Medicinevolume 5, Article number: 34 (2016) | Download Citation
Stem cell treatments are a desirable therapeutic option to regenerate myocardium and improve cardiac function after myocardial infarction. Several different types of cells have been explored, each with their own benefits and limitations. Induced pluripotent stem cells possess an embryonic-like state and therefore have a high proliferative capacity, but they also pose a risk of teratoma formation. Mesenchymal stem cells have been investigated from both bone marrow and adipose tissue. Their immunomodulatory characteristics may permit the use of allogeneic cells as universal donor cells in the future. Lastly, studies have consistently shown that cardiac stem cells are better able to express markers of cardiogenesis compared to other cell types, as well improve cardiac function. The ideal source of stem cells depends on multiple factors such as the ease of extraction/isolation, effectiveness of engraftment, ability to differentiate into cardiac lineages and effect on cardiac function. Although multiple studies highlight the benefits and limitations of each cell type and reinforce the successful potential use of these cells to regenerate damaged myocardium, more studies are needed to directly compare cells from various sources. It is interesting to note that research using stem cell therapies is also expanding to treat other cardiovascular diseases including non-ischemic cardiomyopathies.
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide [1]. MI occurring from coronary artery disease can cause reversible or irreversible ischemic damage, depending on the reperfusion status afterwards. This ischemic damage results in the loss of cardiomyocytes due to apoptosis [2]. Following the formation of necrotic myocardium, a secondary inflammatory immune response occurs as myofibroblasts are recruited to the area resulting in scar formation and reduced ventricular function [3].
Current options to re-perfuse occluded arteries include medical, percutaneous coronary intervention and surgical strategies, which have significantly improved outcomes after MI [4]. However, these techniques do not reverse necrotic or ischemic myocardium. Research is now focusing on techniques to regenerate damaged myocardium to regain heart function, one of which is the use of stem cells.
Studies are currently investigating a number of different cell types including embryonic, induced pluripotent, mesenchymal and cardiac derived stem cells. There are many considerations to be taken into account when selecting an ideal cell type. For example, in order to improve heart function, cells must be able to differentiate into myocytes, vascular endothelial cells and smooth muscle cells or must act via paracrine mechanisms. Their extraction and isolation must be feasible and transplantation into humans must be safe and effective. In the following review, different cell types will be discussed in terms of the benefits and limitations of each type (Table 1).
Table 1 Summary of advantages, disadvantages and current clinical trials for the various sources of stem cells mentioned in this article
Embryonic/induced pluripotent stem cells
Embryonic stem cells can give rise to all cell types found in an organism. They are derived from the inner cell mass of the blastocyst during mammalian embryonic development [5]. However, there are several ethical and political issues surrounding the use of embryonic stem cells as well as a limited supply of donor human embryos. This led to the development of induced pluripotent stem cells (iPSs). IPss were first reprogrammed from adult mouse fibroblasts by the presence of certain factors, including Oct ¾, Sox2, c-Myc and Klf4 in culture. These iPSs successfully demonstrated an embryonic-like state, exhibiting growth properties and specific marker genes of embryonic cells [6, 7]. Shortly later, human iPSs, capable of differentiating into cell types from all three germ layers, were reprogrammed from human fibroblasts using the same four factors [8, 9]. Research has continued to focus on optimizing techniques used to form human iPSs such as using different factors and culture conditions. For example, human iPSs were generated using Oct4, Sox2, Nanog and Lin28 transgenes [10, 11].
For clinical application, these human induced pluripotent stem cells (hiPSs) must be able to differentiate into functional cardiomyocytes or cardiac progenitors. There is a large body of research regarding various differentiation techniques. One research group made use of the transcription factors used to induce pluripotency to also encourage differentiation into cardiac lineages. Oct ¾ is a transcription organizer that plays a gatekeeper role in the pluripotency of embryonic stem cells by interacting with the Sox2 promoter. Once this is achieved, Oct ¾ interacts with the Sox17 promoter to signal cardiogenesis [12]. Another research group used the addition of particular growth factors, including BMP and GSK3, to direct differentiation into cardiac progenitor cells [13]. Cardiac differentiation was confirmed using an embryoid body protocol by electrophysiology studies that verified the formation of nodal, atrial and ventricular-type cardiac cells from these cells [10]. These studies confirm the ability for iPSs to differentiate into cardiac lineages, thus making them good candidates for the treatment of cardiovascular disease.
In order to evaluate the effect of these cells on heart function, differentiated cardiac cells then must be transplanted into hearts. Injection of iPSs into rat myocardium resulted in successful engraftment and differentiation into cardiomyocytes, vascular endothelium and smooth muscle cells along with an increased ejection fraction and decreased fibrosis [14, 15]. In a porcine model, hiPSC-derived cardiomyocytes, endothelial cells and smooth muscle cells were integrated into host myocardium using an intramyocardial microsphere transplantation technique. This resulted in improved LV function, myocardial metabolism and reduced infarct size [16]. In a larger animal model, cardiac committed ESCs were transplanted into infarcted sheep hearts. Results demonstrated successful engraftment and preservation of ejection fraction [17]. Overall, these in vivo studies demonstrate a positive effect of implanted cells on cardiac function.
Although studies mentioned above demonstrate successful use and effect on cardiac function of iPSs in animal studies, progress is still needed in clinical trials. Clinical trials have not yet been initiated for iPSs use for the treatment of myocardial infarction. Before this can be done, there is a need to establish a reproducible and more standardized differentiation technique. In terms of embryonic stem cells, the first clinical trial was recently initiated in Paris. A phase 1 clinical trial, ESCORT, is currently examining the effect of embryonic stem cell derived progenitors on severe heart failure. These cells are driven towards a cardiac fate before transplantation and are embedded into a fibrin gel before being administered via epicardial delivery to patients undergoing coronary artery bypass grafting (CABG) or a mitral valve procedure. The first clinical case report using embryonic stem cell derived cardiac progenitor cells was recently published and demonstrated symptomatic improvement and echocardiographically evident new contractility with an LVEF improving from 26 % to 36 % after 3 months [18].
Induced pluripotent stem cells are attractive because of their ability to differentiate into large numbers of cardiomyocytes. There is better functional integration within host heart cells in comparison to adult cells, specifically in terms of the electromechanical connections with host cardiomyocytes. A limitation to the use of these cells is the associated risk of teratoma formation after transplantation of undifferentiated cells into infarcted hearts. In one study, the transplantation of undifferentiated syngenic iPSs into mice resulted in teratoma formation in 65 % of transplantation sites after 30 days [19, 20]. This result emphasizes the need for a method to control or direct differentiation of iPS towards cardiac progenitor cells before transplantation to avoid the formation of teratomas or alternate and undesired cell types [21]. Overall, additional animal studies are needed to ensure the safety and efficacy of these cells.
Mesenchymal stem cells (MSCs) can be found in bone marrow, adipose tissue, umbilical cord blood and placenta. They are capable of differentiating into lineages such as osteocytes, chondrocytes, adipocytes, myocytes and marrow stroma [22]. These cells are hypothesized to secrete soluble growth factors and cytokines that act in endocrine and paracrine fashions, contributing to their therapeutic effect [23].
MSCs are advantageous due to their immunomodulatory characteristics, which allow them to act as a universal reserve of donor cells (Fig. 1) [24]. These cells have a unique distribution of surface markers that allows them to escape detection from immune cells. Specifically, they possess decreased levels of MHC class I and costimulatory CD40, CD80 and CD86, with no MHC class II molecules [25, 26].
This figure is adapted from [24]
Suggested pathways underlying the immunomodulatory properties of mesenchymal stem cells
Despite low cellular retention and poor differentiation into cardiomyocytes, studies were still demonstrating improved heart function [27], which suggests a potential paracrine mechanism of action for transplanted MSCs. MSCs release angiogenic, apoptotic, mitogenic and homing factors that have cardio-protective actions [28]. Specifically, a recent study demonstrated the importance of hepatocyte growth factor (HGF) in angiogenesis and proliferation of cardiomyocytes [29]. Furthermore, transplantation of MSCs indirectly stimulated endogenous cardiac progenitor cells through a paracrine mechanism. Released factors such as HGF, VEGF and IGF-1 triggered activation, proliferation, and migration of resident cardiac progenitors. Specifically, they inhibited apoptosis of cardiac progenitors and upregulated the expression of cardiomyocyte related genes in order to direct differentiation [30].
