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Polarized distribution of plasma membrane transporters and receptors in epithelia is essential for vectorial functions of epithelia. This polarity is maintained by sorting of membrane proteins into apical or basolateral transport containers in the trans-Golgi network and/or endosomes followed by their delivery to the appropriate plasma membrane domains. Sorting depends on the recognition of sorting signals in proteins by specific sorting machinery. In the present review, we summarize experimental evidence for and against the hypothesis that N-glycans attached to the membrane proteins can act as apical sorting signals. Furthermore, we discuss the roles of N-glycans in the apical sorting event per se and their contribution to folding and quality control of glycoproteins in the endoplasmic reticulum or retention of glycoproteins in the plasma membrane. Finally, we review existing hypotheses on the mechanism of apical sorting and discuss the potential roles of the lectins, VIP36 and galectin-3, as putative apical sorting receptors.
- apical sorting
- apical membrane retention
- H-K-ATPase β-subunit
- lectin
epithelial cells carry out vectorial transport that requires polarized distribution of transporters and receptors to apical or basolateral membrane domains. These domains are separated by tight junctions that connect neighboring cells in the epithelial monolayer and act as diffusion barriers to prevent mixing of apical and basolateral membrane components (22). Asymmetric distribution of plasma membrane proteins is accomplished by their sorting into apical and basolateral containers in the trans-Golgi network (TGN) and/or endosomes followed by vectorial transport of these containers and insertion and retention of the proteins in the appropriate plasma membrane domains. Sorting depends on recognition of apical and basolateral sorting signals within the proteins by cellular sorting machinery (20, 58, 59, 75, 76).
Numerous studies have indicated that both O- and N-glycans attached to the extracellular domains of some membrane proteins are important for apical location of these proteins. This review will focus on the role of N-glycans in polarized distribution of plasma membrane proteins in epithelia. The role of O-glycans in apical sorting has been described in several recent excellent reviews (18, 71) and will not be discussed further here.
A putative role of N-glycans as apical sorting signals was postulated more than 10 years ago (24, 31). However, this hypothesis remains controversial primarily because N-glycans are important for the processes that precede or follow the actual sorting event, such as protein folding, quality control, endoplasmic reticulum (ER)-associated degradation, ER-to-Golgi trafficking, and retention of glycoproteins in the apical membrane. Therefore, merely examining the effect of altering the number or the nature of N-linked glycans on the relative abundance of the glycoprotein in the apical membrane, as has been done in many of the studies reported, does not allow one to distinguish between effects on apical sorting and these other processes. Additionally, the mechanisms by which sorting information encoded by N-glycans is recognized by cellular sorting machinery have not been defined. Two lectins have been identified as potential sorting receptors that recognize N-glycans as apical sorting signals (15, 17, 34, 35). However, it is not clear how glycan-lectin interactions that must occur in the luminal compartments of TGN/endosomes are converted into a cascade of cytoplasmic events resulting in apical delivery of N-glycosylated proteins.
In the present review, we discuss the roles of N-glycans in apical sorting and the processes that precede and follow this event. Furthermore, we summarize the evidence for the importance of glycoprotein clustering in membrane microdomains and putative roles of glycan-binding proteins in apical distribution of N-glycosylated proteins.
Normal N-Glycosylation of Membrane Proteins
All membrane glycoproteins are synthesized by ribosomes attached to the ER and become inserted into the ER membrane via a protein-conducting channel, the translocon. Glycoproteins acquire the N-linked glycans during the process of translocation and elongation of the polypeptide chain. First, while the protein continues to be associated with the translocon, a 14-saccharide core is transferred from the dolichol phosphate precursor to the N-glycosylation site of the nascent membrane protein, an asparagine (Asn) residue within a consensus sequence of Asn-X-Thre/Ser (X is any amino acid residue except Pro). Next, terminal glucose residues of this core are trimmed by ER glucosidases. Then, after removal of one mannose residue by the ER α-mannosidase I, the glycoproteins are exported to the Golgi.
