Oxygen: a master regulator of pancreatic development?

Size: px
Start display at page:

Download "Oxygen: a master regulator of pancreatic development?"

Transcription

1 Biol. Cell (2009) 101, (Printed in Great Britain) doi: /bc Models and Speculations Oxygen: a master regulator of pancreatic development? Scientiae forum Christopher A. Fraker, Camillo Ricordi, Luca Inverardi and Juan Domínguez-Bendala 1 Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, U.S.A. Biology of the Cell Beyond its role as an electron acceptor in aerobic respiration, oxygen is also a key effector of many developmental events. The oxygen-sensing machinery and the very fabric of cell identity and function have been shown to be deeply intertwined. Here we take a first look at how oxygen might lie at the crossroads of at least two of the major molecular pathways that shape pancreatic development. Based on recent evidence and a thorough review of the literature, we present a theoretical model whereby evolving oxygen tensions might choreograph to a large extent the sequence of molecular events resulting in the development of the organ. In particular, we propose that lower oxygenation prior to the expansion of the vasculature may favour HIF (hypoxia inducible factor)-mediated activation of Notch and repression of Wnt/β-catenin signalling, limiting endocrine cell differentiation. With the development of vasculature and improved oxygen delivery to the developing organ, HIF-mediated support for Notch signalling may decline while the β-catenin-directed Wnt signalling is favoured, which would support endocrine cell differentiation and perhaps exocrine cell proliferation/differentiation. Introduction Our understanding of general development and organogenesis has been characterized by the progressive unravelling of layers of complexity not previously suspected. As occurred with the discovery of the epigenetic code and microrna regulatory networks which changed completely our perspective on the beautifully simple central dogma of molecular biology (Crick, 1958) we are just starting to realize that the molecular changes that define the course of development might also be regulated by physical agents acting upon a background of pre-existing molecular factors. For instance, mechanical forces generated by cell division have been found to be powerful regulators of the balance between proliferation and differentiation (Nelson et al., 2005). Applications of these findings include the manipulation of mesenchymal stem cell fate by the microengineering of tissue shape and tension (Chen, 2004) or the use of cyclic compression to promote chondrogenesis (Huang et al., 2004; Pelaez et al., 2008). Similarly 1 To whom correspondence should be addressed ( Key words: β-cells, oxygen, pancreatic development, Notch, Wnt/β-catenin. Abbreviations used: ARNT, aryl hydrocarbon receptor nuclear translocator; Dvl, Dishevelled; HAT, histone acetyl transferase; HDAC, histone deacetylase; HIF, hypoxia inducible factor; NRX, nucleoredoxin. striking effects on development have been described for other physical parameters, such as bioelectrical fields (Nuccitelli, 1988; Levin, 2003; Robinson and Messerli, 2003) or the nature of the cellular substrate (Czyz and Wobus, 2001; Li et al., 2006; Liu et al., 2006a, 2006b). The exploration of the cellular basis of each one of these phenomena could be the subject of several dedicated reviews. Ours will be focused on oxygen, whose ontogenetic role has already been established in various developmental models. Mutations of several components of the oxygen-sensing machinery, for instance, result in aberrant placental development (Gnarra et al., 1997; Adelman et al., 2000; Cowden Dahl et al., 2005; Takeda et al., 2006). Additional evidence was obtained in vitro by culturing human placental cytotrophoblasts, which proliferate at low oxygen tensions (similar to those found during early pregnancy) but develop an invasive phenotype at higher oxygen concentrations, recapitulating their native behaviour when they populate the maternal spiral arterioles to establish the utero-placental circulation (Genbacev et al., 1997; Zhou et al., 1997; Caniggia et al., 2000). Adipogenesis is also affected by oxygenation, as low oxygen tensions activate HIF (hypoxia inducible factor)-1α, inhibiting differentiation by repressing PPARγ (peroxisome proliferator-activated receptor γ)inadec1 Volume 101 (8) Pages

2 C.A. Fraker and others (deleted in esophageal cancer 1)-dependent fashion (Yun et al., 2002). This effect could not be replicated in HIF-1α-deficient mice. Low oxygen tensions have been associated to improved expansion of stem cells in an undifferentiated state, whereas higher oxygenation tends to induce differentiation (Ezashi et al., 2005; D Ippolito et al., 2006; Zscharnack et al., 2008). Reduced oxygen levels normally stimulate proliferation in adult neural progenitors, but hyperoxia induces maturation in a HIF-1-related manner (Zhu et al., 2005; Burgers et al., 2008; Horie et al., 2008). Beyond a mere proliferation/differentiation switch, a dynamic control of oxygen tension has been shown to provide a fine regulation of cell fate at several levels of neural stem cell development (Chen et al., 2007; Pistollato et al., 2007, 2009). Cardiovascular/ pulmonary development, haematopoiesis and bone morphogenesis are other examples of the critical influence of oxygen in many differentiation processes (Csete, 2005; Simon and Keith, 2008). However, there is an enormous void in our knowledge about the influence of oxygen on pancreatic development, which is otherwise one of the best characterized models of organogenesis. Our interest in the topic arises from our recent finding that oxygen plays a major part on the specification of pancreatic endocrine cells in vitro (Fraker et al., 2007). A superficial examination of the potential mechanisms behind this effect reveals the surprising linkage between the cellular oxygensensing machinery and the molecular networks ultimately responsible for entire developmental programs. Since this is a largely untapped field, our goal is not so much to authoritatively describe a novel regulatory mechanism of pancreatic development as it is to make a first attempt at gathering the pieces of an intriguing biological puzzle. Throughout this review we will try to convey the notion that, when the basic oxygen-sensing biology is confronted with key milestones of pancreatic development, a clear picture starts to emerge. Pancreatic development Despite some timing differences (Piper et al., 2004), there is a high degree of conservation between human and mouse pancreatic development. The latter is initiated around E8.5 from a region of the foregut epithelium where Shh (sonic hedgehog) signalling has been down-regulated. The pancreatic primordia (dorsal and ventral) are characterized by the transient expression of the genes Pdx1 and Ptf1α (Kumar and Melton, 2003). Epithelial cells at this stage might be considered equipotent, and their proliferation results from a molecular equilibrium barely maintained by active Notch signalling (Kadesch, 2004). The rupture of this unstable condition results in the first fate decisions: cells subjected to persistent Notch signalling will remain undifferentiated and cycling; down-regulation of Notch, in contrast, will yield cells that express the pro-endocrine gene Ngn3 (Apelqvist et al., 1999). In accordance to the changing signalling microenvironment, these Ngn3-positive cells will differentiate into all the endocrine cell types throughout development: α (glucagon-producing)cells from E9.5; β (insulin-producing) cells from E ; δ (somatostatin-producing) cells from E13.5 and PP (pancreatic polypeptide) cells shortly before birth. As for the exocrine lineage, CRE-ER TM tracing experiments show that acinar cells arise from Pdx1+ progenitors in which neither Notch signalling nor Ptf1α expression are down-regulated (Gu et al., 2002, 2003). The proliferation of exocrine progenitor cells observed at a later point has been associated with sustained Wnt/β-catenin signalling (Murtaugh et al., 2005; Wells et al., 2007). Therefore, it can be said that the proliferation/differentiation balance of the two major pancreatic lineages is regulated to a significant extent by either Notch (endocrine/early exocrine progenitor cell proliferation) or Wnt/β-catenin (late exocrine progenitor cell proliferation). The secondary transition starts around E13.5 and is maintained throughout intrauterine development (Pictet and Rutter, 1972; Pictet et al., 1972). This phase is characterized by a massive wave of endocrine cell differentiation, with a strong reactivation of Pdx1 in newly formed β-cells. An interesting observation that we will revisit later is that this phenomenon is coincident in time with the initiation of blood flow (and therefore higher oxygenation) within the organ (Colen et al., 1999). Effects of oxygen on endocrine/exocrine specification in vitro Despite the major influence of oxygen on pancreatic islet survival and function (Chase et al., 1979; Berggren, 1981; Papas et al., 1996; Kazzaz et al., 1999; Carlsson and Mattsson, 2002; Carlsson et al., 2002, 2003; Ko et al., 2008), the first systematic studies on its participation in the development 432 C The Authors Journal compilation C 2009 Portland Press Ltd