Results from studies using MSCs derived from bone marrow and adipose tissue will be discussed below.
Injury to an organ triggers stem cells from distant sites to migrate to the area of damage, where they can differentiate and help repair the damaged organ. This reparative effect had been demonstrated in muscle, liver and brain tissues [31–33]. In 2001, Orlic et al. investigated whether stem cells from a distant site directly transplanted into the heart could regenerate scarred areas. Results demonstrated that locally delivered autologous bone marrow stem cells could regenerate damaged myocardium in infarcted mice hearts [34]. This finding led to further research examining the differentiation of MSCs into cardiac lineages and the specific effects on cardiac function.
For example, in vitro MSCs were capable of differentiating into cardiomyocytes, as demonstrated when MSCs were co-cultured with neonatal ventricular myocytes [35]. In animal models, MSCs derived from bone marrow injected into mice and rat hearts post MI showed successful engraftment and differentiation into cardiomyogenic and vascular phenotypes [36–38]. It has also been found that the hypoxic environment of infarction may induce the expression of certain factors (vascular endothelial growth factor, myocardin, insulin like growth factor) which can promote the differentiation of MSCs to cardiomyocytes [39, 40]. Percutaneous transendocardial injection of bone marrow derived MSCs into pig hearts post-MI showed an improved ejection fraction after 4 weeks, in comparison to bone marrow derived mononuclear cells [41].
The above studies all used MSCs derived from autologous sources. However, as mentioned, an advantage of MSC is their immunomodulatory characteristics. This led to numerous studies comparing results from allogeneic vs autologous cells. In vitro, MSCs co-cultured with immune cells upregulated the secretion of suppressive cytokines (i.e. IL-4 and IL-10), decreasing the secretion of proinflammatory cytokines (TNF-α and IFN-ɣ) from dendritic cells, T helper cells and macrophages [42]. Soluble mediators including prostaglandin E2 are important for this immunosuppression [43]. In vivo, direct intramyocardial injection of bone marrow derived MSCs 1 month after MI in a porcine model resulted in preserved left ventricular ejection fraction at 60 and 90 days post MI in comparison with the untreated subjects [44]. Similarly, global left ventricular ejection fraction (LVEF) improved along with a decrease in infarct size by 40 % in sheep treated with intracoronary infusion of allogeneic bone marrow derived MSCs in comparison to untreated sheep [45]. With this being said, there is a lack of evidence supporting the benefit of these cells on a long-term basis. For example, intramyocardial injection of MSCs resulted in an initial improvement in cardiac function. This effect was no longer observed after 1 month, and there was noted immune cell infiltration and subsequent rejection of MSCs [46]. Preliminary results demonstrate benefit from the use of allogeneic MSCs. Future studies that focus on enhancing the long term efficacy of these treatments could permit the use of cells from young healthy donors, eliminating the need for MHC matching prior to treatment.
There have been numerous clinical trials evaluating the effect of MSCs in humans with cardiovascular disease. The BOOST trial involved intracoronary administration of autologous bone marrow derived MSCs in patients who received percutaneous coronary intervention for acute STEMI's. After 6 months, the global LVEF increased by 6.7 % in the treated group vs 0.7 % in the control group [47]. Another trial in 2006 assessed cardiac function after intracoronary administration of autologous bone marrow derived MSCs 3–7 days post-MI. After 4 months the LVEF increased by 5.5 % in the treated group vs 3 % in the control group [48]. A phase I trial initiated in 2009 evaluated the safety and efficacy of bone marrow derived allogeneic MSCs (Prochymal) delivered intravenously to patients post-MI. Results demonstrated better global symptom scores and ejection fractions in patients receiving MSC's compared to the control group. Improvements in LVEF were also seen on cardiac MRI in the group treated with MSCs [49].
MSCs can also be isolated from adipose tissue, specifically the stromal fraction of adipose tissue. These cells are attractive due to the ease of extraction using liposuction. Adipose tissue is also considered a richer source of progenitors compared to bone marrow, containing 100–500 times the amount [50].
In animal models, adipose tissue derived MSCs injected into rat myocardium post-MI resulted in an improved LVEF compared to untreated rats [51], as well as reduced fibrosis and less wall thinning [52]. More recently, adipose tissue derived stem cells were used to create cardiac-like progenitors (iCPs). Adipose tissue derived stem cells, induced cardiac progenitors and bone marrow derived stem cells were delivered into mice hearts post-MI. At 1 month post-transplant, mice transplanted with iCPs and adipose derived stem cells showed higher myocardial capillary densities. All three samples showed a decrease in infarct size compared to the control or untreated sample; however the greatest reduction was seen in those transplanted with iCPs, which were derived from adipose tissue stem cells [53].
Similar to bone marrow MSCs, those derived from adipose tissue also possess immunomodulatory properties. In vitro, MSCs derived from adipose tissue showed greater immunosuppressive effects when cultured with immune cells than MSCs derived from bone marrow or umbilical cord matrix. Specifically, they showed a greater inhibitory effect on CD4+ and CD8+ T cell activation and natural killer cell activation. They also displayed a suppressive effect on B cells [54]. In a separate study, adipose tissue MSCs were found to inhibit B cell function more effectively than bone marrow derived cells [55]. These studies indicate the effective immunosuppressive characteristics of MSCs derived from adipose tissue, supporting their use as a future therapeutic agent.
The mesenchymal stromal cell therapy in patients with chronic myocardial ischemia (MyStromalCell Trial) is a phase II study using adipose derived cells, stimulated with VEGF-A165, to determine the effect on patients with chronic ischemic heart disease and refractory angina [56]. The Precise Trial is using adipose tissue derived cells for transendocardial injections in patients with ischemic cardiomyopathy. Preliminary results show improvements in left ventricular mass and motion score index in treated patients after 18 months [57].
These cells continue to be attractive due to their ease of isolation via liposuction and their immunosuppressive qualities.
Cardiac stem cells
Until recently, it was believed that myocytes were incapable of regeneration; however, evidence suggests that myocytes can mitotically divide post MI [58]. The same author studied a subpopulation of cells found within the heart, and proved that they hold properties of cardiac stem cells, with the potential to give rise to myocytes, smooth muscle and endothelial cells [59]. These cells were found to express markers of both mesenchymal stem cells (CD90, CD105), embryonic stem cells (Rex1, Nanog, Sox2) and also early markers of cardiogenesis (platelet derived growth factor receptor-α) [60, 61]. There are multiple different types of cardiac stem cells (CSCs) including ckit+ cells, Isl 1+ cells, cardiac mesoangioblasts, cardiosphere derived cells and epicardial progenitors which all express slightly different but overlapping surface markers [3].
Cardiac stromal cells can be isolated from adult human auricles. These cells expressed cardiovascular markers more efficiently than bone marrow MSCs in vitro. In vivo, cells originating from cardiac tissue differentiated more effectively into cardiomyocytes when injected into rat myocardium post MI [62]. Another study compared the effects of adipose tissue derived stem cells from subcutaneous vs pericardial origin. The cells from a pericardial origin showed better expression of intrinsic transcription factors for cardiogenesis. After administration of cells to infarcted hearts, they demonstrated increased vasculogenesis and myogenesis as well as more effective overall reparative activity [63]. Animal studies consistently demonstrate that cardiac stem cells possess a greater ability to differentiate into cells of cardiac lineages and can more efficiently obtain structural characteristics of myocytes and vessels [64]. Therefore, they are an attractive option for future therapeutics for cardiovascular disease.
Several studies have focused on the use of cardiosphere derived stem cells for treatment post-MI. To generate these cells, percutaneous endomyocardial biopsied cells are grown in culture to form cardiospheres which are then expanded ex vivo to generate cardiosphere derived cells before transplantation. Human and porcine cardiosphere derived cells successfully expressed antigenic characteristics of stem cells. In animal studies, injections of human derived cells into infarcted myocardium resulted in improved LVEF in mice [65] and the formation of new cardiac tissue and a reduction in infarct size in porcine [66]. A challenge associated with the use of cardiac stem cells is harvesting technique. In most studies, autologous cardiac stem cells are isolated from atrial appendages, ventricles or epicardial biopsies and are expanded in culture before use [67]. This method is advantageous because it provides a feasible technique to generate a larger number of cardiac stem cells from very small biopsies.