Some glycoproteins that are trafficked to the plasma membrane move through the Golgi and post-Golgi vesicular compartments to this destination without further processing. These glycans are high-mannose N-glycans (Fig. 1). However, the structure of the majority of N-glycans is altered further in the Golgi. After removal of one, two, or three mannose residues by Golgi mannosidases, various glycosyltransferases catalyze branching and elongation of the carbohydrate chains, producing hybrid or complex N-glycans (Fig. 1 and Table 1) (1, 39). This rebuilding of the N-glycans is initiated by addition of N-acetylglucosamine (GlcNAc) residues to the N-glycan core structure by one or more of the six different N-acetylglucosamine-glycosyltransferases (GnTs) located in the cis-Golgi and medial Golgi.
GnT-I initiates formation of hybrid N-glycans by attachment of GlcNAc to the α3 arm of the core at the stage when the core contains five mannose residues. Following the addition of GlcNAc and further mannose trimming, GnT-II catalyzes formation of the complex-type N-glycans in which GlcNAc is substituted for both α3- and α6-linked mannose residues. The actions of GnTs-III, -IV, -V, and -VI underlie the variability in the number of branches in N-glycans: GnTs-IV, -V, and -VI promote branching of N-glycans, whereas GnT-III stops branching. The latter enzyme adds the bisecting GlcNAc to hybrid or complex N-glycans that prevents the downstream action of the branching enzymes (Fig. 1 and Table 1). Many of the other glycosyltransferases, which compete with each other for the N-glycan substrate in the trans-Golgi, facilitate elongation of the GlcNAc-substituted chains by adding various monosaccharides. Thus individual branches of the mature N-glycan can vary in both their length and carbohydrate composition. Most frequently, individual branches are elongated by addition of galactose and sialic acid residues catalyzed by galactosyltransferases and sialyltransferases. Individual branches can also be elongated by addition of multiple sialic acid residues or polylactosamine sequences (series of repeated galactose-GlcNAc disaccharides).
The diversity of N-glycans in various glycoproteins is a result of the interplay of several factors. The particular set of glycosyltransferases expressed in a specific cell type is one of the most important. This difference in expression of glycosyltransferases likely explains the finding that N-glycans of the Na-K-ATPase β1-subunit and E-cadherin have a more complex structure in the rabbit intestinal cells than in rabbit renal cells (89).
Moreover, the expression of various glycosyltransferases can change during cell or tissue development, resulting in alterations of glycosylation of a particular protein. For example, downregulation of the enzymes GnT-IV and GnT-V, upregulation of GnT-III, and a decrease in the complexity of N-glycans of the Na-K-ATPase β1-subunit and E-cadherin are observed as dispersed Madin-Darby canine kidney (MDCK) cells in culture are transformed into a confluent monolayer (89).
In addition, the presence of certain amino acid motifs or residues in a glycoprotein can affect the nature of its glycosylation. For instance, scattered basic residues and a peptide loop adjacent to the glycosylation site of lysosome-resident acid hydrolases are recognized by a GlcNAc-phosphate transferase in the Golgi. This results in the formation of a mannose 6-phosphate on the termini of high-mannose N-linked glycans, binding to the mannose-6-phosphate receptor, and targeting to lysosomes (30, 45).
The spatial location of N-glycosylation sites in a protein tertiary structure can also affect the type of N-glycans formed. Certain N-glycans are more accessible to the Golgi glycosyltransferases and are therefore more likely to be processed to the complex N-glycans than others. As a result, particular glycosylation sites in a protein may be occupied by complex N-glycans and other sites by high-mannose or hybrid N-glycans. As an example, the mature Eag1 potassium channel has two N-glycans, but one of the N-glycans is complex while the other is high-mannose (61). Also, in the bovine lysosomal α-mannosidase, three of the six N-glycosylation sites carry only high-mannose N-glycans while the other three sites are occupied by various types of N-glycans (21). These studies indicate that the nature of N-glycan processing is dependent on the position of a particular N glycosylation site within the protein.