3 Oxygen and pancreatic development Scientiae forum of the pancreas were reported only recently (Fraker et al., 2007). The apparent oversight might have been due to the inability of standard culture mechanisms to deliver oxygen in a physiological fashion, which has complicated the appropriate design of in vitro studies. This limitation was finally overcome with the development of novel culture vessels designed to minimize the formation of gas diffusion gradients, maintaining relatively constant oxygen levels throughout cellular aggregates (Fraker et al., 2007). These culture devices are generally based on the replacement of the plastic bottom of a flask or dish by air-permeable membranes. By culturing the cells atop these vessels, they receive oxygen both from the top (via diffusion through the culture medium) and the bottom (through the breathable membrane). Variations of this concept were previously used to increase pancreatic islet culture density without loss of viability and function (Papas et al., 2005) and to maintain long-term hepatocyte phenotype in culture (De Bartolo et al., 2006). Using an evolved system based on the use of perfluorocarbon in the basal membrane, Fraker et al. (2007) exposed E13.5 mouse pancreatic buds (at the initiation of the secondary transition) to physiologically high oxygenation (Carlsson and Mattsson, 2002) for three days. The differentiation outcome was compared with that of control explants, grown in regular (hypoxic) conditions. Two significant effects were observed in the experimental group: (a) faster proliferation of non-endocrine progenitor cells; and (b) enhanced endocrine differentiation. The profile of pancreatic buds cultured in this way was largely indistinguishable from that observed during normal native development at corresponding time points, suggesting that physiological oxygenation is critical for appropriate pancreatic development. Although there is no literature yet on the effects of oxygenation on pancreatic development in vivo,these results are consistent with those of preliminary experiments in which exposure of pregnant mice to hyperbaric oxygen led to an acceleration of pancreatic, but not overall embryo, development (C.A. Fraker, S. Álvarez, L. Inverardi, C. Ricordi and J. Dominguez- Bendala, unpublished work). The oxygen-sensing machinery and pancreatic development Cells respond to low oxygen concentrations by activating the HIF-1 pathway. HIF-1 is a heterodimer consisting of two basic helix-loop-helix/pas protein subunits: (a) the aryl hydrocarbon nuclear translocator (ARNT or HIF-1β), which is constitutively expressed in an oxygen-independent manner; and (b) the oxygen-dependent α domain (Pugh and Ratcliffe, 2003). Evidence also indicates that human islet expression of ARNT/HIF-1β expression is dramatically reduced in Type 2 diabetes, and β-cellspecific mutations in HIF-1β lead to impaired glucose tolerance and insulin secretion (Gunton et al., 2005; Levisetti and Polonsky, 2005; Czech, 2006). As for the α domain, HIF-1α is the most widely expressed member of its family in mammals, and knockouts exhibit embryonic lethality (Iyer et al., 1998). HIF-2α and HIF-3α are more specialized and have more tissue-specific functions (Semenza, 2000; Maynard et al., 2003, 2007; Wiesener et al., 2003; Warnecke et al., 2004; Chavez et al., 2006). Although HIF-2α is also highly expressed in the pancreas (Wiesener et al., 2003), there are no reports suggesting that its function in this organ is dissimilar to that of HIF-1α. Therefore, for the sake of simplicity, we will base our models on the latter. In normoxia, HIF-1α is polyubiquitinatedand targeted for degradation by an E3 ubiquitin ligase complex that contains, among other protein associates, the tumour suppressor protein pvhl (von Hippel Lindau protein). Hypoxia, however, stabilizes the protein (Pugh and Ratcliffe, 2003; Bell et al., 2005), allowing it to interact with downstream genes involved in processes such as angiogenesis (Pugh and Ratcliffe, 2003; Diez et al., 2007), erythropoiesis (Stockmann and Fandrey, 2006), glucose transport/glycolysis (Wenger, 2002), apoptosis (Moritz et al., 2002) and stem cell self-renewal/proliferation (Jogi et al., 2002; Ezashi et al., 2005; Gustafsson et al., 2005; Diez et al., 2007). The Notch pathway is generally involved in proliferation and the maintenance of an undifferentiated state (Kadesch, 2004), and its down-regulation is the first step in the initiation of the pancreatic endocrine differentiation cascade (Apelqvist et al., 1999; Jensen et al., 2000; Lammert et al., 2000; Edlund, 2001; Hart et al., 2003; Murtaugh et al., 2003). HIF-1α is known to interact with the intracellular domain of Notch, activating this pathway under hypoxic conditions (Cejudo-Martin and Johnson, 2005; Gustafsson et al., 2005; Pearand Simon, 2005; Sainson and Harris, 2006; Diez et al., 2007). This is in agreement Volume 101 (8) Pages

4 C.A. Fraker and others with the observation that hypoxic areas during embryonic development are generally associated with proliferation (Lee et al., 2001). In this context, one potential explanation of the in vitro effects of oxygen on endocrine differentiation is that high oxygen tensions de-activate HIF-1α, which in turns results in an overall down-regulation of Notch signalling and an outburst of endocrine cell differentiation. But what is high oxygen during pancreatic development in vivo? It is generally accepted that mammalian development occurs at very low oxygen levels prior to the onset of blood circulation (Mitchell and Yochim, 1968; Rodesch et al., 1992; Simon and Keith, 2008). In the rat embryo, the yolk sac becomes the first important organ of O 2 /CO 2 exchange around E10.5 (New, 1978). Prior to that, the embryo receives oxygen mainly through diffusion (New, 1978; Miki et al., 1988). Even in full environmental oxygenation ( po 2 of 160 mmhg), the maximal tissue volume that can be oxygenated by simple diffusion is approx. 1mm 3 (Burggren, 2004). If we factor in the observation that the po 2 of the mammalian reproductive tract is less than half that of the atmosphere, the upper limit of diffusion in the pre-circulation embryo is even smaller (Gassmann et al., 1996). Therefore, it is reasonable to expect that pancreatic development occurs at oxygen concentrations barely above anoxia, at least until the advent of blood flow in the organ at E13.5 (Colen et al., 1999). In the absence of direct measurements of pancreatic oxygen tension in the embryo, we can speculate that the above event will mark a turning point in the availability of oxygen to the tissue. Thus, physiological oxygen concentrations are expected to be low prior to E13.5 and high afterwards, which is in line with the developmental patterns observed before (Notch-dependent expansion of endocrine progenitors) and during (endocrine cell differentiation) the secondary transition. Since blood vessel formation is promoted by HIF-1 under hypoxic conditions (Pugh and Ratcliffe, 2003; Diez et al., 2007), vasculogenesis/blood flow could be considered both cause and consequence of pancreatic development. Of course, developmental events rarely surprise us with single explanations. Higher oxygenation may also prevent the differentiation and promote the proliferation of certain cell types, which would be difficult to explain by the HIF-1/Notch interaction. Of particular interest for pancreatic development is the potential role of oxygen in the Wnt pathway. While Wnt signalling has been traditionally divided in canonical (β-catenin-dependent) and non-canonical (β-catenin-independent) from a ligand point of view (i.e. some Wnt ligands will lead to β-catenin accumulation, whereas others act through other mechanisms), a more recent reassessment of the evidence suggests that Wnt ligands are not intrinsically canonical or non-canonical, but that they operate through different pathways depending on the nature of their receptors (van Amerongen et al., 2008). In the Wnt/β-catenin pathway, when ligands bind to the Frizzled receptor, the β-catenin destruction complex is inhibited. Accumulated β-catenin migrates subsequently to the nucleus, where it binds to TCF (T-cell factor)/lef (lymphoid enhancer factor) complexes to activate target genes normally involved in a variety of processes, including proliferation (Hoppler andkavanagh, 2007). Wnt/β-catenin activation has been shown to be essential for the maintenance of undifferentiated proliferating exocrine progenitor cells in the developing pancreas (Murtaugh et al., 2005; Wells et al., 2007), and there is significant evidence that Wnt/β-catenin signalling is inhibited in hypoxia. For instance, HIF-1α has been shown to compete with TCF4 for direct binding to β-catenin (Kaidi et al., 2007). Also, the redox-regulating protein NRX (nucleoredoxin) inhibits Wnt/β-catenin signalling by binding to Dvl (Dishevelled), a critical component of the pathway (Funato et al., 2006). However, the oxidation of NRX results in its dissociation from Dvl, which results in a net downregulation of Wnt/β-catenin activity (Figure 1). Therefore, in specific cell types (such as exocrine progenitor cells), high oxygen may promote proliferation through Wnt/β-catenin activation. Summarizing what has been proposed so far, the hypoxia-induced initiation of blood flow in the pancreas would: (a) down-regulate Notch signalling in endocrine progenitors, promoting their differentiation into islet endocrine cell types; (b) up-regulate Wnt/β-catenin signalling in exocrine progenitor cells, taking over Notch to stimulate their proliferation throughout the rest of development. It is important to stress that, even though both the endocrine and the exocrine compartments are differentiating and expanding during the same developmental windows (which would argue against the differential impact of higher oxygenation), the mechanisms by which 434 C The Authors Journal compilation C 2009 Portland Press Ltd

5 Oxygen and pancreatic development Scientiae forum Figure 1 Notch and Wnt/β-catenin pathways are differentially affected by oxygen levels In low oxygen concentrations (left), HIF-1α is stable and dimerizes with HIF-1β. The complex is known to bind to the intracellular domain of Notch (bottom; interaction represented by an arrow), favouring the transcription of target genes. However, higher oxygen levels (right) induce the degradation of HIF-1α by the E3 ubiquitin ligase complex, decreasing the net activity of Notch. Upon activation of the Wnt receptor (top), β-catenin destruction is halted and the protein migrates to the nucleus, where it forms a complex with other proteins to activate target genes. Low oxygen conditions (left) favour the sequestration of Dvl (an essential component of the pathway) by NRX. In addition, stabilized HIF-1α will compete with β-catenin co-factors. Hypoxia, therefore, is associated with an overall down-regulation of the pathway. In contrast, higher oxygen tensions (right) will (a) oxidize NRX, releasing Dvl; and (b) destabilize the HIF-1 complex, eliminating the competition for β-catenin co-factors. A high oxygen concentration is thus conducive to enhanced Wnt/β-catenin activity. they do so are not the same and may have different kinetics. As mentioned earlier, an up-regulation of any given signalling mechanism will have different effects depending on the receptors expressed in the different cell subsets (van Amerongen et al., 2008). Endocrine cells arise from pancreatic progenitors in a Notch-dependent fashion at early stages of development (Apelqvist et al., 1999), when oxygen tensions are low. Upon vascularization and in the presence of high oxygenation, they progressively start to increase their numbers by proliferation of differentiated cells (Zhang et al., 2006). This would be consistent with the recent observation that Wnt signalling (which is up-regulated in high oxygen) has been associated with increased β-cell proliferation (Liu and Habener, 2008). Exocrine cells behave in a similar way prior to the secondary transition, but their main expansion, which is believed to occur through progenitor cells and not by self-replication, occurs in a Wnt-mediated manner from the onset of the secondary transition onwards (Murtaugh et al., 2005; Wells et al., 2007). Thus, the increase in Wnt activity associated with higher oxygen availability might have the twofold effect of increasing (a) endocrine cell mass by selfreplication and (b) exocrine cell mass by progenitor cell expansion. Oxygen may have an additional function during pancreatic development, one even subtler than that Volume 101 (8) Pages