Clinical trials have already begun. The stem cell infusion in patients with ischemic cardiomyopathy (SCIPIO) is a phase I clinical trial administering autologous cardiac stem cells to patients with heart failure undergoing CABG. Preliminary results demonstrate an increase in LVEF at 4 and 12 months after infusion as well as a decrease in infarct size [68]. The Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS) trial is a phase 1 study examining the use of autologous cells grown from percutaneous endomyocardial biopsies. MRI results after 6 months showed reductions in scar mass, increases in viable heart mass and contractility in the treated group [69].
An obstacle to the use of cardiac stem cells would be the fact that they need to be expanded ex vivo before transplantation, which can be costly [70]. Non-specific differentiation into other lineages such as adipocytes and skeletal muscle has been observed on occasion [71, 72]. Some techniques are focusing on activating endogenous cardiac stem cell pools using growth factors, microRNAs or drugs rather than actually transplanting cells. For example, one study identified a hepatocyte growth factor and insulin growth like factor receptor system in cardiac stem cells. Infarcted dog hearts were injected with these factors, resulting in the formation of new myocytes and coronary vessels in the infarcted region, with expressed proteins specific for cardiomyocytes [73]. This method would avoid complications associated with ex vivo expansion of cells.
Despite the challenges, studies have consistently demonstrated that cardiac stem cells possess the ability to more efficiently differentiate into cardiomyocytes and vascular endothelial cells as well as improve cardiac function [74]. There is also potential for expansion to treat a variety of cardiovascular diseases. For example, a study in 2014 even demonstrated the capability of CSCs isolated from mouse hearts to differentiate into sinus node like cells when co-cultured with mouse sinus node tissue [75]. This would have potential clinical applications for the treatment of sick sinus syndrome. More studies are needed to determine the feasibility of using cardiac stem cells.
Myocardial infarction is a leading cause of death worldwide. The use of stem cells to regenerate damaged myocardium and restore function continues to be a potential therapeutic option. Several different types of stem cells have been investigated for this purpose. Ideal stem cells must be capable of differentiating into cardiomyocytes and vascular endothelial cells. They must be able to successfully engraft and integrate within the host myocardium, mechanically and electrically [67] or provide benefit via paracrine mechanisms [30]. It is important that the source of cells demonstrates cardiogenic potential. Another consideration is the ease of isolation.
There are ethical issues regarding the use of embryonic stem cells. However, induced pluripotent stem cells formed from fully differentiated somatic cells were found to possess an embryonic-like state. These cells have the ability to easily differentiate into large numbers of cardiomyocytes [14]. However, the use of proliferative undifferentiated pluripotent cells carries the risk of teratoma formation. Therefore, it is essential to differentiate the cells into cardiac lineages prior to transplantation.
Mesenchymal stem cells can be isolated from several sources including bone marrow and adipose tissue. Both sources have demonstrated successful differentiation into cardiac lineages as well as positive impacts on cardiac function in animal models. An advantage of mesenchymal stem cells is their immunomodulatory properties. It has been shown that there is a limited capacity for proliferation in cells from aged individuals who may or may not have additional comorbidities [76]. This would permit the use of allogeneic stem cells from young healthy donors for elderly patients to treat acute MI.
Studies have consistently demonstrated that cardiac stem cells possess the ability to more efficiently differentiate into cardiomyocytes and vascular endothelial cells as well as improve cardiac function. However, these cells may be more difficult to obtain compared to the other cell types. In one study, cardiac stem cells were isolated via endomyocardial biopsies of explanted hearts or at the time of left ventricular assist device implantation. This research showed that growth characteristics of cells taken from small endomyocardial biopsies (5 mg in size) in patients with heart failure were comparable to those from larger biopsies [77]. Although these samples are more difficult to obtain, studies are focusing on the use of expansion ex vivo before transplantation into damaged hearts.
Overall, this research offers a new method to treat myocardial infarction. Each cell type has its own benefits and limitations but more studies that directly compare the effectiveness of each cell type are warranted. Initially, studies focused on regeneration of myocardium for ischemic heart disease; however, studies are now expanding to include a larger spectrum of cardiovascular diseases.
iPSs:
induced pluripotent stem cells
hiPSs:
human induced pluripotent stem cells
MSCs:
LVEF:
left ventricular ejection fraction
iCPs:
cardiac like progenitors
CSCs:
CABG:
coronary artery bypass grafting
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Qayyum AH-S, Haack-Sørensen M, Mathiasen A, Jorgensen E, Ekblond A, Kastrup J (2012) Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regen Med 7(3):421–428
Perin E, Sanz-Ruiz R, Sanchez P, Lasso J, Perez-Cano R, Alonso-Farto J, Perez-David E, Fernandez-Santos M, Serruys P, Duckers H, Kastrup J, Chamuleau S, Zheng Y, Silva G, Willerson J, Fernandez-Aviles F (2014) Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE Trial. Am Heart J 168(1):88–95
Beltrami A, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344(23):1750–1757
Beltrami A, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114(6):763–776
Tateishi K, Ashihara E, Honsho S, Takehara N, Nomura T, Takahashi T, Ueyama T, Yamagishi M, Yaku H, Matsubara H, Oh H (2007) Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3beta signaling. Biochem Biophys Res Commun 352(3):635–641
Chong JJ, Reinecke H, Iwata M, Torok-Storb B, Stempien-Otero A, Murry CE (2013) Progenitor cells identified by PDGFR-alpha expression in the developing and diseased human heart. Stem Cells Dev. 22(13):1932–1943
Rossini A, Frati C, Lagrasta C, Graiani G, Scopece A, Cavalli S et al (2011) Human cardiac and bone marrow stromal cells exhibit distinctive properties related to their origin. Cardiovasc Res 89(3):650–660
Wang X, Zhang H, Nie L, Xu L, Chen M, Ding Z (2014) Myogenic differentiation and reparative activity of stromal cells derived from pericardial adipose in comparison to subcutaneous origin. Stem Cell Res Ther. 5(92):1–11
Li TS, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B et al (2012) Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 59(10):942–953
Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E et al (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115(7):896–908
Johnston PV, Sasano T, Mills K, Evers R, Lee ST, Smith RR et al (2009) Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120(12):1075–1083
Dixit P, Katare R (2015) Challenges in identifying the best source of stem cells for cardiac regeneration therapy. Stem Cell Res Ther. 6:26
Chugh AR, Beache GM, Loughran JH, Mewton N, Elmore JB, Kajstura J, Pappas P, Tatooles A, Stoddard MF, Lima JA, Slaughter MS (2012) Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 126(11 suppl 1):S54–S64
Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LEJ, Berman D et al (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 379(9819):895–904
Davis DR, Kizana E, Terrovitis J, Barth AS, Zhang Y, Smith RR et al (2010) Isolation and expansion of functionally-competent cardiac progenitor cells directly from heart biopsies. J Mol Cell Cardiol 49(2):312–321
Miyamoto S, Kawaguchi N, Ellison G, Matsuoka R, Shin'oka T, Kurosawa H (2010) Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts. Stem Cells Dev 19(1):105–116
Hou J, Wang L, Jiang J, Zhou C, Guo T, Zheng S et al (2013) Cardiac stem cells and their roles in myocardial infarction. Stem Cell Rev. 9(3):326–338
Linke A, Muller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A et al (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci USA. 102(25):8966–8971
Li Q, Guo Y, Ou Q, Chen N, Wu WJ, Yuan F et al (2011) Intracoronary administration of cardiac stem cells in mice: a new, improved technique for cell therapy in murine models. Basic Res Cardiol 106(5):849–864
Fang YB, Liu X, Wen J, Tang XJ, Yu FX, Deng MB, Wu CX, Liao B (2014) Differentiation induction of mouse cardiac stem cells into sinus node-like cells by co-culturing with sinus node. Int J Clin Exp Pathol 7(5):1868–1879
Huang XP, Sun Z, Miyagi Y, McDonald Kinkaid H, Zhang L, Weisel RD et al (2010) Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation 122(23):2419–2429
D'Amario D, Fiorini C, Campbell PM, Goichberg P, Sanada F, Zheng H et al (2011) Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies. Circ Res 108(7):857–861
WF was involved in the conception, design and drafting of the manuscript. RA was involved in the conception, revision and final acceptance of the manuscript. Both authors read and approved the final manuscript.
Division of Cardiac Surgery, Health Sciences North, 41 Ramsey Lake Road, Sudbury, ON, P3E 5J1, Canada
Whitney Faiella
& Rony Atoui
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Correspondence to Rony Atoui.
Stem Cell Therapies