Role of N-Glycans in Protein Folding, Stability, and Quality Control in the ER
Folding of proteins in the ER is initiated cotranslationally and is completed posttranslationally. Heat shock proteins, such as GRP78/BIP, act as chaperones facilitating the normal folding of proteins and their delivery from the ER to the Golgi. However, N-linked glycans also play a major role in folding and quality control of newly synthesized glycoproteins, helping to ensure that only properly folded proteins are delivered from the ER to the Golgi and thence to their final destination.
N-linked glycans can contribute to proper folding both directly and indirectly. Addition of bulky polar carbohydrate chains can modify the properties of the polypeptide (7, 70). Glycosylation can affect the local secondary structure of proteins by stabilizing the conformation of residues proximal to the glycosylation site (42). An interaction of N-glycan with the polypeptide chain can induce a β-turn structure (7). Also, glycoproteins are more stable and more resistant to proteolysis than their corresponding unglycosylated counterparts (42, 46). For example, the normally fully glycosylated wild-type β-subunit of the apical transport enzyme, the gastric H-K-ATPase, is more resistant to proteolysis by trypsin (13) or proteinase K (5) than its glycosylation-deficient mutants. Resistance to proteolysis has been attributed to restricted access of the protease to cleavage sites within the protein after it achieves its normal configuration.
N-glycans also can promote folding and quality control indirectly by serving as recognition "tags," or sorting signals, that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltransferases (37, 39, 40, 77) (Table 2). Immediately after coupling the oligosaccharide core to the asparagine of the N-glycosylation consensus site, the two outermost terminal glucose residues are removed sequentially by glucosidase I and glucosidase II. The monoglucosylated form of N-linked glycan binds to calnexin, the membrane-bound lectin, or to calreticulin, the homologous soluble lectin. Calnexin and calreticulin are associated with ERp57, a thiol-disulfide oxidoreductase that is involved in disulfide bond formation that influences protein folding (32, 33, 40). When glucosidase II removes the remaining glucose, the glycoprotein dissociates from calnexin and calreticulin.
The protein now meets one of three possible fates. If properly folded, it moves to the Golgi. Exit from the ER may be assisted by mannose-binding lectins, such as ERGIC-53, VIP36, and VIPL (2, 62, 83). If the glycoprotein is incompletely folded, it becomes a substrate for a luminal ER glucosyltransferase that reglucosylates the glycans located in improperly folded regions. Via these reformed glycans, the glycoprotein again binds to calnexin, calreticulin, and ERp57 and other folding factors to achieve its correctly folded state (40). If, despite repeated cycles of deglycosylation-reglucosylation, a glycoprotein fails to fold properly, it is retained in the ER and eventually degraded. Targeting of misfolded proteins to the ER-associated degradation (ERAD) is facilitated by lectin EDEM (57). ER retention and subsequent ERAD are critical for normal cellular function because they prevent accumulation of dysfunctional proteins in the cell (39, 40, 77). The contribution of N-glycans to the complex ER quality control system is emphasized by some of the functional abnormalities that arise in the presence of defective N-glycosylation (52, 64, 65).
In some glycoproteins with multiple N-glycosylation sites, individual N-glycans are not of equal importance in mediating the processes of folding, ER retention, and export from the ER to the Golgi. For example, only one of the six glycans of the apically located protein, influenza virus hemaglutinin, is essential for folding and exit from the ER (38).
Studies of the β-subunit of the gastric H-K-ATPase expressed in LLC-PK1 cells have also shown that mutation of some of its seven N-glycosylation sites affect its exit from the ER, while mutations of others have little impact. The normally glycosylated β-subunit is distributed between the plasma membrane and the intracellular compartments. At steady state, ∼40% of the protein is detected in the ER, and the remaining 60% is distributed among the plasma membrane, Golgi, TGN, and endosomes (90). Removal of the seventh N-glycosylation site, N7, leads to virtually total retention of the subunit in the ER. Mutation of N1 increases the amount retained in the ER to 75%. Similarly, mutation of N3 and N5 also significantly increases the relative amount of the ER-resident fraction, but to a lesser extent. However, mutation of N2, N4, or N6 does not appreciably alter the quantity of protein retained in the ER.