6 C.A. Fraker and others of modifying the general activity of large signalling pathways such as Notch and Wnt/β-catenin. We are referring to its direct influence on local chromatin reorganization, which may lead to the expression or silencing of genes critically involved in the progression of pancreatic development. Among the many post-translational modifications of the nucleosome that affect DNA compactness, and therefore accessibility of the transcriptional machinery, one of the best characterized is lysine acetylation. The net level of acetylation at any given locus is the result of the balance between HATs (histone acetyl transferases) and HDACs (histone deacetylases). Highly acetylated loci (with high HAT activity) have a looser DNA coiling, which is typically indicative of elevated transcription. Strong HDAC activity, in contrast, is likely to lead to gene silencing. HDACs 1, 2, 3, 4 and 7 are known to interact with HIF-1α, and hypoxic conditions have been unequivocally linked to enhanced nuclear HDAC-mediated transcriptional repression (Simon and Keith, 2008). Indeed, the promoter of NeuroD/Beta2, a downstream target of Ngn3 and fundamental component of the pancreatic β-cell differentiation cascade (Naya et al., 1997), is transcriptionally repressed by a protein complex that includes HDACs 1 and 3 (Liu et al., 2006c). Intrauterine growth retardation, which is commonly associated with lower oxygen transport to the uteroplacental unit (Martin-Gronert and Ozanne, 2007), results in the progressive epigenetic silencing of Pdx1 through the recruitment of HDAC-1 to its promoter (Park et al., 2008). With both NeuroD/Beta2 and Pdx1, transcriptional repression could be reversed by HDAC inhibition (Liu et al., 2006c; Park et al., 2008). A recent study on explanted murine embryonic pancreatic rudiments found that treatment with different HDAC inhibitors enhanced ductal at the expense of acinar differentiation, upregulated the Ngn3-positive pro-endocrine lineage and enhanced the pool of β-cells (Haumaitre et al., 2008). Additional indirect evidence on the importance of HDAC down-regulation for the progression of pancreatic development comes from in vitro differentiation experiments where HDAC inhibitors were successfully used to induce the expression of essential markers of pancreatic development (Goicoa et al., 2006; Jiang et al., 2007). The study of the many other cellular processes affected by oxygen-regulated chromatin reorganization, including DNA repair (Mihaylova et al., 2003), inflammation (Rahman et al., 2004; Rahman and Adcock, 2006), senescence (Dohi et al., 2008) or other types of differentiation (Yun et al., 2005), is obviously beyond the scope of this review. In the case of pancreatic development, the evidence gathered so far suggests that high oxygen conditions present after E13.5 may favour reorganization by depleting HDACs from protein complexes that repress the expression of relevant genes. Another indirect effect of oxygen in shaping overall pancreatic development is observed through the HIF-1α-dependent formation of vasculature. In vitro experiments showed that blood vessel endothelium is capable of inducing expression of the insulin gene in explanted mouse embryonic endoderm. Vascularization in the posterior foregut in transgenic mice expressing VEGF (vascular endothelial growth factor) under the control of the Pdx1 promoter led to ectopic insulin expression and islet hyperplasia. Conversely, removal of the developing dorsal aorta in frog embryos abrogated insulin expression in vivo (Lammert et al., 2001). Subsequent studies demonstrated that endothelial cell signals from the aorta were instrumental in the earlier stages of pancreatic development, up-regulating the expression of the critical pancreatic morphogen p48/ptf1a (Lammert et al., 2003; Yoshitomi and Zaret, 2004). The theoretical interaction of all the above pathways is depicted in Figure 2. This model conforms to the evidence presented herein, but we propose it only as a working hypothesis that needs to be experimentally tested. In this context, the recent availability of floxed HIF-1α mice (Ryan etal., 2000) mighthelpus explore in detail the effect of variable oxygen tensions on individual cellular subsets within the developing pancreas. A view of oxygen as the top ruler of all these molecular networks would be overly simplistic. In fact, we must emphasize that, whereas mechanical and other external factors do play an important role in development, their input is based on the availability of molecular factors capable of replying to such input within a window of developmental potential. However, a deeper knowledge of the influence that physical variables have on fundamental cell processes might lead to the realization that there is yet another level of regulation orchestrating gene expression, cell behaviour and, ultimately, the unfolding of 436 C The Authors Journal compilation C 2009 Portland Press Ltd

7 Oxygen and pancreatic development Scientiae forum Figure 2 A theoretical framework to explain the role of oxygen in pancreatic development Hypoxic conditions present in the pancreatic buds prior to the initiation of blood flow (E8.5 E13.5, top) will lead to the stabilization of HIF-1α, which in turn will (a) activate Notch, repressing endocrine differentiation from multipotential progenitors; (b) induce the expression of VEGF; and (c) bind to HDACs to repress target genes such as Pdx1, Ngn3 and Beta2/NeuroD. The Wnt/β-catenin pathway remains down-regulated under hypoxic conditions. This developmental setting (high Notch and low Wnt/βcatenin activity) results in multipotential progenitor cell proliferation and repression of endocrine differentiation. VEGF synthesis as a result of HIF-1 activity is a main determinant of vascularization. Blood starts to flow in the pancreatic buds around E13.5, with a consequent increase in the availability of oxygen (bottom). Under these conditions: (a) HIF-1α will be degraded, slowing down Notch activity and preventing the HDAC-mediated repression of target genes; and (b) the blockages on the Wnt/β-catenin pathway are removed. This setting (low Notch and high Wnt/β-catenin activity) favours endocrine differentiation and exocrine precursor cell proliferation. embryonic development. This putative physiological code might not just overlap known regulatory pathways, but perhaps even override them under certain circumstances. Deciphering such a code would be of enormous interest not only from a basic science perspective but also for biomedical purposes -where the discovery of another level of complexity might paradoxically result in an overall simplification of the problem. Funding Our work is or has been funded by the American Diabetes Association (ADA) [grant number 1-04-ISLET- 18], the William H. Wallace Coulter Foundation and the Diabetes Research Institute Foundation (DRIF). References Adelman, D.M., Gertsenstein, M., Nagy, A., Simon, M.C. and Maltepe, E. (2000) Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, Apelqvist, A., Li, H., Sommer, L., Beatus, P., Anderson, D.J., Honjo, T., Hrabe de Angelis, M., Lendahl, U. and Edlund, H. (1999) Notch signalling controls pancreatic cell differentiation. Nature 400, Bell, E.L., Emerling, B.M. and Chandel, N.S. (2005) Mitochondrial regulation of oxygen sensing. Mitochondrion 5, Berggren, P.O. (1981) Characteristics of Ba 2+ -stimulated insulin release with special reference to pancreatic β-cells sensitized by cyclic AMP. Acta Biol. Med. Ger. 40, Volume 101 (8) Pages

8 C.A. Fraker and others Burgers, H.F., Schelshorn, D.W., Wagner, W., Kuschinsky, W. and Maurer, M.H. (2008) Acute anoxia stimulates proliferation in adult neural stem cells from the rat brain. Exp. Brain Res. 188, Burggren, W.W. (2004) What is the purpose of the embryonic heart beat? Or how facts can ultimately prevail over physiological dogma. Physiol. Biochem. Zool. 77, Caniggia, I., Mostachfi, H., Winter, J., Gassmann, M., Lye, S.J., Kuliszewski, M. and Post, M. (2000) Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ(3). J. Clin. Invest. 105, Carlsson, P.O. and Mattsson, G. (2002) Oxygen tension and blood flow in relation to revascularization in transplanted adult and fetal rat pancreatic islets. Cell Transplant 11, Carlsson, P.O., Palm, F. and Mattsson, G. (2002) Low revascularization of experimentally transplanted human pancreatic islets. J. Clin. Endocrinol. Metab. 87, Carlsson, P.O., Kozlova, I., Andersson, A. and Roomans, G.M. (2003) Changes in intracellular sodium, potassium, and calcium concentrations in transplanted mouse pancreatic islets. Transplantation 75, Cejudo-Martin, P. and Johnson, R.S. (2005) A new notch in the HIF belt: how hypoxia impacts differentiation. Dev. Cell 9, Chase, H.P., Ocrant, I. and Talmage, D.W. (1979) The effects of different conditions of organ culture on the survival of the mouse pancreas. Diabetes 28, Chavez, J.C., Baranova, O., Lin, J. and Pichiule, P. (2006) The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J. Neurosci. 26, Chen, C. (2004) Using microenvironment to engineer stem cell function. Conf. Proc. IEEE Eng. Med. Biol. Soc. 7, 4964 Chen, H.L., Pistollato, F., Hoeppner, D.J., Ni, H.T., McKay, R.D. and Panchision, D.M. (2007) Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25, Colen, K.L., Crisera, C.A., Rose, M.I., Connelly, P.R., Longaker, M.T. and Gittes, G.K. (1999) Vascular development in the mouse embryonic pancreas and lung. J. Pediatr. Surg. 34, Cowden Dahl, K.D., Fryer, B.H., Mack, F.A., Compernolle, V., Maltepe, E., Adelman, D.M., Carmeliet, P. and Simon, M.C. (2005) Hypoxia-inducible factors 1α and 2α regulate trophoblast differentiation. Mol. Cell. Biol. 25, Crick, F.H. (1958) On protein synthesis. Symp. Soc. Exp. Biol. 12, Csete, M. (2005) Oxygen in the cultivation of stem cells. Ann. NY Acad. Sci. 1049, 1 8 Czech, M.P. (2006) ARNT misbehavin in diabetic β cells. Nat. Med. 12, Czyz, J. and Wobus, A. (2001) Embryonic stem cell differentiation: the role of extracellular factors. Differentiation 68, D Ippolito, G., Diabira, S., Howard, G.A., Roos, B.A. and Schiller, P.C. (2006) Low oxygen tension inhibits osteogenic differentiation and enhances stemness of human MIAMI cells. Bone 39, De Bartolo, L., Salerno, S., Morelli, S., Giorno, L., Rende, M., Memoli, B., Procino, A., Andreucci, V.E., Bader, A. and Drioli, E. (2006) Long-term maintenance of human hepatocytes in oxygenpermeable membrane bioreactor. Biomaterials 27, Diez, H., Fischer, A., Winkler, A., Hu, C.J., Hatzopoulos, A.K., Breier, G. and Gessler, M. (2007) Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp. Cell. Res. 313, 1 9 Dohi, Y., Ikura, T., Hoshikawa, Y., Katoh, Y., Ota, K., Nakanome, A., Muto, A., Omura, S., Ohta, T., Ito, A. et al. (2008) Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin. Nat. Struct. Mol. Biol. 15, Edlund, H. (2001) Developmental biology of the pancreas. Diabetes 50, Suppl 1, S5 S9 Ezashi, T., Das, P. and Roberts, R.M. (2005) Low O 2 tensions and the prevention of differentiation of hes cells. Proc. Natl. Acad. Sci. U.S.A. 102, Fraker, C.A., Alvarez, S., Papadopoulos, P., Giraldo, J., Gu, W., Ricordi, C., Inverardi, L. and Dominguez-Bendala, J. (2007) Enhanced oxygenation promotes β cell differentiation in vitro. Stem Cells 25, Funato, Y., Michiue, T., Asashima, M. and Miki, H. (2006) The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-β-catenin signalling through dishevelled. Nat. Cell. Biol. 8, Gassmann, M., Fandrey, J., Bichet, S., Wartenberg, M., Marti, H.H., Bauer, C., Wenger, R.H. and Acker, H. (1996) Oxygen supply and oxygen-dependent gene expression in differentiating embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 93, Genbacev, O., Zhou, Y., Ludlow, J.W. and Fisher, S.J. (1997) Regulation of human placental development by oxygen tension. Science 277, Gnarra, J.R., Ward, J.M., Porter, F.D., Wagner, J.R., Devor, D.E., Grinberg, A., Emmert-Buck, M.R., Westphal, H., Klausner, R.D. and Linehan, W.M. (1997) Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 94, Goicoa, S., Álvarez, S., Ricordi, C., Inverardi, L. and Domínguez- Bendala, J. (2006) Sodium butyrate activates genes of early pancreatic development in ES cells. Cloning Stem Cells 8, Gu, G., Dubauskaite, J. and Melton, D.A. (2002) Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, Gu, G., Brown, J.R. and Melton, D.A. (2003) Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis. Mech. Dev. 120, Gunton, J.E., Kulkarni, R.N., Yim, S., Okada, T., Hawthorne, W.J., Tseng, Y.H., Roberson, R.S., Ricordi, C., O Connell, P.J., Gonzalez, F.J. and Kahn, C.R. (2005) Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122, Gustafsson, M.V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J.L., Poellinger, L., Lendahl, U. and Bondesson, M. (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, Hart, A., Papadopoulou, S. and Edlund, H. (2003) Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells. Dev. Dyn. 228, Haumaitre, C., Lenoir, O. and Scharfmann, R. (2008) Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol. Cell. Biol. 28, Hoppler, S. and Kavanagh, C.L. (2007) Wnt signalling: variety at the core.j.cellsci.120, Horie, N., So, K., Moriya, T., Kitagawa, N., Tsutsumi, K., Nagata, I. and Shinohara, K. (2008) Effects of oxygen concentration on the proliferation and differentiation of mouse neural stem cells in vitro. Cell. Mol. Neurobiol. 28, Huang, C.Y., Hagar, K.L., Frost, L.E., Sun, Y. and Cheung, H.S. (2004) Effects of cyclic compressive loading on chondrogenesis of rabbit bone-marrow derived mesenchymal stem cells. Stem Cells 22, C The Authors Journal compilation C 2009 Portland Press Ltd