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Posted inHousing & Development
Berkeley mayor on Wiener-Skinner housing bill: 'A declaration of war against our neighborhoods'
SB 827, that would have California cities allow denser, taller housing developments near transit hubs, has ignited controversy in Berkeley and nationally.
by Janis Mara Jan. 22, 2018, 3:00 p.m. August 4, 2022
Checking out a rainbow at Totland near North Berkeley BART. The SB 827 bill calls for denser, taller housing developments near transit hubs. Photo: Koseli Cummings
New proposed legislation, introduced by Sen. Scott Wiener and co-authored by Sen. Nancy Skinner, that would require California cities to allow denser, taller housing developments near transit hubs and bus lines, has ignited controversy in Berkeley and nationally.
With some limitations, SB 827 would eliminate restrictions on the number of houses that can be built within a half-mile of BART and within a quarter-mile of major bus routes, including Muni and AC Transit. It would also block cities from mandating parking requirements.
Skinner said the bill would help supply much-needed housing in Berkeley and the state.
Read recent news about housing in Berkeley.
"In the Bay Area alone, we've added thousands more jobs than we have housing units," she said. "More housing is essential to reduce the pressure that lack of supply is causing in all our communities. And there's no more logical place for housing than near transit."
But the bill has drawn strong opposition from many who believe it would deprive cities of their rights to control their own zoning and could also lead to unwanted density. In fact Berkeley Mayor Jesse Arreguín characterizes the bill as "a declaration of war against our neighborhoods."
Housing crisis: Everyone agrees something must be done
Not everyone agrees on how to solve the housing crisis, but everyone agrees that something needs to be done.
California's population grew from 35 million at the start of 2002 to 40 million as of Jan. 1, 2017, an increase of about 5 million, or nearly 14%, according to the state Department of Finance. During that same period, only about 2 million housing units were added by the state, a 13% increase, to 14 million.
This means the state was about 100,000 housing units short of what it needed just to keep up with population growth, potentially leaving more than 300,000 Californians without the housing they required.
It's bad enough on the state level, but in the Bay Area, things are even worse, according to the San Francisco Planning Urban Research Association. As of early 2o16, the Bay Area economy had added 480,000 private-sector jobs over the previous five years, but only 50,000 housing units.
In the San Francisco metro area, which includes Berkeley, the median rent now requires almost half of the median income – 42% – according to real estate site Zillow. From 1985 to 2000, the median rent required 31% of the median income.
Mortgage payments require a larger share of income than they did before 2000; the share is 41% today, compared to 38% historically. This means homeowners spend an additional $2,189 per year on home payments.
A rendering for a proposed multi-residential building at 3031 Adeline St. in Berkeley, which is close to Ashby BART. Image: Dinar & Associates
Lack of housing stalls greenhouse gas reduction goals
There's an environmental piece to the puzzle as well. State officials have said California will not be able to meet its goals to reduce greenhouse gas emissions by 40% below 1990 levels unless a huge number of new homes is built in job centers and near transit.
"We cannot meet climate targets if we do not permit homebuilding near transit," said Brian Hanlon, leader of pro-development group California YIMBY and an Oakland resident.
Matt Lewis, a Berkeley resident and climate and energy policy consultant, said, "If you put a bus or train within a five- or 10-minute walk of someone's house they will use it, and that is how you reduce pollution."
Pollution from cars is the biggest cause of global warming pollution in the state, responsible for 25% of such pollution.
"Scott Wiener has taken what all the planning literature says is important — this is how you reduce pollution — and put it in this bill," Lewis said.
In the Bay Area, SB 827 would affect neighborhoods close to BART, Caltrain and Muni stations. It would override certain local zoning rules in those areas to permit homes to be built nearby, but the local permitting and approval processes would not be affected.
A natural continuation of climate change laws
To Lewis, the bill is a natural continuation of California's existing climate change laws.
In 2006, then-governor Arnold Schwarzenegger signed AB 32, the groundbreaking Global Warming Solutions Act, which kick-started the process for state agencies to figure out how to reduce pollution across the California economy.
A host of subsequent legislation followed. One of the most recent bills was SB 375, which passed in the fall, directing metropolitan planning organizations to plan for building housing near transit areas.
"Pollution from cars is getting worse," Lewis said.
Because cities across the state fell behind in building enough housing, people must drive further and further from their homes to get to work in San Francisco and Los Angeles' job centers, he said.
SB 375 addressed this problem, and SB 827 codifies some of its recommendations, he said.
"No guarantee the cities will get benefits"
Berkeley Mayor Jesse Arreguín said he is on board with SB 375, but not SB 827.
"It allows 85-foot buildings throughout Berkeley and the state of California with no protection against demolition of rent-controlled housing, with no guarantee the cities will get benefits out of the out-of-scale buildings built," the mayor said.
In fact, the provisions of the bill governing 85-foot buildings only apply to buildings on streets at least 45 feet wide and one block from transit hubs such as BART.
Nancy Skinner: "I think it's always good for officials to read a bill before they use incendiary language to describe it."
"Not that many areas of Berkeley have 45-foot streets," said Thomas Lord, a housing policy advocate who is a member of Berkeley's Housing Advisory Commission. Lord emphasized that he was not speaking for the commission or the city.
"Mostly this would just apply to Sacramento Street and San Pablo Avenue," said Lord, who himself has a number of criticisms of the bill. "Surprisingly enough, Ashby (Avenue) is too narrow. Fifty-five feet would be the limit on a lot of streets, parts of Russell Street, for example."
With regard to the mayor's remark about demolition, "I think it's always good for officials to read a bill before they use incendiary language to describe it," Skinner said. "First off, the bill does not touch any local government's demolition controls. For example, in Berkeley, the Neighborhood Preservation Ordinance has very strong anti-demolition policies. The type of scenario the mayor describes would require demolition around our transit areas. That's not going to happen."
Meanwhile Wiener wrote in a Jan 14 article: "If a city has rent control, it will continue to have rent control. If a city has an inclusionary housing ordinance (i.e, requiring a portion of new units to be affordable to low-income people), it will continue to have that ordinance,"
In response to Skinner's comments, "She's technically right, those laws aren't changing," Lord said. However, he said, "if this bill raises the financial incentives, yes, local control over demolition hasn't changed, but the incentives and probability of demolition have changed."
For example, Lord said, "in South Berkeley, we have old housing stock with lower-income families. At present it's not economically advantageous for an owner to evict those tenants, tear down the house and build something else." This is because the demolition ordinance calls for compensation for the tenants and zoning limitations that limit how many units could be built.
"In this way, we encourage the owners of this naturally occurring affordable housing stock to keep the place up and provide some stability for the community," Lord said.
Lord said the bill would greatly raise the potential profit for paying the fees, then tearing down the buildings and replacing them with more units, with a potential for income that would more than offset the financial penalties.
This would lead to displacement of some of Berkeley's most economically vulnerable residents, Lord said.
Alex Casey, a policy adviser for Zillow, disagreed.
"Much of price growth is driven by scarcity," he said. "What the data show, when you look at the community as a whole, if you are not adding new units, then you are going to see existing units become more and more pricey and unable to sustain the current community members.
"Displacement is often more a product of rising prices and stale buildings than it is a block-by-block transformation," Casey said.
Jesse Arreguín: "Even if we streamlined completely, it still takes time to build new housing."
In response to Casey's comments, Arreguín said, "The reality is we're not going to build enough housing now. There's not enough land in the city of Berkeley and the amount of time it takes to build is significant. Even if you wipe out regulations, you still have to get financing. Even if we streamlined completely, it still takes time to build new housing."
While Skinner said she believed there was not enough land in Berkeley to build the amount of housing we need if we retain single-family. "If we don't densify, we are not going to be able to address the need for the number of units," she said.
Berkeley Councilwoman Lori Droste noted that the introduction of the bill is making waves, not just in California, where it's received coverage in the Los Angeles Times, but nationally; online magazine Slate ran a story about the bill, as did the Boston Globe, running an opinion piece titled, "Go on, California — blow up your lousy zoning laws."
"It's (SB 827) going to undergo several iterations before it lands in committee in March and it will be a much different bill. I think it needs to change in some ways. You want to get as many people on board as possible," she said.
Wiener has said that he is looking at ways to include anti-displacement provisions directly in SB 827, in particular around demolition controls and affordability requirements.
Lord agrees that there's a way to go on the bill. ,"The bill needs a considerable amount of amendments so it lives up to Wiener's promise that it won't lead to displacement," he said. "What Berkeley needs to do is weigh in on this bill as it makes its way through the legislature and figure out what protections Berkeley needs so the bill won't cause displacement."
Arreguín was steadfast in his opposition to the bill.
Asked if he would feel more positively about it if his concerns were addressed, he said, "No." The mayor pointed out that thousands of units are currently under construction or in the permitting process, with 910 units built since 2014 across 11 projects that are now occupied, and many more on the way.
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"I'd like to see how SB 375 is implemented," Arreguin said. "There are things underway on the state and local level to increase production but make sure we balance more housing with preventing displacement."
Skinner said, "Certainly the legislature did take some positive action to help get more affordable housing and more housing overall by approving Sen. Jim Beall's bill (SB 3, which would place a $4 billion statewide housing bond on a future ballot) and some other bills including my bill (SB 167) that strengthens the Housing Accountability Act.
"All of these were very good, but they're not enough to get us out of this crisis," Skinner said. "Anyone can see the equivalent of Hoovervilles up and down San Francisco and Berkeley. People are homeless because of a lack of affordability."
A call for Berkeley to live by its stated beliefs
Greg Magofna of East Bay for Everyone, a pro-housing organization, echoed Skinner's sentiments.
"Yes, there are projects underway, but it's not enough," Magofna said. "People are living on the streets today."
The housing advocate, who grew up in Alameda in subsidized housing and lives in Berkeley, called on the city to "live by our stated beliefs."
He said, "Sens. Wiener and Skinner are taking action to make real inclusive communities."
According to Magofna, "The Bay Area, and specifically Berkeley, talk about how we are a sanctuary city and welcoming to everyone. But by saying, 'Let's not build new housing,' we're saying, 'Come to our city and we will be a sanctuary for you if you are rich. Alternatively, you can live on the street.'"
YIMBY is short for "yes in my backyard," as opposed to the infamous NIMBY attitude, "not in my backyard." A series of groups calling themselves YIMBYs have formed in the country and across the world, lobbying for development as a cure for housing shortages and unaffordable rents. Magofna's group is a chapter of the organization.
Magofna described a recent proposed project by All Souls Episcopal Parish, 34 units of affordable senior housing at the corner of Cedar and Oxford streets with underground parking that would also house the All Souls office and meeting room.
"The neighbors showed up at a Zoning Adjustment Board meeting this fall and protested because they were afraid the building would affect the availability of parking on the street," Magofna said. "These are Berkeley values today. I am disgusted that a city championing human rights and fighting climate change would (seek to) block a project because there's not enough parking. People in Berkeley only care when it's hard for them to find a parking spot, and it's OK because they have an electric vehicle."
Tagged: Affordable housing, Greg Magofna, Home: Lead, Housing
Janis Mara
janismara@gmail.com
Janis Mara covers East Bay real estate as a freelancer for Berkeleyside. She has worked at the Oakland Tribune, the Marin Independent Journal, the Contra Costa Times, Adweek and Inman News, an Emeryville-based... More by Janis Mara