On the other hand, for some glycoproteins, the number of N-glycans rather than a specific N-glycan is important for their normal folding and production of fully functional glycoproteins. Mutagenic removal of one or two of the four N-glycosylation sites from the apical bile salt export pump (ABCB11) did not significantly affect its stability, trafficking, or function (56). However, removal of three or all four N-glycosylation sites dramatically increased the rate of proteasome-dependent degradation and resulted in significant intracellular retention of the protein. Comparison of mutants of ABCB11 with various combinations of mutated glycosylation sites showed that presence of at least two N-glycans is required for normal folding and trafficking of the protein (56).
In oligomeric proteins, N-glycans can be important for subunit assembly and/or correct folding of the assembled complex. For example, studies using several different cell lines have shown that the catalytic α-subunits of either the Na-K-ATPase or the gastric H-K-ATPase are unable to exit the ER when expressed without their corresponding glycosylated β-subunits (29). These observations suggest that the β-subunit acts as a chaperone to ensure that the α-subunit is properly folded so it can exit the ER.
Role of N-Glycans in Post-Golgi Trafficking and Retention in the Apical Membrane
N-glycans are required for polarized apical distribution of many membrane proteins in epithelia.
Removal of N-glycans from many apical proteins has been shown to decrease their abundance in the apical membrane. For example, mutagenic removal of N-glycosylation sites in the gastric H-K-ATPase β-subunit (90), bile salt export pump (56), and glycine transporter 2 (51, 94) significantly decreased their apical content and increased their intracellular accumulation (Table 3). Similarly, prevention of N-glycosylation by tunicamycin resulted in complete intracellular retention of the normally apically located membrane-bound enteropeptidase (95) (Table 3).
One explanation for these findings is that normal N-glycosylation is required for apical sorting of these glycoproteins. Alternatively, since N-glycosylation is necessary for proper folding of proteins for them to exit the ER, the lack of N-glycans could result in ER retention, which of course would prevent trafficking to any membrane. To account for this, it is necessary to subtract the fraction of the protein retained in the ER from the total cellular pool of the protein. The majority of mature glycoproteins that traverse the Golgi carry complex N-glycans, whereas those residing in the ER are of the high-mannose type. They can be distinguished from each other after treatment with EndoH, since high-mannose and hybrid glycans are sensitive to, whereas complex N-glycans are resistant to, cleavage by EndoH (Fig. 2). Only the quantity of mature, EndoH-resistant protein should be considered when the percentage of glycoprotein that is delivered to the apical membrane is calculated.
Using this approach, the abundance of glycosylation-deficient mutants and wild-type H-K-ATPase β-subunit present in the apical membrane, as determined using surface-selective biotinylation, was compared after normalization for the total cellular amount of the mature subunit (90). The relative quantity of the subunit in the apical membrane was greatly decreased after mutation of N1, N3, N5, or N7, but not after mutation of N2, N4, or N6. By contrast, these mutations had no effect on the relative abundance of this subunit in the basolateral membrane (90). These findings indicate that N-glycans at N1, N3, N5, and N7 are important for apical membrane localization of this β-subunit.
Similarly, comparison of a wild-type and a series of glycosylation-deficient mutants of the sialomucin endolyn expressed in MDCK cells has shown that only two specific sites (N68 and N74) of the eight N-glycosylation sites are important for apical distribution of this protein (72). Disturbance of N-glycosylation of several other membrane proteins, such as the tail-anchored chimeric protein (10), glycine transporter 2 (51, 94), membrane dipeptidase (67), ecto-nucleotide pyrophosphatase/phosphodiesterase NPP3 (19, 53), and chimeric Fc receptor (31) reduced their apical expression compared with their basolateral expression (Table 3). However, the relative importance of specific N-glycans in apical localization of these proteins has not been determined.