9 Oxygen and pancreatic development Scientiae forum Iyer, N.V., Kotch, L.E., Agani, F., Leung, S.W., Laughner, E., Wenger, R.H., Gassmann, M., Gearhart, J.D., Lawler, A.M., Yu, A.Y. and Semenza, G.L. (1998) Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, Jensen, J., Pedersen, E.E., Galante, P., Hald, J., Heller, R.S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P. and Madsen, O.D. (2000) Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, Jiang, J., Au, M., Lu, K., Eshpeter, A., Korbutt, G., Fisk, G. and Majumdar, A.S. (2007) Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells 25, Jogi, A., Ora, I., Nilsson, H., Lindeheim, A., Makino, Y., Poellinger, L., Axelson, H. and Pahlman, S. (2002) Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc. Natl. Acad. Sci. U.S.A. 99, Kadesch, T. (2004) Notch signaling: the demise of elegant simplicity. Curr. Opin. Genet. Dev. 14, Kaidi, A., Williams, A.C. and Paraskeva, C. (2007) Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat. Cell. Biol. 9, Kazzaz, J.A., Horowitz, S., Li, Y. and Mantell, L.L. (1999) Hyperoxia in cell culture. A non-apoptotic programmed cell death. Ann. NY Acad. Sci. 887, Ko, S.H., Ryu, G.R., Kim, S., Ahn, Y.B., Yoon, K.H., Kaneto, H., Ha, H., Kim, Y.S. and Song, K.H. (2008) Inducible nitric oxide synthase-nitric oxide plays an important role in acute and severe hypoxic injury to pancreatic β cells. Transplantation 85, Kumar, M. and Melton, D. (2003) Pancreas specification: a budding question. Curr. Opin. Genet. Dev. 13, Lammert, E., Brown, J. and Melton, D.A. (2000) Notch gene expression during pancreatic organogenesis. Mech. Dev. 94, Lammert, E., Cleaver, O. and Melton, D. (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294, Lammert, E., Cleaver, O. and Melton, D. (2003) Role of endothelial cells in early pancreas and liver development. Mech. Dev. 120, Lee, Y.M., Jeong, C.H., Koo, S.Y., Son, M.J., Song, H.S., Bae, S.K., Raleigh, J.A., Chung, H.Y., Yoo, M.A. and Kim, K.W. (2001) Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev. Dyn. 220, Levin, M. (2003) Bioelectromagnetics in morphogenesis. Bioelectromagnetics 24, Levisetti, M.G. and Polonsky, K.S. (2005) Diabetic pancreatic β cells ARNT all they should be. Cell Metab. 2, Li, W.J., Jiang, Y.J. and Tuan, R.S. (2006) Chondrocyte phenotype in engineered fibrous matrix is regulated by fiber size. Tissue Eng. 12, Liu, H., Collins, S.F. and Suggs, L.J. (2006a) Three-dimensional culture for expansion and differentiation of mouse embryonic stem cells. Biomaterials 27, Liu, H., Lin, J. and Roy, K. (2006b) Effect of 3D scaffold and dynamic culture condition on the global gene expression profile of mouse embryonic stem cells. Biomaterials 27, Liu, W.D., Wang, H.W., Muguira, M., Breslin, M.B. and Lan, M.S. (2006c) INSM1 functions as a transcriptional repressor of the neurodbeta2 gene through the recruitment of cyclin D1 and histone deacetylases. Biochem. J. 397, Liu, Z. and Habener, J.F. (2008) Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic β cell proliferation. J. Biol. Chem. 283, Martin-Gronert, M.S. and Ozanne, S.E. (2007) Experimental IUGR and later diabetes. J. Intern. Med. 261, Maynard, M.A., Qi, H., Chung, J., Lee, E.H., Kondo, Y., Hara, S., Conaway, R.C., Conaway, J.W. and Ohh, M. (2003) Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J. Biol. Chem. 278, Maynard, M.A., Evans, A.J., Shi, W., Kim, W.Y., Liu, F.F. and Ohh, M. (2007) Dominant-negative HIF-3α4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle 6, Mihaylova, V.T., Bindra, R.S., Yuan, J., Campisi, D., Narayanan, L., Jensen, R., Giordano, F., Johnson, R.S., Rockwell, S. and Glazer, P.M. (2003) Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol. Cell. Biol. 23, Miki, A., Fujimoto, E., Ohsaki, T. and Mizoguti, H. (1988) Effects of oxygen concentration on embryonic development in rats: a light and electron microscopic study using whole-embryo culture techniques. Anat. Embryol. 178, Mitchell, J.A. and Yochim, J.M. (1968) Intrauterine oxygen tension during the estrous cycle in the rat: its relation to uterine respiration and vascular activity. Endocrinology 83, Moritz, W., Meier, F., Stroka, D.M., Giuliani, M., Kugelmeier, P., Nett, P.C., Lehmann, R., Candinas, D., Gassmann, M. and Weber, M. (2002) Apoptosis in hypoxic human pancreatic islets correlates with HIF-1α expression. FASEB J. 16, Murtaugh, L.C., Stanger, B.Z., Kwan, K.M. and Melton, D.A. (2003) Notch signaling controls multiple steps of pancreatic differentiation. Proc. Natl. Acad. Sci. U.S.A. 100, Murtaugh, L.C., Law, A.C., Dor, Y. and Melton, D.A. (2005) β-catenin is essential for pancreatic acinar but not islet development. Development 132, Naya, F.J., Huang, H.P., Qiu, Y., Mutoh, H., DeMayo, F.J., Leiter, A.B. and Tsai, M.J. (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in beta2/neurod-deficient mice. Genes Dev. 11, Nelson, C.M., Jean, R.P., Tan, J.L., Liu, W.F., Sniadecki, N.J., Spector, A.A. and Chen, C.S. (2005) Emergent patterns of growth controlled by multicellular form and mechanics. Proc. Natl. Acad. Sci. U.S.A. 102, New, D.A. (1978) Whole-embryo culture and the study of mammalian embryos during organogenesis. Biol. Rev. Camb. Philos. Soc. 53, Nuccitelli, R. (1988) Ionic currents in morphogenesis. Experientia 44, Papas, K.K., Long, Jr, R.C., Constantinidis, I. and Sambanis, A. (1996) Effects of oxygen on metabolic and secretory activities of beta TC3 cells. Biochim. Biophys. Acta 1291, Papas, K.K., Avgoustiniatos, E.S., Tempelman, L.A., Weir, G.C., Colton, C.K., Pisania, A., Rappel, M.J., Friberg, A.S., Bauer, A.C. and Hering, B.J. (2005) High-density culture of human islets on top of silicone rubber membranes. Transplant Proc. 37, Park, J.H., Stoffers, D.A., Nicholls, R.D. and Simmons, R.A. (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J. Clin. Invest. 118, Pear, W.S. and Simon, M.C. (2005) Lasting longer without oxygen: the influence of hypoxia on Notch signaling. Cancer Cell 8, Pelaez, D., Huang, C.Y. and Cheung, H.S. (2008) Cyclic compression maintains viability and induces chondrogenesis of human mesenchymal stem cells in fibrin gel scaffolds. Stem Cells Dev. 18, Pictet, R. and Rutter, W.J. (1972) Development of the embryonic endocrine pancreas in Handbook of Physiology, Baltimore, Williams & Wilkins. Pictet, R.L., Clark, W.R., Williams, R.H. and Rutter, W.J. (1972) An ultrastructural analysis of the developing embryonic pancreas. Dev. Biol. 29, Volume 101 (8) Pages