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Chargers/Chiefs will kick off week 15 on Thursday Night Football. Find out who the optimal plays and bets are for the AFC West divisional rivalry.
Welcome to a single game installment of the Monday Night Football bets and DFS picks for the Washington vs Philadelphia game tonight on Monday Night Football.


As part of the national Teachers' Day 2014 celebrations, Malaysian Communication and Multimedia Minister Datuk Seri Ahmad Shabery Cheek has announced that 400,000 teachers around the country will receive a free 1Malaysia Netbook.
Revealing the news via his official Facebook account, Datuk Seri Shabery stated that the 1Malaysia Netbook program – a 2010 initiative under the National Broadband Initiative to distribute one million 1Malaysia Netbooks to students in rural areas – will now extend to teachers. To date, over 1.7 million 1Malaysia Netbooks have been distributed to Malaysian students since the start of the program.
According to Datuk Seri Shabery, the Cabinet has approved to start the program and extend the devices to almost 400,000 teachers in government schools around the country. He further added that this was the Government's gift to all teachers for this year's Teachers' Day celebrations.


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Montreal real estate: Commercial investment on the rise
July 3, 2019/ By / no Comments
It isn't just home and condo sales that are booming in Montreal. Investment in land, retail, hotel, industrial properties, and apartment buildings are also picking up.
Briana Tomkinson, Special to the Montreal Gazette, Updated: May 13, 2019
Record-breaking residential sales in Greater Montreal continued in April, increasing for a 50th consecutive month, according to the latest numbers from the Quebec Professional Association of Real Estate Brokers. But it isn't just home and condo sales that are booming. Investment in land, retail, hotel, industrial properties and apartment buildings is also picking up.
As analyst Vincent Shirley and co-author Jenny-Kate Sgarbi note in an Altus Group Montreal Flash report released last week, while total sales of investment property across Canada declined last year because of softening markets in Vancouver and Toronto, here in Montreal, investment volume jumped 18 per cent, to the tune of $6.5 billion in sales.
The bulk of investment dollars went into apartment buildings in 2018, Shirley said, with the value of sales increasing 22 per cent compared with 2017 figures, to a total of $2.1 billion or about one-third of all real estate investment activity in the Montreal area. But the most notable increase, Shirley said, was in the industrial sector, which posted the largest absolute year-over-year dollar increase, rising $474 million to $1.2 billion.
Shirley said there had not been much activity in industrial real estate over the past decade, but the need for large-scale, automated distribution centres to keep up with demand from online shopping has retail giants looking to the outskirts of the city, where big parcels of industrial land are still available at a relatively affordable price per square foot.
While the main demand for investment property is coming from institutional investors and pension funds based in Quebec or other parts of Canada, Shirley said there are signs that foreign interest in Montreal apartment buildings, hotels and retail projects is increasing.
"Overall, the main demand is still local, but it is growing nationally and recently it is becoming global as well," he said. "It's all new for Montreal, but if Montreal aspires to be a city of the world, a world-class city, you have to expect the interest from the rest of the world. It's a part of the game. It's not a bad thing."
According to the Altus report, foreign investment in Montreal real estate increased sharply last year, rising 183 per cent compared with 2017. The bump was largely due to what CBRE vice-president Marc Hetu characterized as an "acquisition binge" of apartment buildings by Sweden-based Akelius, which owns more than 50,000 apartments in five countries.
Akelius first entered the Montreal market in 2014, and has acquired a suite of properties in and around the downtown area. In 2018, the company bought three more: Peel Plaza and Regency Apartments in Golden Square Mile, and Le Montfort in Shaughnessy Village.
Hetu said a notable entry into the Montreal market in 2018 was that of U.S.-based Blackstone Property Partners, which he said was one of the largest and most powerful real estate investment firms in the world.
Blackstone partnered with Toronto-based Starlight Investments last June for its first investment in Canadian multi-family properties, purchasing a portfolio of six buildings: five in the Toronto area and one in Montreal.
Hetu said a company like Blackstone would be unlikely to settle for just one smaller property upon entering the Montreal market and predicted they'll soon be looking to grow their interest in Montreal.
CBRE, an international commercial real estate and investment firm, provides market research, information and statistics to investment heavyweights worldwide. Hetu said international investors have been asking for information on Montreal for years, but until recently that interest hasn't generated much action.
"We've seen a lot of tire-kicking, a lot of studying, but little execution, with a few exceptions," he said.
Hetu said the growth in well-paid jobs, strong economic growth, new investments in infrastructure and apparent political stability, coupled with the comparatively lower prices of Montreal real estate, are a potent draw for investors.
"We're still playing catch up in Montreal. We've been undervalued for a very long time," Hetu said.
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California Coastal Commission Fines Hotel Developer Record $15M For 'Bait And Switch'
Why mortgage reform may have to wait for legislation, despite Poloz's musings


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Analysis: Kavanaugh allegations come at the worst time for GOP
The decision by Christine Blasey Ford to reveal her identity, days after reports that an anonymous woman had alleged she was sexually assaulted by Supreme Court nominee Brett Kavanaugh in high school, is a total game-changer, not just for Kavanaugh's chances of making it to the nation's highest court but also for Republicans looking for some way -- any way -- to preserve their congressional majorities in exactly 50 days' time.
TMZ Live: Tom Arnold & Mark Burnett Pre-Emmy Party Brawl
Hear how Oculus is minimizing VR's content problem at TC Sessions: AR/VR


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Q: Update an existing file in java I write this code to write data in a text file.
 Writer output = null;
   File file = new File("C:/HEADER.txt");
   output = new BufferedWriter(new FileWriter(file));
    output.write("hello");
    output.close();

I write this code to write over the file but what happened is that the data got deleted, and the only the new data appeared.
Writer output = null;
   File file = new File("C:/HEADER.txt");
   output = new BufferedWriter(new FileWriter(file));
    output.write("how are you");
    output.close();

A: try
new FileWriter(file, true)

this will open the file in append mode

A: Try this
Writer output = null;
File file = new File("C:/HEADER.txt");
output = new BufferedWriter(new FileWriter(file, true));
output.write("how are you");
output.close();

FileWriter(File file, boolean append) constructs a FileWriter object given a File object. If the second argument is true, then bytes will be written to the end of the file rather than the beginning.
reference : Java Doc

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5/5, what an amazing photo, as close to technically perfect as is possible. RIP Mr. Haney.
5 stars, no doubt about it. R.I.P. captain.
The snow mountains background: Marvelous!!!
10 stars on this one. You had perfect timing with the lighting. The skin of the aircraft in this light reveals all its ripples and irregularities.
What can I say? Just beautiful.
It's so simple to comment on this photo.... it's simply the best ever, and I can't imagine that we will se something better for a very long time !
One of the most beautiful pictures I have seen on this website in awhile! 5 stars fully deserved.
I've got a 1:72 model of a Raptor and you could make a few different planes from Elmendorf and Langley and so on and I made exactly this plane. It looks fabulous. Very good job mate!
One word, WOW!! Incredible shot man. One of the best photos I've seen on a.net in a while. 5 stars!!!!
If this was a scene in a movie I'd probably be complaining how fake it looked. Amazing!
It's dedication to the late Captain Jeffrey Haney.
Would love to be air to air with a Raptor, but to capture it over snowy mountains in great light....Superb.
Great work on the photo, but even better as a dedication. A thing of beauty Titan! ***** Wayne C.
Great lighting, beautiful contrast with the background, a little action with the refueling port open... Absolutely stunning photo!
Remarkable shot. You are very fortunate to be in the position to take this shot and it is top quality. Great everything.
What is opened door behind the cockpit for? Refuelling point? Excellent photo,five stars,of course.
This is an amazing photo! Congratulations on getting such a perfect one!
For me THE raptor shot!
I wonder how it possible to take such a perfect shot. This plane is of an incredible elegance, and the Alaskan background is stunning.
Although we never met. We are very proud of your accomplishment's God Bless you. Friends of Mick.
Superb photograph taken of a superb airplane !! You can't get better that this !!
The lighting and composition is simply amazing!
:O Wow... what a shot.... well done.
Photo Copyright © Titan Miller. All rights reserved. Airliners.net is not affiliated with any entity mentioned or pictured herein.