Further evidence for the role of N-glycans in apical distribution of proteins has been derived from studies in which the effect of addition of N-glycans to various proteins on their localization was examined. A truncated occludin and a chimeric ERGIC-53 residing in the Golgi in their nonglycosylated forms were redistributed to the apical membrane after addition of N-glycans (31) (Table 4). Similarly, addition of N-glycans to chimeric non-raft-associated transmembrane protein and tail-anchored chimeric protein, both residing on the basolateral membrane, caused them to be redistributed to the apical membrane (6, 10) (Table 4). Finally, the sequential addition of one to five N-glycans to the basolaterally located Na-K-ATPase β1-subunit, a protein with three N-glycans, caused an increasing fraction of this subunit to be distributed to the apical membrane of HGT-1 cells (91). The mutant of Na-K-ATPase β1 which contained eight N-glycans in a pattern identical to that of the homologous isoform, the Na-K-ATPase β2-subunit (which normally resides on the apical membrane in HGT-1 cells), was predominantly detected on the apical membrane (91).
These data are consistent with an important role for the N-glycans in promoting distribution of a number of proteins to the apical membrane of polarized cells. However, the presence of N-glycans on a protein does not ensure it will be distributed to the apical membrane. Several N-glycosylated proteins, including but not restricted to the transferrin receptor (63), liver sodium-dependent bile acid transporter (87), and E-cadherin (54, 55) are located only on the basolateral membrane of polarized cells.
Furthermore, several proteins such as transmembrane neurotrophin receptor p75 (93), the sodium-dependent purine-selective nucleoside transporter SPNT (50), the sodium-sulfate cotransporter Na,Si-1 (74), and M2 muscarinic acetylcholine receptor (12) are N-glycosylated, but normal N-glycosylation is not necessary for their apical localization. Presumably, these proteins contain other intrinsic sorting signals that are sufficient to ensure their apical distribution. It has been shown that the O-glycosylated stem region of p75 acts as the apical sorting signal (93). The M2 muscarinic acetylcholine receptor contains apical sorting information in its third intracellular loop (12). However, the apical sorting signals for SPNT and Na,Si-1 remain to be identified. It is unclear why N-glycans are important for the apical delivery of some N-glycosylated proteins, but not for others. This remains fertile ground for further studies.
N-glycans are required for both apical membrane delivery and retention of glycoproteins in the apical membrane.
Many glycoproteins require intact N-glycans to be located on the apical membrane. One possible explanation is that N-glycans act as apical sorting signals and thus promote apical membrane delivery of the proteins. However, the quantity of protein on the apical membrane depends on the rate of both its delivery to this location and endocytosis of the protein.
As noted above, the mutations of N1, N3, N5, or N7 significantly decreased the relative apical content of the H-K ATPase β-subunit (90). Mutations of N1, N3, or N5 also increased the rate of endocytosis of the β-subunit. The rate of endocytosis of the N7 mutant could not be measured due to the very low apical content of the mutant. Mutations of N2, N4, or N6 did not change either the relative apical content or endocytosis. None of the mutations affected the rate of degradation (90). The decrease in the relative apical content of the H-K ATPase β-subunit N1, N3, and N5 mutants could be due to impaired apical membrane delivery and/or enhanced endocytosis. The apical content of all three mutants was decreased to a greater extent than could be expected from an increase in the rate of endocytosis. For example, in the N1 mutant, the apical content was decreased sixfold, but the rate of endocytosis was increased only threefold. This indicates that the apical membrane delivery from the TGN/endosomes was also affected by the mutation.
Therefore, the presence of specific N-glycans is required for both apical delivery and membrane retention of the H-K-ATPase β-subunit. The rate of delivery of a protein from the TGN/endosomes to the apical membrane depends on the efficiency of protein sorting into apical transport containers and the rate of delivery of these containers to the apical membrane. The mutation of N-glycosylation sites in a cargo protein is unlikely to affect export and transport of the containers. Thus the decreased rate of delivery of the glycosylation-deficient mutants to the apical membrane is consistent with the hypothesis that N-glycans facilitate apical sorting. However, it is not clear whether N-glycans per se serve as apical sorting signals or whether they facilitate recognition of other apical sorting signals present in a glycoprotein by providing an optimal conformation of the protein. Also, it is possible that N-glycans facilitate association of glycoproteins with other proteins that contain apical sorting information, thus promoting cosorting of glycoproteins into vesicles destined for the apical membrane.