10 C.A. Fraker and others Piper, K., Brickwood, S., Turnpenny, L.W., Cameron, I.T., Ball, S.G., Wilson, D.I. and Hanley, N.A. (2004) β cell differentiation during early human pancreas development. J. Endocrinol. 181, Pistollato, F., Chen, H.L., Schwartz, P.H., Basso, G. and Panchision, D.M. (2007) Oxygen tension controls the expansion of human CNS precursors and the generation of astrocytes and oligodendrocytes. Mol. Cell. Neurosci. 35, Pistollato, F., Chen, H.L., Rood, B.R., Zhang, H.Z., D Avella, D., Denaro, L., Gardiman, M., Te Kronnie, G., Schwartz, P.H., Favaro, E. et al. (2009) Hypoxia and HIF1α repress the differentiative effects of BMPs in high grade glioma. Stem Cells 27, 7 17 Pugh, C.W. and Ratcliffe, P.J. (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 9, Rahman, I. and Adcock, I.M. (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur. Respir. J. 28, Rahman, I., Marwick, J. and Kirkham, P. (2004) Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-κB and pro-inflammatory gene expression. Biochem. Pharmacol. 68, Robinson, K.R. and Messerli, M.A. (2003) Left/right, up/down: the role of endogenous electrical fields as directional signals in development, repair and invasion. Bioessays 25, Rodesch, F., Simon, P., Donner, C. and Jauniaux, E. (1992) Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet. Gynecol. 80, Ryan, H.E., Poloni, M., McNulty, W., Elson, D., Gassmann, M., Arbeit, J.M. and Johnson, R.S. (2000) Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 60, Sainson, R.C. and Harris, A.L. (2006) Hypoxia-regulated differentiation: let s step it up a Notch. Trends Mol. Med. 12, Semenza, G.L. (2000) Oxygen-regulated transcription factors and their role in pulmonary disease. Respir. Res. 1, Simon, M.C. and Keith, B. (2008) The role of oxygen availability in embryonic development and stem cell function. Nat. Rev. Mol. Cell Biol. 9, Stockmann, C. and Fandrey, J. (2006) Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clin. Exp. Pharmacol. Physiol. 33, Takeda, K., Ho, V.C., Takeda, H., Duan, L.J., Nagy, A. and Fong, G.H. (2006) Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2. Mol. Cell. Biol. 26, van Amerongen, R., Mikels, A. and Nusse, R. (2008) Alternative wnt signaling is initiated by distinct receptors. Sci. Signal 1, re9 Warnecke, C., Zaborowska, Z., Kurreck, J., Erdmann, V.A., Frei, U., Wiesener, M. and Eckardt, K.U. (2004) Differentiating the functional role of hypoxia-inducible factor (HIF)-1α and HIF-2α (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2α target gene in Hep3B and Kelly cells. FASEB J. 18, Wells, J.M., Esni, F., Boivin, G.P., Aronow, B.J., Stuart, W., Combs, C., Sklenka, A., Leach, S.D. and Lowy, A.M. (2007) Wnt/β-catenin signaling is required for development of the exocrine pancreas. BMC. Dev. Biol. 7, 4 Wenger, R.H. (2002) Cellular adaptation to hypoxia: O 2 -sensing protein hydroxylases, hypoxia-inducible transcription factors, and O 2 -regulated gene expression. FASEB J. 16, Wiesener, M.S., Jurgensen, J.S., Rosenberger, C., Scholze, C.K., Horstrup, J.H., Warnecke, C., Mandriota, S., Bechmann, I., Frei, U.A., Pugh, C.W. et al. (2003) Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, Yoshitomi, H. and Zaret, K.S. (2004) Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131, Yun, Z., Maecker, H.L., Johnson, R.S. and Giaccia, A.J. (2002) Inhibition of PPARγ2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev. Cell 2, Yun, Z., Lin, Q. and Giaccia, A.J. (2005) Adaptive myogenesis under hypoxia. Mol. Cell. Biol. 25, Zhang, W., Feng, D., Li, Y., Iida, K., McGrath, B. and Cavener, D.R. (2006) PERK EIF2AK3 control of pancreatic β cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab. 4, Zhou, Y., Fisher, S.J., Janatpour, M., Genbacev, O., Dejana, E., Wheelock, M. and Damsky, C.H. (1997) Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J. Clin. Invest. 99, Zhu, L.L., Wu, L.Y., Yew, D.T. and Fan, M. (2005) Effects of hypoxia on the proliferation and differentiation of NSCs. Mol. Neurobiol. 31, Zscharnack, M., Poesel, C., Galle, J. and Bader, A. (2008) Low oxygen expansion improves subsequent chondrogenesis of ovine bone-marrow-derived mesenchymal stem cells in collagen type I hydrogel. Cells Tissues Organs, doi: / Received 1 October 2008/12 January 2009; accepted 14 January 2009 Published on the Internet 4 June 2009, doi: /bc C The Authors Journal compilation C 2009 Portland Press Ltd

Victims Compensation Claim Status of All Pending Claims and Claims Decided Within the Last Three Years

Victims Compensation Claim Status of All Pending Claims and Claims Decided Within the Last Three Years Claim#:021914-174 Initials: J.T. Last4SSN: 6996 DOB: 5/3/1970 Crime Date: 4/30/2013 Status: Claim is currently under review. Decision expected within 7 days Claim#:041715-334 Initials: M.S. Last4SSN: 2957

More information

STEM CELL FELLOWSHIP

STEM CELL FELLOWSHIP Module I: The Basic Principles of Stem Cells 1. Basics of Stem Cells a. Understanding the development of embryonic stem cells i. Embryonic stem cells ii. Embryonic germ cells iii. Differentiated stem cell

More information

The Need for a PARP in vivo Pharmacodynamic Assay

The Need for a PARP in vivo Pharmacodynamic Assay The Need for a PARP in vivo Pharmacodynamic Assay Jay George, Ph.D., Chief Scientific Officer, Trevigen, Inc., Gaithersburg, MD For further infomation, please contact: William Booth, Ph.D. Tel: +44 (0)1235

More information

Regenerative Medicine : A Promising Approach In Overcoming Diabetes As An Increasing Economic Health Burden

Regenerative Medicine : A Promising Approach In Overcoming Diabetes As An Increasing Economic Health Burden Journal of Emerging Economies and Islamic Research www.jeeir.com Regenerative Medicine : A Promising Approach In Overcoming Diabetes As An Increasing Economic Health Burden Nafeeza Mohd Ismail a, Renu

More information

Control of Gene Expression

Control of Gene Expression Control of Gene Expression (Learning Objectives) Explain the role of gene expression is differentiation of function of cells which leads to the emergence of different tissues, organs, and organ systems

More information

Neurotrophic factors and Their receptors

Neurotrophic factors and Their receptors Neurotrophic factors and Their receptors Huang Shu-Hong Institute of neurobiology 1 For decades, scientists believed that brain cells of the central nervous system could not regrow following damage due

More information

Stem cells for brain cures

Stem cells for brain cures 13-14/11/2006, Istituto Superiore di Sanità Rome, Italy Frontiers in Imaging Science: High Performance Nuclear Medicine Imagers for Vascular Disease Imaging (Brain and Heart) Stem cells for brain cures

More information

Publikationsliste Claudia Götz

Publikationsliste Claudia Götz Publikationsliste Claudia Götz 1. Reinhard,B., Götz, C., and Faillard, H.: Synthesis of N-Acetyl-9-Oacetylneuraminic acid α-p-aminophenylthioketoside and its application as ligand in the affinity chromatography

More information

Cancer SBL101. James Gomes School of Biological Sciences Indian Institute of Technology Delhi

Cancer SBL101. James Gomes School of Biological Sciences Indian Institute of Technology Delhi Cancer SBL101 James Gomes School of Biological Sciences Indian Institute of Technology Delhi All Figures in this Lecture are taken from 1. Molecular biology of the cell / Bruce Alberts et al., 5th ed.

More information

Control of Gene Expression

Control of Gene Expression Control of Gene Expression What is Gene Expression? Gene expression is the process by which informa9on from a gene is used in the synthesis of a func9onal gene product. What is Gene Expression? Figure

More information

Department of BioScience Technology Chung Yuan Christian University 2015/08/13

Department of BioScience Technology Chung Yuan Christian University 2015/08/13 Department of BioScience Technology Chung Yuan Christian University 2015/08/13 Cancer Cells Cancer, the 1st leading cause of death, is an example of a disease that arises from abnormalities in cell function

More information

Support Program for Improving Graduate School Education Advanced Education Program for Integrated Clinical, Basic and Social Medicine

Support Program for Improving Graduate School Education Advanced Education Program for Integrated Clinical, Basic and Social Medicine Support Program for Improving Graduate School Education Advanced Education Program for Integrated Clinical, Basic and Social Medicine January 27, 2009 Dear Professors (representative) of departments, Subject:

More information

Biotechnology. Srivatsan Kidambi, Ph.D.

Biotechnology. Srivatsan Kidambi, Ph.D. Stem Stem Cell Cell Engineering-What, Biology and it Application Why, How?? to Biotechnology Srivatsan Kidambi, Ph.D. Assistant Professor Department of Chemical & Biomolecular Engineering University of

More information

LESSON 3.5 WORKBOOK. How do cancer cells evolve? Workbook Lesson 3.5

LESSON 3.5 WORKBOOK. How do cancer cells evolve? Workbook Lesson 3.5 LESSON 3.5 WORKBOOK How do cancer cells evolve? In this unit we have learned how normal cells can be transformed so that they stop behaving as part of a tissue community and become unresponsive to regulation.

More information

AUTOHEPARIN - 227975 (ERC-2008-AdG) Automated Synthesis of Heparin and Chondroitin Libraries for the Preparation of Diverse Carbohydrate Arrays

AUTOHEPARIN - 227975 (ERC-2008-AdG) Automated Synthesis of Heparin and Chondroitin Libraries for the Preparation of Diverse Carbohydrate Arrays ERC grantees based in Berlin/ Potsdam Prof. Peter H. Seeberger Max Planck Institute of Colloids and Interfaces AUTOHEPARIN - 227975 (ERC-2008-AdG) Automated Synthesis of Heparin and Chondroitin Libraries

More information

LEUKEMIA LYMPHOMA MYELOMA Advances in Clinical Trials

LEUKEMIA LYMPHOMA MYELOMA Advances in Clinical Trials LEUKEMIA LYMPHOMA MYELOMA Advances in Clinical Trials OUR FOCUS ABOUT emerging treatments Presentation for: Judith E. Karp, MD Advancements for Acute Myelogenous Leukemia Supported by an unrestricted educational

More information

Version 1 2015. Module guide. Preliminary document. International Master Program Cardiovascular Science University of Göttingen

Version 1 2015. Module guide. Preliminary document. International Master Program Cardiovascular Science University of Göttingen Version 1 2015 Module guide International Master Program Cardiovascular Science University of Göttingen Part 1 Theoretical modules Synopsis The Master program Cardiovascular Science contains four theoretical

More information

CONTRACTING ORGANIZATION: University of Alabama at Birmingham Birmingham, AL 35294

CONTRACTING ORGANIZATION: University of Alabama at Birmingham Birmingham, AL 35294 AD Award Number: W81XWH-08-1-0030 TITLE: Regulation of Prostate Cancer Bone Metastasis by DKK1 PRINCIPAL INVESTIGATOR: Gregory A. Clines, M.D., Ph.D. CONTRACTING ORGANIZATION: University of Alabama at

More information

STEM CELL FACTS. The ISSCR is an independent, nonproft organization providing a global forum for stem cell research and regenerative medicine.