How far along are you? 17 Weeks and 4 days! I feel like this pregnancy has flown by. I can't believe in less than 3 weeks, I'll be halfway through it. Crazy!
Cravings: Peanut butter, apples, oatmeal, chocolate and smoothies. Pizza is another craving, but I haven't had it lately.
General Mood: Tired... I'm pretty much always tired. I'm trying to workout more even if it's nothing too exciting, because it makes me feel better.
Things I was surprised by: I'm feeling the baby more. Everyday, I feel him move. I feel flutters. It's nothing too obvious yet. I thought I would go to my doctor for every appointment like I did this time, but I haven't been. I've been switching it up each time, because it's a gamble who I'll get for the birth. I didn't do this last time, and I had only seen the doctor who had delivered me once.
Things I'm most looking forward to: I'm can't wait to see how Liam reacts to the new baby. I think he'll be completely mesmerized. Every time we see a baby, he points them out and has to look at them. It's super cute.
I keep thinking about Thanksgiving and Christmas. I'm really excited for both. I can't wait to do all the holiday things and be further along. Also, the Gilmore Girls revival comes out in November after Thanksgiving.
Sleep: Sleep is going a little bit better than last time. I can sleep on my side if I want to. Last time, I would get muscle cramps when I attempted to lay on my side. They hurt horribly so I never slept that way. I also sleep propped up with three king sized pillows in bed. I've been doing that since week 8, and I'm taking a break from it now since I was getting sick of it. My back doesn't hurt yet. I was reading back through my old posts with Liam, and it already hurt at 17 weeks. I'm glad I'm experiencing something different this time around.
Food aversions: None. I don't think I've ever really had one.
Maternity Clothes: Yes, I've been wearing them since 8 weeks like last time. I have all my shirts, dresses and pants in my closet now. It's nice having it all set up.


text:
Q: CocoaPods Pod install weird behavior I am currently trying to install these Pods in my Xcode project but am getting the following screen when I try pod install. I have been getting this message in xCode when trying to run my project so I thought I would just try and re-install pods. But get the error below.

platform :ios, '8.0'
use_frameworks!

source 'https://github.com/CocoaPods/Specs.git'

platform :ios, '8.1'
pod 'SwiftyJSON', :git => 'https://github.com/SwiftyJSON/SwiftyJSON.git'
pod 'Alamofire', '~> 3.0'
pod 'GooglePlacesAutocomplete'
pod 'Spring', :git => 'https://github.com/MengTo/Spring.git', :branch => 'swift2'
pod 'DropDown'
pod 'AlamofireImage', '~> 2.0'

When I run pod install I get the following message on screen in the terminal.

A: If you are using Cocoapods v0.39 you need to define a target for your pods
target :'nameOfTheScheme' do
  pod 'SwiftyJSON', :git => 'https://github.com/SwiftyJSON/SwiftyJSON.git'
  pod 'Alamofire', '~> 3.0'
  pod 'GooglePlacesAutocomplete'
  pod 'Spring', :git => 'https://github.com/MengTo/Spring.git', :branch => 'swift2'
  pod 'DropDown'
  pod 'AlamofireImage', '~> 2.0'
end


PSI for sand, beach trails?
Going to float some sand, off-road beach trails, dune grass etc. I'm 190 lbs and read the 'divide by 10 to get recommended PSI for hard surfaces' so that's 190 PSI. Should I drop the PSI a few more pounds for sandy off-road action?
Hey - I'm in St Pete, 2 weeks into my XR and loving it. I'd be up for a group ride - let me know.
I may have missed it and if I did somebody set me straight but can we have this Forum in the OW app or a simple link from the OW app?
If OW wanted to ship charging cables and even some stands to local establishments in communities where OW are popular and then put the locations on the OW maps and slap a OW sign in the shop's window, I know I'd certainly be likely to hit these spots. Grabbing a burger, beer and a charge would be extra stoke to the Saturday ride.
Oh yeah, don't drink and Wheel.


text:
Jobs for Extroverts
by William McCoy
Sales is a common position for extroverted people.
Picking the right career for you is about more than just considering your skills. If your personality doesn't mesh with your job, you'll need to adapt quickly or face being miserable. When selecting a career, think about your personality type. If you've got a bubbly, extroverted personality, a job dealing with people will be far more rewarding than one in which you spend long hours working by yourself.
Outgoing, extroverted people often succeed in many types of sales jobs because they aren't intimidated to talk to people they haven't previously met. Likewise, consumers will often gravitate toward extroverted people in sales because of their cheerful demeanor. If possible, seek a job in an area about which you're passionate; if you enjoy fashion, a sales job in a clothing store is a logical choice and if you're athletic, apply at a sporting goods company. Long-term careers in sales include residential and commercial real estate, advertising sales for media companies and product sales for any type of business.
Many types of medical and health jobs are often ideal for extroverts, given that you spend your day dealing with a long list of patients. Medical jobs to consider include such positions as doctors, dentists, nurses, orthodontists, pharmacists and paramedics. Suitable health-related jobs include working as a chiropractor, massage therapist, occupational therapist or athletic trainer. Jobs in medicine require a lengthy amount of schooling, but if you're passionate about such topics as science and enjoy working with people, this type of career is ideal.
Public Service Jobs
People who opt for careers in which they deal with people throughout the day are more likely to succeed if they're extroverts. If you have a deep desire to help people in any capacity, consider working as a police officer, firefighter, teacher, mediator or member of the clergy. Police officers and firefighters meet new people daily, while teachers typically work with the same group of students and peers throughout the year, but each of these jobs provides a needed service to any community.
If you're an extrovert with a creative side, consider a career in acting or music. People who are passionate about creating change often gravitate toward jobs in politics, even at a grassroots level by leading a community or parents' group. People who work as accountants, lawyers or designers often spend significant time alone, but must be able to work with members of the public, and in the case of a career in law, speak in front of a group.
Chicago Tribune: Jobs for Introvert and Extrovert Personalities
CareerBuilder.com: 10 Jobs for Extroverts
TotalJobs.com: Outgoing Jobs for Extroverts
Monster: 10 Ways Introverts Can Promote Themselves to Extroverts
Toronto-based journalist William McCoy has been writing since 1997, specializing in topics such as sports, nutrition and health. He serves as the Studio's sports and recreation section expert. McCoy is a journalism graduate of Ryerson University.
Jobs That Involve Writing
The Top Careers for Introverts
The Average Salary of Estheticians
Career Opportunities for the Spontaneous Idealist
Jobs for Laid-Off Teachers
Jobs for Speech Majors with a Bachelor's Degree
Careers for Teachers Other Than Teaching
How Much Does a Health Care Administrator Get Paid?
Types of Jobs for the Disabled
Jobs for Teachers Outside of Education
Jobs That Show Kindness
How to Get Started in Healthcare Administration
Great Reasons to Become a Teacher
Who Employs a Pediatrician?
What Are the Most Important Rewards You Expect in Your Job?
List of Careers That Involve Children


text:
2-я стрелковая дивизия (формирования ноября 1941 года) — воинское соединение Вооружённых сил СССР в Великой Отечественной войне.

История дивизии
Сформирована 23 ноября 1941 года приказом по Приморской армии № 00011 на базе 2-й кавалерийской дивизии в Севастополе в связи с почти полной утерей конного состава.

В действующей армии с 23 ноября 1941 по 29 января 1942. Участвовала в обороне Севастополя, южный сектор.

На момент формирования состав дивизии включал:
 Управление дивизии: комначсостав 65 человек, младший комсостав 18 человек, рядовой состав 70 человек. Легковых машин — 2, грузовых — 4, винтовок и карабинов — 50, ручных пулемётов — 1, ППД — 5.
 Сводный полк НКВД (два батальона, третий на формировании). Общая численность полка 1345 человек, две 45-мм пушки, 17 миномётов, 987 винтовок и карабинов, 9 станковых и 14 ручных пулемётов, 3 полевые кухни, 2 радиостанции.
 383-й полк. Общая численность полка 1211 человек, вооружение 912 винтовок и карабинов, 5 станковых и 12 ручных пулемётов, 2 миномёта.
 1330-й полк. 1314 человек, все со стрелковым оружием, две 76-мм пушки, две 45-мм пушки, 19 миномётов.
 51-й артполк двухдивизионного состава. В каждом дивизионе две батареи по два орудия (пушки-гаубицы МЛ-20, всего 8 шт.)

В ходе боевых действий в составе дивизии были созданы подразделения:
 Заградительный батальон. Создан в ноябре 1941 г. В составе батальона 2 роты.
 Отдельный миномётный дивизион. Сформирован в декабре 1941 г.
 Отдельная сапёрная рота. Создана в декабре 1941 г.
 Отдельный батальон связи. Создан в декабре 1941 г.