It is remarkable that the same N-glycans (N1, N3, and N5) of the H-K-ATPase β-subunit that are important for ER-to-Golgi trafficking are also important for apical delivery and membrane retention of the protein (90). These results suggest that, similar to ER-to-Golgi trafficking, both apical delivery and apical membrane retention of the H-K-ATPase β-subunit are lectin dependent and only specific N-glycans are accessible to these lectins. Reduced retention of the mutants in the apical membrane might result from disruption of the interaction of specific N-glycans of the H-K-ATPase β-subunit with an unidentified integral or extracellular lectin at the apical membrane, which acts to anchor the protein in the membrane. As a consequence, the rate of constitutive endocytosis of the mutant subunit would increase. Interactions of lectins with N-glycans attached to other membrane proteins have been shown to be important for their retention in the plasma membrane in several different cell types (11, 47, 64, 65, 68).
The majority of mature glycoproteins are of the complex type. The complex-glycosylated proteins contain the three-mannosyl core (Fig. 1, green rectangle) and terminal chains that are added during rebuilding of high-mannose N-glycans in the Golgi. To examine whether the core region, the terminal chains, or both are necessary for delivery and membrane retention of apical proteins, various inhibitors of N-glycan processing have been employed. Treatment of cells with these inhibitors prevents trimming and further terminal glycosylation of high-mannose N-glycans. This results in the absence of either all (dMM) or most (swainsonine) of the terminal sugars normally present in the complex N-glycans (Fig. 1). Similar to dMM, kifunesine, the inhibitor of the ER α-mannosidase 1, abolishes addition of terminal chains to the high-mannose glycans (not shown).
Treatment of MDCK cells expressing endolyn with dMM or kifunesine decreased the relative apical abundance, biosynthetic apical delivery, and postendocytic apical delivery of the protein to the same extent as tunicamycin (72, 73). These results suggest that the terminal chains rather than the residues of the core region of N-glycans are important for apical sorting of endolyn. However, endolyn contains not only N-glycans, but also O-glycans. It has been shown that disruption of N-glycan processing by dMM dramatically inhibited O-glycosylation of several proteins that contain both N- and O-glycosylation sites (60). Therefore, the possibility that dMM or kifunesine affected apical distribution of endolyn due to the impairment of its O-glycosylation cannot be excluded. In accord with the latter possibility, benzyl-N-acetyl-α-d-galactosaminide that inhibits elongation of both O- and N-glycans also impaired apical polarity of endolyn (72).
In contrast, the apical localization of gp114 (recently identified as a dog homolog of CEACAM proteins) (27) in MDCK cells was not affected by dMM (48), indicating that terminal chains are not important for apical distribution of this protein. Consistently, exposure of LLC-PK1 cells expressing the H-K-ATPase β-subunit to dMM or swainsonine led to only a slight decrease in the relative apical content of the H-K-ATPase β-subunit, while mutation of one of the seven N-glycosylation sites, either N1, N3, N5, or N7, resulted in a severalfold greater reduction in relative apical abundance (90). On the other hand, the rate of endocytosis of the β-subunit was significantly higher in cells exposed to swainsonine than with any of the single site-deficient mutants (90). These data suggest that the core region sugars play the major role in apical delivery of the β-subunit, whereas the terminal monosaccharide residues are important for stabilization and retention of the β-subunit in the apical membrane.
Putative Apical Sorting Machinery that Recognizes N-Glycans
Search for apical sorting receptors.