STEM CELL FACTS. The ISSCR is an independent, nonproft organization providing a global forum for stem cell research and regenerative medicine. STEM CELL FACTS The ISSCR is an independent, nonproft organization providing a global forum for stem cell research and regenerative medicine. WHAT ARE STEM CELLS? Stem cells are the foundation cells for

More information

Stem Cell Therapy In Diabetes Mellitus. Professor Megahid Abuelmagd Diabetes And Endocrine Unit. Mansoura Faculty Of Medicine

Stem Cell Therapy In Diabetes Mellitus. Professor Megahid Abuelmagd Diabetes And Endocrine Unit. Mansoura Faculty Of Medicine Stem Cell Therapy In Diabetes Mellitus Professor Megahid Abuelmagd Diabetes And Endocrine Unit. Mansoura Faculty Of Medicine For many years, there has been great interest in approaches to the replacement

More information

INTRODUCTION % Cells of Control % Cells of Control % Cells of Control A B Rapamycin 24 Hour 48 Hour MS-275 24 Hour 48 Hour 120.000 120.000 100.000 100.000 80.000 80.000 60.000 60.000 40.000 40.000

More information

Stem Cells: Scientific Progress and Future Research Directions

Stem Cells: Scientific Progress and Future Research Directions 2001 Terese Winslow Stem Cells: Scientific Progress and Future Research Directions STEM CELLS: SCIENTIFIC PROGRESS AND FUTURE RESEARCH DIRECTIONS June 2001 This page intentionally left blank TABLE OF CONTENTS

More information

PART 3.3: MicroRNA and Cancer

PART 3.3: MicroRNA and Cancer BIBM 2010 Tutorial: Epigenomics and Cancer PART 3.3: MicroRNA and Cancer Dec 18, 2010 Sun Kim at Indiana University Outline of Part 3.3 Background on microrna Role of microrna in cancer MicroRNA pathway

More information

International Journal of Pharma and Bio Sciences STEM CELL TREATMENT FOR DIABETES SAKTHIVEL.K*, RAJESH.C AND SENTHAMARAI.R

International Journal of Pharma and Bio Sciences STEM CELL TREATMENT FOR DIABETES SAKTHIVEL.K*, RAJESH.C AND SENTHAMARAI.R International Journal of Pharma and Bio Sciences STEM CELL TREATMENT FOR DIABETES SAKTHIVEL.K*, RAJESH.C AND SENTHAMARAI.R Department of, Periyar College of Pharmaceutical Sciences for Girls Tiruchirappalli

More information

Hormones & Chemical Signaling

Hormones & Chemical Signaling Hormones & Chemical Signaling Part 2 modulation of signal pathways and hormone classification & function How are these pathways controlled? Receptors are proteins! Subject to Specificity of binding Competition

More information

Intracellular Calcium and Phosphatidylserine Exposure in the red Blood Cells

Intracellular Calcium and Phosphatidylserine Exposure in the red Blood Cells Intracellular Calcium and Phosphatidylserine Exposure in the red Blood Cells Biotechnology Seminar 2 Yaser Alkhaled 30.10.13 Table of Content 1. Introduction.... 3 2. Membrane of red blood cell.... 4 3.

More information

No Disclosures. Learning Objectives 10/25/13

No Disclosures. Learning Objectives 10/25/13 No Disclosures Gregory A. Brent, MD Departments of Medicine and Physiology David Geffen School of Medicine at UCLA VA Greater Los Angeles Healthcare System Learning Objectives Describe the pathways that

More information

Lecture 8. Protein Trafficking/Targeting. Protein targeting is necessary for proteins that are destined to work outside the cytoplasm.

Lecture 8. Protein Trafficking/Targeting. Protein targeting is necessary for proteins that are destined to work outside the cytoplasm. Protein Trafficking/Targeting (8.1) Lecture 8 Protein Trafficking/Targeting Protein targeting is necessary for proteins that are destined to work outside the cytoplasm. Protein targeting is more complex

More information

THE ENDOCANNABINOID SYSTEM AS A THERAPEUTIC TARGET FOR LIVER DISEASES. Key Points

THE ENDOCANNABINOID SYSTEM AS A THERAPEUTIC TARGET FOR LIVER DISEASES. Key Points December 2008 (Vol. 1, Issue 3, pages 36-40) THE ENDOCANNABINOID SYSTEM AS A THERAPEUTIC TARGET FOR LIVER DISEASES By Sophie Lotersztajn, PhD, Ariane Mallat, MD, PhD Inserm U841, Hôpital Henri Mondor,

More information

Stem Cell Information

Stem Cell Information Stem Cell Information The official National Institutes of Health resource for stem cell research Stem Cell Basics Stem cells have the remarkable potential to develop into many different cell types in the

More information

Settore Scientifico disciplinare MED. 13/ENDOCRINOLOGIA

Settore Scientifico disciplinare MED. 13/ENDOCRINOLOGIA Dipartimento Biomedico di Medicina Interna e Specialistica Sezione di Endocrinologia, Diabetologia e Metabolismo Dottorato di ricerca in Genomica e Proteomica nella ricerca oncologica ed endocrino metabolica

More information

S1 Text. Modeling deterministic single-cell microrna-p53-mdm2 network Figure 2 Figure 2

S1 Text. Modeling deterministic single-cell microrna-p53-mdm2 network Figure 2 Figure 2 S1 Text. Modeling deterministic single-cell microrna-p53-mdm2 network The schematic diagram of the microrna-p53-mdm2 oscillator is illustrated in Figure 2. The interaction scheme among the mrnas and the

More information

Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies. Biochemistry Journal. August 1, 2007 405, pp.

Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies. Biochemistry Journal. August 1, 2007 405, pp. Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies 1 Biochemistry Journal August 1, 2007 405, pp. 559 568 Joseph Friedman, Sarah Kraus, Yirmi Hauptman, Yoni Schiff

More information

HyStem. Hydrogels CELLULAR MATRICES FOR TRANSLATIONAL RESEARCH. esibio.com

HyStem. Hydrogels CELLULAR MATRICES FOR TRANSLATIONAL RESEARCH. esibio.com HyStem Hydrogels CELLULAR MATRICES FOR TRANSLATIONAL RESEARCH HyStem Hydrogel Extracellular Matrices Chemically-defined For use in 2D and 3D formats in vitro and in vivo applications Customizable for many

More information

J D R F R E Q U E S T S L E T T E R S O F I N T E N T F O R : B I O M AR K E R S O F P AN C R E A T I C B E T A C E L L S T R E S S AN D H E AL T H

J D R F R E Q U E S T S L E T T E R S O F I N T E N T F O R : B I O M AR K E R S O F P AN C R E A T I C B E T A C E L L S T R E S S AN D H E AL T H J D R F R E Q U E S T S L E T T E R S O F I N T E N T F O R : B I O M AR K E R S O F P AN C R E A T I C B E T A C E L L S T R E S S AN D H E AL T H PURPOSE JDRF, the world s leading non-profit organization

More information

Unit 2 Metabolism and Survival Summary

Unit 2 Metabolism and Survival Summary Unit 2 Metabolism and Survival Summary 1 Metabolism pathways and their control (a) Introduction to metabolic pathways This involves integrated and controlled pathways of enzymecatalysed reactions within

More information

Development of pharyngeal pouches endoderm-derived glands Thymus: from organogenesis to involution

Development of pharyngeal pouches endoderm-derived glands Thymus: from organogenesis to involution Development of pharyngeal pouches endoderm-derived glands Thymus: from organogenesis to involution Unidade de Organogénese (IHBD-FMUL/IMM) Rita Zilhão ENCONTRO FCUL, 4 February, 2013 Faculdade de Medicina

More information

High throughput screening, high content screening, primary and stem cells. new techniques now converging

High throughput screening, high content screening, primary and stem cells. new techniques now converging High throughput screening:layout 1 26/3/09 13:32 Page 25 High throughput screening, high content screening, primary and stem cells new techniques now converging Over the past decade, the use of cell-based

More information

Vitamin D deficiency exacerbates ischemic cell loss and sensory motor dysfunction in an experimental stroke model

Vitamin D deficiency exacerbates ischemic cell loss and sensory motor dysfunction in an experimental stroke model Vitamin D deficiency exacerbates ischemic cell loss and sensory motor dysfunction in an experimental stroke model Robyn Balden & Farida Sohrabji Texas A&M Health Science Center- College of Medicine ISC

More information

Newborn Stem Cells from Cord Blood and the Brain: Repairing Injury and Improving Function

Newborn Stem Cells from Cord Blood and the Brain: Repairing Injury and Improving Function BACKROUNDER: Newborn Stem Cells from Cord Blood and the Brain: Repairing Injury and Improving Function Introduction WITH ONGOING DEVELOPMENTS IN RESEARCH, it is estimated that 1 in every 3 people may benefit

More information

Lesson 3 Reading Material: Oncogenes and Tumor Suppressor Genes

Lesson 3 Reading Material: Oncogenes and Tumor Suppressor Genes Lesson 3 Reading Material: Oncogenes and Tumor Suppressor Genes Becoming a cancer cell isn t easy One of the fundamental molecular characteristics of cancer is that it does not develop all at once, but

More information

GENE REGULATION. Teacher Packet

GENE REGULATION. Teacher Packet AP * BIOLOGY GENE REGULATION Teacher Packet AP* is a trademark of the College Entrance Examination Board. The College Entrance Examination Board was not involved in the production of this material. Pictures

More information

In Vivo and In Vitro Screening for Thyroid Hormone Disruptors

In Vivo and In Vitro Screening for Thyroid Hormone Disruptors In Vivo and In Vitro Screening for Thyroid Hormone Disruptors Kevin M. Crofton National lhealth and Environmental Research Laboratory California Environmental Protection Agency Human Health Hazard Indicators

More information

Stamcelleforskning- helbreder diabetes? Diabetes, beta cells and stem cell based therapy

Stamcelleforskning- helbreder diabetes? Diabetes, beta cells and stem cell based therapy 1 Stamcelleforskning- helbreder diabetes? Diabetes, beta cells and stem cell based therapy Ole D. Madsen Senior Principal Scientist Diabetes Biology Novo Nordisk A/S Honorary Professor in Diabetes Stem

More information

5 Frequently Asked Questions About Adult Stem Cell Research

5 Frequently Asked Questions About Adult Stem Cell Research 5 Frequently Asked Questions About Adult Stem Cell Research Stem cells are often referred to in the sociopolitical realm with some level of controversy and beyond that, some level of confusion. Many researchers