17 декабря 1941 года с началом 2-го штурма, противник повёл активные действия, правда, носившие демонстративный характер. Сначала в 7 часов с высоты 386.6 атаковали два взвода немецкой пехоты (124-й ПП 72-й ПД), затем, около 9 часов, снова последовала атака незначительными силами. В отражении этих двух атак, бойцам 1-го батальона 383-го полка содействовали зенитчики 3-ей батареи 2-го ЗенАП. В ночь с 17 на 18 декабря, 1-й батальон 383-го полка вновь получил задание овладеть тремя домами на юго-восточных скатах высоты 212.1. В ходе ночного боя захвачен язык. При допросе он показал, что в ходе боевых действий его рота понесла тяжёлые потери. Из 178 человек на данный момент в ней осталось всего 67 человек. Штаб батальона в это время находился на высоте 212.1, штаб полка в Варнутке, штаб дивизии в Байдарах. Потери в этой атаке составили 37 человек убитыми (в их числе два командира взвода).

20 декабря 1941 года части дивизии вели артиллерийский, миномётный и пулемётный огонь по позициям противника и его огневым точкам. Разведкой было установлено, что на высоте 440.8 установлена тяжелая батарея противника из двух тяжёлых орудий и трёх миномётов, при этом противник ведёт на этой высоте окопные работы. При обстреле нашей артиллерией (51-й АП) уничтожена миномётная батарея, окопные работы были прекращены.

Диспозиция дивизии на 20 декабря 1941. Сводный полк НКВД занимал границу справа: высота 57.7, отдельные строения на северных скатах, слева 99.4 включительно, оборона по западным скатам высоты «Старая крепость» и высоты 99.4. 1-й батальон 383-го полка занимал позиции от северных скатов высоты 212.1 до совхоза Благодать. Далее шли позиции 1330-го полка.

25 декабря 41 г. 2-й батальон 1330-го полка переброшен во 2-й сектор обороны, в район Итальянского кладбища.

27 декабря 41 г. Части 1-го сектора находятся в прежнем положении. В 1-м секторе во время 2-го штурма наблюдалось затишье. В то время как в Севастополе в срочном порядке формировали сводные батальоны из последних резервов, ни одного бойца, до конца 2-го штурма, из 1-го сектора не забрали. Численность личного состава дивизии не только не уменьшилась, но и увеличилась, за счёт пополнений.

30.12.41 г. по приказу командующего Приморской армией была произведена перегруппировка. В распоряжение 1-го сектора прибыла 388-я дивизия, сменившая на позициях 1330-й полк, который сдвинулся левее, на позиции 161-го полка, снятого и отправленного севернее. При этом один батальон 1330-го полка был выведен в резерв. За счёт ввода 388-й дивизии был выведен в резерв и 1-й батальон 383-го полка.

Первой значимой операцией в 1-м секторе стало новогоднее наступление. 31 декабря 41 г. в 15 часов был получен приказ командующего армией перейти в наступление 1 января 1942 г., с задачей овладеть высотами 212.1 и 440.8 и закрепиться на них. Выполняя боевой приказ командующего армией № 0028 и приказ командующего дивизией № 007, две роты 2-го стрелкового батальона и одна рота 1-го батальона полка НКВД, после артиллерийско-миномётной подготовки, перешли в наступление с задачей овладеть высотой 212.1 и хутором юго-восточнее высоты.
В 10.20 1 января 1942 г. начав штурм указанной высоты, роты вышли на линию 100 метров ниже первой траншеи противника юго-западнее высоты 212.1. При наступлении части были встречены ураганным миномётно-пулемётным огнём с высоты 386.6 и автоматным огнём с высоты 212.1. Понеся большие потери, роты к вечеру заняли прежние позиции.

Из воспоминаний М. Розина: «Ровно в 9 часов 1.01.42г. началась артподготовка на высоту 212.1, и весь огонь и дальнобойное орудие обернулось на эту высоту…
И наши войска были в готовности овладеть высотой, ждали приказа. Когда через 45 минут прекратили огонь, батальон занявший оборону вокруг высоты, поднялся в атаку с трёх сторон. В это время противник с высоты 386.6 открыл ураганный огонь по нашим войскам, и многим нашим не пришлось вернуться обратно. Но больше было раненых. … Медсестра Тамара вынесла 41 раненого, на 42-м была тяжело ранена сама….
Хочу добавить к этому бою, что проходил он неважно. Мне не нравится его разработка. Почему? Потому что огонь, начатый на высоту 212.1, вёлся неправильно, нужно было весь огонь направить на 386-ю высоту, а 212-й было достаточно и 3 миномётов. И наступление нужно было делать не на 212-ю высоту, а полным ходом, под полным прикрытием нужно было делать на 386-ю высоту. Но я только солдат-разведчик, и в такие вопросы вмешиваться не могу…»

Атака в лоб на крутые склоны высоты 212.1, на которой находится форт «Северный», изначально была труднореализуема. Система полудолговременных Балаклавских фортов как раз и строилась с расчётом штурма их стрелковыми частями. Подавить немецкие огневые точки было нечем: атакующие имели мало пулемётов, и почти не имели полковой артиллерии. Разведчики полка много раз ходили в разведку, и все эти обстоятельства были известны, но их не учли.

1.01.42 г. 1-й и 2-й батальоны 383-го полка на машинах был переброшены в район станции Мекензиевы горы, и введены в бой против немецкого 16-го пехотного полка 22-й ПД в районе отметки 60.0 (высота Героев). В этом бою, батальоны потеряли убитыми 47 человек. На второй день потери составили 37 человек. Был ранен командир батальона старший лейтенант Морозов И. Г.

3.01.42 г. батальоны 383-го полка снимаются с позиций, и отводятся для посадки на боевые корабли. Готовится Евпаторийский десант.
В составе первого эшелона десанта было достаточно много бойцов батальона МПО НКВД (около ста человек).
Остальной личный состав 383-го полка и остатки 2-го полка морской пехоты должны были стать вторым эшелоном Евпаторийского десанта. Возглавить его должен был командир 2-го ПМП капитан Н. Н. Таран. Но, в связи с гибелью первого эшелона, второй эшелон не высаживался.

Батальону был дан трёхдневный отдых на мысе Феолент, одновременно, производилось переформирование частей. Остатки двух батальонов 11 января 1942 г. были слиты в один батальон 383-го полка, (командир М. Титочка), было начато формирование нового второго батальона, командиром которого был назначен капитан В. Бондарь.

Остававшиеся на своих позициях в районе Балаклавы сводный полк НКВД и 1330-й полки 2 и 3-го января пытались перейти в наступление, но неудачно. 1-й батальон 1330-го полка (1-я и 2-я роты) и 2-й батальон (5 и 6-я роты) 1330-го полка, пытались отрезать немцев на высоте 386.6 Части продвинулись вперед, но наткнувшись на минное поле залегли.
Сводный полк НКВД 3.01.42 г. повёл небольшими силами разведку боем. Группа около 14 часов была накрыта пулемётным, а затем в 15:20 миномётным огнём.
В ходе боев у станции Мекензиевы горы 383-му полку удалось отбить у противника два орудия, ранее принадлежавшее Богдановскому 265-му полку, захваченное в ходе 2-го штурма.

10.01.42 г. 1-й и 2-й батальоны 1330-го полка поступили в распоряжение коменданта 3-го сектора. Батальоны на позициях сменил 773-й полк 388-й дивизии. 3-й батальон 1330-го полка остался на прежних позициях в районе посёлка Благодать. В этот же день, 383-й полк (без 3-го батальона), находившийся на переформировании, получил приказ о передислокации в 3-й сектор.
Перед переброской, 383-й полк был пополнен до двух батальонов по 600 человек в каждом.

Из журнала боевых действий: «17.01.42 г. части дивизии занимают прежнее положение. 1-й и 2-й батальоны 383-го полка и 1-й и 2-й батальоны 1330-го полка, действуют в 3-м секторе, по овладению высотой 115.7 и 90.0 (высота Трапеция). Особенно отличились в овладении высотами 2-й батальон 1330-го полка (командир капитан Говорунов) и 2-й батальон 383-го полка (командир капитан Бондарь). …
В результате боев, два батальона 1330-го полка и части 383-го полка вышли на юго-западные скаты высоты 292.0 и овладели высотой 115.7.
383-й полк был в затруднительном положении, но разведкой боем, в течение 14 января, подразделениями 2-го батальона, и 15-го января подразделениями 1-го батальона, выяснилось, что в полосе наступления полка противник насчитывает 200—250 человек пехоты, 2-3 миномётных батареи и 12 пулемётов, находящиеся в дотах и дзотах. Для наступления на высоту 115,7 383-й полк имел приданными: один дивизион (152 мм пушки) и танковую роту (7 танков Т-26). В 9.00. 17.01.42г. 383-й полк атаковал высоту, попав под сильный артминометный огонь. В 17 и в 18 часов противник дважды переходил в контрнаступление, но хорошо организованной обороной был отбит. Танки ввиду пересечённой местности результатов не показали. Части понесли тяжёлые потери»

Высота 115.7 была взята в результате ночного боя с 17 на 18 января. Ночной бой в лесистой местности на плато Мекензиевых гор закончился полным поражением немецких войск.

20.01.42 г. батальоны 383-го полка были отведены на отдых в район Георгиевского монастыря.

Боевые действия частей 2-й дивизии в 3-м секторе привели к большим потерям. Количество раненых превысило восемьсот человек, то есть батальоны потеряли до 30 % личного состава. Сразу по возвращении в 1-й сектор 2-я рота 1-го батальона была выведена на передовую в районе совхоза Благодать. Два батальона 1330-го полка временно остались в распоряжении коменданта 3-го сектора. На позициях 1-го сектора появилась артиллерия 388-й СД.
По состоянию на 20.01.42г. дивизией получено пополнение. После получения пополнения общая численность дивизии составляла 6416 человек.

26.01.42 г. были намечены мероприятия по инженерному оборудованию рубежей:
 В течение 2-3 дней оборудовать в инженерном отношении высоту 164.9.
 Рубеж от высоты 164.9 до Федюхиных высот прикрыть противотанковыми минами.
 С целью экономии живой силы на участка 383-го полка и полка НКВД, провести следующие мероприятия:
 на западных скатах высоты 212.1 установить минные поля и часть подразделений отвести в резерв.
 оборудовать два батальонных опорных пункта на рубеже Кадыковка — изгиб балаклавской дороги — высота 123.3 и прикрыть весь рубеж минами.
 установить управляемые фугасы на Ялтинском шоссе у развилки дорог, оборудовать укрытия для сапёров, замаскировать и закопать все сапёрные провода. Подчинить сапёров командирам подразделений.

29 января 1942 года переименована в 109-ю стрелковую дивизию.

Подчинение

Состав
 383-й стрелковый полк
 1330-й стрелковый полк
 сводный полк пограничных войск НКВД
 51-й артиллерийский полк
 105-й медико-санитарный батальон
 881-я полевая почтовая станция

Командиры
 Новиков, Пётр Георгиевич, генерал-майор — (23.11.1941 — 29.01.1942)

Примечания

Ссылки
 Справочник
 База данных стрелковых дивизий
 Проект Память
 История одной дивизии (2-я стрелковая дивизия)

Стрелковые дивизии СССР во время Великой Отечественной войны
Воинские части и формирования, созданные в 1941 году
Воинские части и формирования, расформированные в 1942 году
Стрелковые дивизии СССР

redpajama_set_name: RedPajamaWikipedia


text:
Xbox One Hard Drive Can Only Hold 20 Games
By Will Usher published 9 December 13
I hope you aren't planning on collecting a large library for your Xbox One, because if you're knee-deep into video game collecting the pre-installed hard drive of the Xbox One will limit you to accessing only 20 retail-sized games at a time (depending on the size of the games).
Our previous report about the non-replaceable hard drive (unless you want to void your warranty) in Microsoft's Xbox One having only 391GB free for game storage was incorrect. I'm not afraid to say that I was wrong, the report was wrong, the information was not entirely factual.
The Xbox One actually only has 362GB free for game storage.
Super epic, omega fail.
So how was it discovered that the previous reports about the Xbox One's hard drive free space was incorrect? Well, IGN did a surprisingly thorough video to test the actual capacity of the Xbox One and it turns out that the free space available to gamers is a heck of a lot smaller than we originally thought... by 29 gigabyte. Now some of you might think that 29GB isn't much, but keep in mind that that's enough space to install Dead Rising 3 and FIFA 14.
IGN took time to install 25 apps – most of which approximated around 25 megabyte but some extended as far as 100MB – and that totaled 1.6GB. They also installed 20 of the available games they had on hand, which filled up 362GB of hard drive space on the Xbox One. When they tried to install Zoo Tycoon (which would have been the 21st game), they were all out of space.
Compare this to the PlayStation 4 and you can see that Sony's system offers you the option to replace the hard drive right out of the box with something bigger, and also offers 408GB of free space out of the 500GB hard drive. That's a 46GB difference, which is around the install size of 2K Games' NBA 2K14, a game that has an install size that clocks in at 43GB.
The video from IGN also notes that the save data and video storage is rather small, clocking in at less than 100MB. This means that minus the apps, which amount to 1.6GB – out of the 500GB hard drive – the Xbox One's three operating systems and OS reserves clock in at an absolutely massive 136.4GB.
Can you believe that? 136.4GB?
Just for reference, Windows 7 64-Bit Home Premium Edition with all the latest updates and Aero accoutrements clocks in at approximately 18GB. By comparison, that means that one of the more powerful, high-end versions of Windows 7 is only 12% the size of the Xbox One's operating system space. Also keep in mind that Windows 7 uses only a third of the RAM requirements that power the Xbox One's Windows 8-based tablet OS.
Any gamer, fanboy or Xbox fanatic who even tries to use efficiency, memory management or RAM utilization as an excuse for the Xbox One having better optimization than a PC just needs to sit in a corner and zip their lips like Link in every Zelda game that wasn't on the Intellivision.
Anyway, some gamers feel that filling up a hard drive with 20 games isn't that big a deal considering that the library of Xbox One titles is paltry at the moment. However, Microsoft has yet to roll out an actual release window for external hard drive support, so game collectors will have to start counting every megabyte to a gigabyte when installing a game because games certainly aren't getting smaller.
Will Usher
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The first year curriculum affords our interns excellent experience. Our program is "front-loaded" in that the intern year is the most demanding.
The second year shifts to a more outpatient focus. With a diversity of rotations and much less call we have an opportunity to read and get the most from our rotations.
The third year continues with an outpatient focus and many opportunities to explore your own interests. Call is very light; about 13-15 days in-house per year.
During 2nd year and 3rd year, residents have the opportunity to do two electives each year. Available elective opportunities range and can be adjusted to each individual's interest. Away electives are allowed with prior program approval once a year.


text:
Owning Mahoney
Genres: Drama, Thriller
Starring: Philip Seymour Hoffman, Minnie Driver, John Hurt
Director: Richard Kwietniowski
Based on the true story of the largest one-man bank fraud in Canadian history, Philip Seymour Hoffman (The Talented Mr. Ripley), Minnie Driver (Good Will Hunting) and John Hurt (Harry Potter and the Sorcerer's Stone) star in the coolest, smartest, most stylish thriller of the year!
Dan Mahowny (Hoffman) is a mild-mannered bank manager with a nasty gambling habit and a job that gives him access to a $20 million account. When a major losing streak leaves him busted and unable to cover his losses, Mahowny develops an ingenious plan to play the bank against the casino. But with time running out and the odds stacked against him, obsession becomes compulsion and the thrill of the bet is quickly replaced with a primal desire to stay in the game. "Engrossing, wryly funny and strangely poetic!" - Glenn Kenny, Premiere
See what folks are saying about this title in our forums.
Check out our full list of Amazon pre-order titles.
MPAA Rating: Rated R
Movie Studio: Sony
Length:105 Minutes


The Sunnyland Neighborhood Association has been in operation as the City of Bellingham's official neighborhood association for at least 25 years. Its leadership, board, membership and mission has changed over time, as has the City's definition of the role of the neighborhood associations within the larger structure of the City itself. The current board has been in place since the summer of 2016.
What is the objective of the SNA?
The SNA is organized to support quality of life, community preservation and enhancement, citizen involvement in civic affairs for residents, businesses, organizations and institutions within the Sunnyland neighborhood.
Who can be a member of the SNA?
Anyone 18 years or older who lives, owns property, operates a business or represents an organization (church, school etc.) within the neighborhood.
What are some of the ways that members can participate in the SNA?
Join us at one of the quarterly membership meetings or social events. Follow the SNA on social media to get meeting notices and information. Volunteer to become a board member (or nominate/encourage someone else to be a board member.) Contact the board to request a particular discussion topic/ speaker at a general membership meeting at sunnylandneighbors (at) gmail (dot) com.
Does it cost money to be a member?
No. Donations, however, are accepted to support costs such as rent for meeting spaces, printing, website fees, etc.
What is the purpose of the SNA Board and how does one become a board member?
The board conducts the business of the neighborhood association, which is a Washington State non-profit, and plans and organizes the quarterly membership meetings. Nominations and voting on board members occurs at the general membership meeting in February each year. The SNA strives for representation of the neighborhood's geography as well as both resident and business representatives. The by-laws are available here.
Does the SNA recommend specific action to the city and the mayor?
The SNA acts primarily as a conduit for information and as a resource to foster participation in public input processes related to development, codes and other issues which impact the quality of life in the neighborhood.
The board and the SNA do not typically take positions on a specific issue. A representative from the SNA is nominated by the Mayor to sit on the Mayor's Neighborhood Advisory Council (MNAC). The MNAC provides a venue to share the concerns and interests of each neighborhood with the mayor and city administration.
Where and when are membership meetings typically held?
The meeting schedule is set annually by the board, and typically falls on the 1st Tuesday of February, May, August and November from 6-7:30pm. Please check the Facebook page or the website to verify times and locations. Room/speaker availability sometimes affects this schedule.
Meeting agendas typically include an invited speaker, updates from the neighborhood police officer, announcements about upcoming SNA events and public comments/announcements from attendees.