More information

guides BIOLOGY OF AGING STEM CELLS An introduction to aging science brought to you by the American Federation for Aging Research

guides BIOLOGY OF AGING STEM CELLS An introduction to aging science brought to you by the American Federation for Aging Research infoaging guides BIOLOGY OF AGING STEM CELLS An introduction to aging science brought to you by the American Federation for Aging Research WHAT ARE STEM CELLS? Stem cells are cells that, in cell cultures

More information

FACULTY OF MEDICAL SCIENCE

FACULTY OF MEDICAL SCIENCE Doctor of Philosophy in Biochemistry FACULTY OF MEDICAL SCIENCE Naresuan University 73 Doctor of Philosophy in Biochemistry The Biochemistry Department at Naresuan University is a leader in lower northern

More information

glucose and fatty acids to raise your blood sugar levels.

glucose and fatty acids to raise your blood sugar levels. Endocrine & Cell Communication Part IV: Maintaining Balance (Homeostasis) TEACHER NOTES needs coding 1 Endocrine & Cell Communication Part IV: Maintaining Balance (Homeostasis) 2 AP Biology Curriculum

More information

CHARACTERISTIC FEATURES OF STEM CELLS. CLONING TECHNOLOGIES

CHARACTERISTIC FEATURES OF STEM CELLS. CLONING TECHNOLOGIES CHARACTERISTIC FEATURES OF STEM CELLS. CLONING TECHNOLOGIES 1 Science is discovering the unknown Stem cell field is still in its infancy Human embryonic stem cell research is a decade old, adult stem cell

More information

Softwell. Petrisoft. Collagen. Ultrasoft. 25 kpa. 8 kpa. Easy Coat. 1 kpa. Softview. Hydrogel-coated wells for cell culture. Non-activated 0.

Softwell. Petrisoft. Collagen. Ultrasoft. 25 kpa. 8 kpa. Easy Coat. 1 kpa. Softview. Hydrogel-coated wells for cell culture. Non-activated 0. Softwell Hydrogel-coated wells for cell culture Non-activated 0.2 kpa 25 kpa Collagen 8 kpa Easy Coat Petrisoft Ultrasoft Softview 1 kpa Introducing Softwell It s like a Petri dish. Only to a cell, it

More information

Postnatal Muscle Growth. Postnatal Muscle Growth. Postnatal Muscle Growth. DNA and Growth. DNA Accumulation. Postnatal muscle growth

Postnatal Muscle Growth. Postnatal Muscle Growth. Postnatal Muscle Growth. DNA and Growth. DNA Accumulation. Postnatal muscle growth Postnatal Muscle Growth Feedlot Cattle on High Concentrate Diet Postnatal muscle growth Postnatal muscle growth curve?? Key characteristics of muscle: fiber # fixed at birth increased size/wt. (length/diameter)

More information

a future of glucoseresponsive secretion: bionics versus nature

a future of glucoseresponsive secretion: bionics versus nature science at the cutting edge a future of glucoseresponsive insulin secretion: bionics versus nature Pratik Choudhary, John Pickup, Peter Jones, Stephanie A Amiel people with diabetes constantly walk a tight

More information

AAGPs TM Anti-Aging Glyco Peptides. Enhancing Cell, Tissue and Organ Integrity Molecular and biological attributes of lead AAGP molecule

AAGPs TM Anti-Aging Glyco Peptides. Enhancing Cell, Tissue and Organ Integrity Molecular and biological attributes of lead AAGP molecule AAGPs TM Anti-Aging Glyco Peptides Enhancing Cell, Tissue and Organ Integrity Molecular and biological attributes of lead AAGP molecule 1 Acknowledgements This presentation was prepared by Dr. Samer Hussein

More information

Growth of Animal Cells in Culture

Growth of Animal Cells in Culture Growth of Animal Cells in Culture The ability to study cells depends largely on how readily they can be grown and manipulated in the laboratory. Although the process is technically far more difficult than

More information

Stem Cell Quick Guide: Stem Cell Basics

Stem Cell Quick Guide: Stem Cell Basics Stem Cell Quick Guide: Stem Cell Basics What is a Stem Cell? Stem cells are the starting point from which the rest of the body grows. The adult human body is made up of hundreds of millions of different

More information

Human Cloning The Science and Ethics of Nuclear Transplantation

Human Cloning The Science and Ethics of Nuclear Transplantation Human Cloning The Science and Ethics of Transplantation Rudolf Jaenisch, M.D. In addition to the moral argument against the use of somatic-cell nuclear for the creation of a child ( reproductive cloning

More information

MULTIPLE MYELOMA. Dr Malkit S Riyat. MBChB, FRCPath(UK) Consultant Haematologist

MULTIPLE MYELOMA. Dr Malkit S Riyat. MBChB, FRCPath(UK) Consultant Haematologist MULTIPLE MYELOMA Dr Malkit S Riyat MBChB, FRCPath(UK) Consultant Haematologist Multiple myeloma is an incurable malignancy that arises from postgerminal centre, somatically hypermutated B cells.

More information

Stem Cells. Part 1: What is a Stem Cell?

Stem Cells. Part 1: What is a Stem Cell? Stem Cells Part 1: What is a Stem Cell? Stem cells differ from other kinds of cells in the body. When a stem cell divides by mitosis, each new cell has the potential to either remain a stem cell or become

More information

Should Stem Cells Be Used To Treat Human Diseases?

Should Stem Cells Be Used To Treat Human Diseases? SAMPLE ESSAY C Should Stem Cells Be Used To Treat Human Diseases? Stem cells can be defined as undifferentiated cells that are generated during the development of the embryo. There are two functions ascribed

More information

Unit I: Introduction To Scientific Processes

Unit I: Introduction To Scientific Processes Unit I: Introduction To Scientific Processes This unit is an introduction to the scientific process. This unit consists of a laboratory exercise where students go through the QPOE2 process step by step

More information

http://www.springer.com/3-540-23372-5

http://www.springer.com/3-540-23372-5 http://www.springer.com/3-540-23372-5 Chromatin Remodeling Factors and DNA Replication Patrick Varga-Weisz Abstract Chromatin structures have to be precisely duplicated during DNA replication to maintain

More information

Regulation of Protein Translation and c-jun expression by Prostate Tumor Overexpressed1 (PTOV1)

Regulation of Protein Translation and c-jun expression by Prostate Tumor Overexpressed1 (PTOV1) Regulation of Protein Translation and c-jun expression by Prostate Tumor Overexpressed1 (PTOV1) Verónica Cánovas, PhD Student Laboratory of Cell Signalling and Cancer Progression, Dra. Rosanna Paciucci

More information

Copyright 2000-2003 Mark Brandt, Ph.D. 54

Copyright 2000-2003 Mark Brandt, Ph.D. 54 Pyruvate Oxidation Overview of pyruvate metabolism Pyruvate can be produced in a variety of ways. It is an end product of glycolysis, and can be derived from lactate taken up from the environment (or,

More information

CURRICULUM VITAE DONNA C. HERMEY. Ph.D. (Anatomy and Cell Biology) June 1994 Temple University School of Medicine Philadelphia, PA

CURRICULUM VITAE DONNA C. HERMEY. Ph.D. (Anatomy and Cell Biology) June 1994 Temple University School of Medicine Philadelphia, PA CURRICULUM VITAE DONNA C. HERMEY EDUCATION: B.S. (Biology) May 1988 Muhlenberg College Allentown, PA PROFESSIONAL POSITIONS: Ph.D. (Anatomy and Cell Biology) June 1994 Temple University School of Medicine

More information

Respiration occurs in the mitochondria in cells.

Respiration occurs in the mitochondria in cells. B3 Question Which process occurs in the mitochondria in cells? Why do the liver and muscle cells have large number of mitochondria? What is the function of the ribosomes? Answer Respiration occurs in the

More information

Chem 115 POGIL Worksheet - Week 4 Moles & Stoichiometry

Chem 115 POGIL Worksheet - Week 4 Moles & Stoichiometry Chem 115 POGIL Worksheet - Week 4 Moles & Stoichiometry Why? Chemists are concerned with mass relationships in chemical reactions, usually run on a macroscopic scale (grams, kilograms, etc.). To deal with

More information

Micro RNAs: potentielle Biomarker für das. Blutspenderscreening

Micro RNAs: potentielle Biomarker für das. Blutspenderscreening Micro RNAs: potentielle Biomarker für das Blutspenderscreening micrornas - Background Types of RNA -Coding: messenger RNA (mrna) -Non-coding (examples): Ribosomal RNA (rrna) Transfer RNA (trna) Small nuclear

More information

Unit 1 Higher Human Biology Summary Notes

Unit 1 Higher Human Biology Summary Notes Unit 1 Higher Human Biology Summary Notes a. Cells tissues organs body systems Division of labour occurs in multicellular organisms (rather than each cell carrying out every function) Most cells become

More information

Support structure for genetic material

Support structure for genetic material Support structure for genetic material 1 Making proteins in the RER Making copies of humans 2 Making copies of cells Making copies of genetic material 3 Making copies of genetic material Making copies

More information

Mitochondria Organelle Transplantation: The Mitochondrion, An Intracellular Organelle for Cell-Based Therapy Opinion Commentary

Mitochondria Organelle Transplantation: The Mitochondrion, An Intracellular Organelle for Cell-Based Therapy Opinion Commentary Mitochondria Organelle Transplantation: The Mitochondrion, An Intracellular Organelle for Cell-Based Therapy Opinion Commentary R. L. Elliott, X.P. Jiang, J. F. Head Elliott-Baucom-Head Breast Cancer Research

More information

B I N G O B I N G O. Hf Cd Na Nb Lr. I Fl Fr Mo Si. Ho Bi Ce Eu Ac. Md Co P Pa Tc. Uut Rh K N. Sb At Md H. Bh Cm H Bi Es. Mo Uus Lu P F.

B I N G O B I N G O. Hf Cd Na Nb Lr. I Fl Fr Mo Si. Ho Bi Ce Eu Ac. Md Co P Pa Tc. Uut Rh K N. Sb At Md H. Bh Cm H Bi Es. Mo Uus Lu P F. Hf Cd Na Nb Lr Ho Bi Ce u Ac I Fl Fr Mo i Md Co P Pa Tc Uut Rh K N Dy Cl N Am b At Md H Y Bh Cm H Bi s Mo Uus Lu P F Cu Ar Ag Mg K Thomas Jefferson National Accelerator Facility - Office of cience ducation

More information

Influence of the skin mechanical and microbial properties on hair growth

Influence of the skin mechanical and microbial properties on hair growth Call for Interdisciplinary Projects Sevres 2014 A General Information Project title Influence of the skin mechanical and microbial properties on hair growth Acronym TADDEI: The Ambiguous Dupond and Dupont

More information

Module 3 Questions. 7. Chemotaxis is an example of signal transduction. Explain, with the use of diagrams.

Module 3 Questions. 7. Chemotaxis is an example of signal transduction. Explain, with the use of diagrams. Module 3 Questions Section 1. Essay and Short Answers. Use diagrams wherever possible 1. With the use of a diagram, provide an overview of the general regulation strategies available to a bacterial cell.

More information

Purification and Expansion of Hematopoietic Stem Cells Based on Proteins Expressed by a Novel Stromal Cell Population

Purification and Expansion of Hematopoietic Stem Cells Based on Proteins Expressed by a Novel Stromal Cell Population Purification and Expansion of Hematopoietic Stem Cells Based on Proteins Expressed by a Novel Stromal Cell Population Our bodies are constantly killing old, nonfunctional, and unneeded cells and making

More information

Diabetes and Insulin Signaling

Diabetes and Insulin Signaling Diabetes and Insulin Signaling NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE by Kristy J. Wilson School of Mathematics and Sciences Marian University, Indianapolis, IN Part I Research Orientation

More information

An Introduction to Stem Cells

An Introduction to Stem Cells By Kirstin Matthews, Ph.D. An Introduction to Stem Cells Overview Stem cells are cells that have the potential to replicate themselves for indefinite periods and to divide, producing one of themselves

More information

Stem Cell Research: Adult or Somatic Stem Cells

Stem Cell Research: Adult or Somatic Stem Cells Chiang 1 Stem Cell Research: Adult or Somatic Stem Cells Abstract Kelly Chiang Cluster 7 Dr. LeFebvre 07/26/10 Over the past few decades, stem cells have been a controversial topic in the scientific field.

More information

CURRICULUM VITAE. - Instructor, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis Oregon (2010-2011

CURRICULUM VITAE. - Instructor, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis Oregon (2010-2011 CURRICULUM VITAE Personal Information Kathleen S. Howe, Ph.D. Instructor School of Biological and Population Health Sciences, College of Public Health and Human Sciences Oregon State University kathy.howe@oregonstate.edu

More information

Cancer Immunotherapy: Can Your Immune System Cure Cancer? Steve Emerson, MD, PhD Herbert Irving Comprehensive Cancer Center

Cancer Immunotherapy: Can Your Immune System Cure Cancer? Steve Emerson, MD, PhD Herbert Irving Comprehensive Cancer Center Cancer Immunotherapy: Can Your Immune System Cure Cancer? Steve Emerson, MD, PhD Herbert Irving Comprehensive Cancer Center Bodnar s Law Simple Things are Important Very Simple Things are Very Important

More information

Describe how these hormones exert control quickly by changes in phosphorylation state of enzyme, and more slowly by changes of gene expression

Describe how these hormones exert control quickly by changes in phosphorylation state of enzyme, and more slowly by changes of gene expression Section VIII. Section VIII. Tissue metabolism Many tissues carry out specialized functions: Ch. 43 look at different hormones affect metabolism of fuels, especially counter-insulin Ch. 44 Proteins and

More information

7 Answers to end-of-chapter questions

7 Answers to end-of-chapter questions 7 Answers to end-of-chapter questions Multiple choice questions 1 B 2 B 3 A 4 B 5 A 6 D 7 C 8 C 9 B 10 B Structured questions 11 a i Maintenance of a constant internal environment within set limits i Concentration

More information

Stem Cell:The Promise and The Challenge

Stem Cell:The Promise and The Challenge Stem Cell:The Promise and The Challenge Chia-Cheng Cheng Chang, Ph.D. Department of Pediatrics and Human Development Michigan State University Stem cells are undifferentiated cells with the capacity for

More information

An Introduction to Stem Cell Biology. Michael L. Shelanski, MD,PhD Professor of Pathology and Cell Biology Columbia University

An Introduction to Stem Cell Biology. Michael L. Shelanski, MD,PhD Professor of Pathology and Cell Biology Columbia University An Introduction to Stem Cell Biology Michael L. Shelanski, MD,PhD Professor of Pathology and Cell Biology Columbia University Figures adapted from ISSCR. Presentations of Drs. Martin Pera (Monash University),

More information

San Diego Stem Cell Treatment Center Frequently Asked Questions

San Diego Stem Cell Treatment Center Frequently Asked Questions San Diego Stem Cell Treatment Center Frequently Asked Questions What is a Stem Cell? A stem cell is basically any cell that can replicate and differentiate. This means the cell can not only multiply, but

More information

What is Cancer? Cancer is a genetic disease: Cancer typically involves a change in gene expression/function:

What is Cancer? Cancer is a genetic disease: Cancer typically involves a change in gene expression/function: Cancer is a genetic disease: Inherited cancer Sporadic cancer What is Cancer? Cancer typically involves a change in gene expression/function: Qualitative change Quantitative change Any cancer causing genetic

More information

Control of Gene Expression

Control of Gene Expression Home Gene Regulation Is Necessary? Control of Gene Expression By switching genes off when they are not needed, cells can prevent resources from being wasted. There should be natural selection favoring

More information

Notch 1 -dependent regulation of cell fate in colorectal cancer

Notch 1 -dependent regulation of cell fate in colorectal cancer Notch 1 -dependent regulation of cell fate in colorectal cancer Referees: PD Dr. Tobias Dick Prof. Dr. Wilfried Roth http://d-nb.info/1057851272 CONTENTS Summary 1 Zusammenfassung 2 1 INTRODUCTION 3 1.1

More information

Endocrine System: Practice Questions #1

Endocrine System: Practice Questions #1 Endocrine System: Practice Questions #1 1. Removing part of gland D would most likely result in A. a decrease in the secretions of other glands B. a decrease in the blood calcium level C. an increase in

More information

Endocrine Glands and the General Principles of Hormone Action

Endocrine Glands and the General Principles of Hormone Action Endocrine Glands and the General Principles of Hormone Action Cai Li, Ph.D. Assistant professor Touchstone Center for Diabetes Research Departments of Physiology and Internal Medicine The University of

More information

ANATOMY & PHYSIOLOGY MODULE 2015/16

ANATOMY & PHYSIOLOGY MODULE 2015/16 ANATOMY & PHYSIOLOGY MODULE 2015/16 STUDENT INFORMATION MODULE CO-ORDINATOR: Email: edged@tcd.ie DEPARTMENT OF PHYSIOLOGY, BIOMEDICAL SCIENCES INSTITUTE, TRINITY COLLEGE, PEARSE STREET, DUBLIN 2. Module

More information

Chapter 47: Animal Development

Chapter 47: Animal Development Name Period Overview 1. An organism s development is controlled by the genome of the zygote as well as by molecules from the mother that are in the cytoplasm of the egg. What are these proteins and RNAs

More information

tem ells /background /information Stem cell research Copyright 2007 MRC Centre for Regenerative Medicine, Institute for Stem Cell Research

tem ells /background /information Stem cell research Copyright 2007 MRC Centre for Regenerative Medicine, Institute for Stem Cell Research tem ells /background /information Stem cell research Copyright 2007 MRC Centre for Regenerative Medicine, Institute for Stem Cell Research /02 /information Table of contents Page 01. What are stem cells?

More information

What makes cells different from each other? How do cells respond to information from environment?

What makes cells different from each other? How do cells respond to information from environment? What makes cells different from each other? How do cells respond to information from environment? Regulation of: - Transcription - prokaryotes - eukaryotes - mrna splicing - mrna localisation and translation

More information

Psychoonkology, Sept. 2010 lifestyle factors and epigenetics

Psychoonkology, Sept. 2010 lifestyle factors and epigenetics Psychoonkology, Sept. 2010 lifestyle factors and epigenetics Alexander G. Haslberger Dep. für Ernährungswissenschaften Univ. of Vienna Working group: Food, GI-Microbiology, Epigenetics Content Health:

More information

treatments) worked by killing cancerous cells using chemo or radiotherapy. While these techniques can

treatments) worked by killing cancerous cells using chemo or radiotherapy. While these techniques can Shristi Pandey Genomics and Medicine Winter 2011 Prof. Doug Brutlag Chronic Myeloid Leukemia: A look into how genomics is changing the way we treat Cancer. Until the late 1990s, nearly all treatment methods

More information

Plant Growth & Development. Growth Stages. Differences in the Developmental Mechanisms of Plants and Animals. Development

Plant Growth & Development. Growth Stages. Differences in the Developmental Mechanisms of Plants and Animals. Development Plant Growth & Development Plant body is unable to move. To survive and grow, plants must be able to alter its growth, development and physiology. Plants are able to produce complex, yet variable forms

More information

Actions of Hormones on Target Cells Page 1. Actions of Hormones on Target Cells Page 2. Goals/ What You Need to Know Goals What You Need to Know

Actions of Hormones on Target Cells Page 1. Actions of Hormones on Target Cells Page 2. Goals/ What You Need to Know Goals What You Need to Know Actions of Hormones on Target Cells Graphics are used with permission of: Pearson Education Inc., publishing as Benjamin Cummings (http://www.aw-bc.com) Page 1. Actions of Hormones on Target Cells Hormones

More information

CHAPTER 9 IMMUNOGLOBULIN BIOSYNTHESIS

CHAPTER 9 IMMUNOGLOBULIN BIOSYNTHESIS CHAPTER 9 IMMUNOGLOBULIN BIOSYNTHESIS Although the process by which a functional gene for immunoglobulin HEAVY and LIGHT CHAINS is formed is highly unusual, the SYNTHESIS, POST- TRANSLATIONAL PROCESSING

More information

PGY 206 ELEMENTARY PHYSIOLOGY. (3) An introductory survey course in basic human physiology. Prereq: One semester of college biology.

PGY 206 ELEMENTARY PHYSIOLOGY. (3) An introductory survey course in basic human physiology. Prereq: One semester of college biology. 206 ELEMENTARY PHYSIOLOGY. (3) An introductory survey course in basic human physiology. Prereq: One semester of college biology. 207 CASE STUDIES IN PHYSIOLOGY. (1) Group discussions of clinical cases

More information

Uses of Flow Cytometry

Uses of Flow Cytometry Uses of Flow Cytometry 1. Multicolour analysis... 2 2. Cell Cycle and Proliferation... 3 a. Analysis of Cellular DNA Content... 4 b. Cell Proliferation Assays... 5 3. Immunology... 6 4. Apoptosis... 7

More information