The mechanism by which the presence of N-glycans can facilitate apical sorting of glycoproteins is poorly understood. The μ1B-subunit of the AP-1B adaptor protein complex binds specifically to basolateral sorting motifs present in the cytoplasmic domains of basolateral proteins, promoting their placement into the basolateral transport containers and subsequent delivery to the basolateral membrane (25, 26, 28). It seems logical that a similar coupling between a sorting receptor and N-glycans would be used by the cell for delivery of glycoproteins to the apical membrane. Since N-glycans are composed of carbohydrate moieties, a priori the apical sorting receptor must be a lectin, i.e., a carbohydrate-binding protein.
One potential apical sorting receptor, the mannose-binding lectin VIP36 (43, 44, 79), is predominantly localized in ERGIC and the cis-Golgi (36, 83), and to a lesser extent in the TGN and plasma membrane (34, 82). VIP36 plays a role in the export of glycoproteins from the ER (36, 83) (Table 2). VIP36 was also found to promote apical sorting of several glycoproteins. The apical membrane content of this lectin in MDCK cells was found to be twice as high as the basolateral content, and the plasma membrane glycoproteins recognized by VIP36 were also twofold enriched in the apical membrane compared with the basolateral membrane (34). Overexpression of VIP36 in MDCK cells increased the relative apical content of both VIP36 and VIP36-recognized glycoproteins. In contrast, the overproduction of a mutant version of VIP36, which has no lectin activity, had no effect. Furthermore, VIP36 has been shown to bind to clusterin and α-amylase and to increase the relative apical abundance of these proteins (34, 35). Consistent with a specificity of VIP36 for high-mannose-type glycans (43, 44, 79), both clusterin and α-amylase carry not only complex-type N-glycans but also the high-mannose-type N-glycans (34, 35). However, since the majority of mature glycoproteins contain predominantly complex-type N-glycans, VIP36 is unlikely a universal apical sorting receptor.
A galactose-binding lectin, galectin-3, is another potential apical sorting receptor. This lectin was detected in raft-independent apical carrier vesicles in MDCK cells (15). Galectin-3 has been found to directly interact with three apical glycoproteins, lactase-phlorizin hydrolase, transmembrane neurotrophin receptor p75, and gp114 (15, 17). This interaction is competitively inhibited by lactose, suggesting that galectin-3 binds to the glycans attached to these proteins. Lactase-phlorizin hydrolase and transmembrane neurotrophin receptor p75 contain both N- and O-glycans, whereas gp114 has only N-glycans Carbohydrate-dependent binding of galectin-3 to p75 requires the presence of the O-glycosylated stalk domain that does not contain putative N-glycosylation sites (15, 17). These data suggest that galectin-3 can bind to both N- and O-glycans.
Depletion of galectin-3 from MDCK cells prevents formation of the high-molecular-weight clusters containing lactase-phlorizin hydrolase, transmembrane neurotrophin receptor p75 or gp114 and results in missorting of all three apical membrane proteins to the basolateral membrane (15, 17). These findings suggest that galectin-3 cross-links glycoproteins to form large galectin-3-containing clusters in the TGN membranes. These clusters presumably bud from the TGN to form apical transport containers (15, 17).
Galectin-3 binds to galactose, a terminal residue that might be exposed at the carbohydrate chain termini of the mature complex N-glycans (69). Consistently, the efficiency of coimmunoprecipitation of gp114 with galectin-3 and formation of the high-molecular-weight clusters containing gp114 and galectin-3, as well as apical distribution of gp114 are severely impaired in galactosylation-deficient MDCKII-RCAr cells (15, 17, 48). However, the apical localization of gp114 in wild-type MDCK cells is not affected by the mannosidase I inhibitor dMM, which prevents formation of hybrid and complex N-glycans and thus abolishes the insertion of the galactose residues into N-glycans (48). The explanation for these contradictory experimental observations is unknown.
Relationship between N-glycans and lipid rafts.
Significant evidence has accumulated to suggest involvement of lipid rafts in sorting and delivery of proteins to the apical membrane. Lipid rafts are rigid membrane microdomains enriched in glycolipids, sphingolipids, and cholesterol embedded in the fluid membrane (81). In 1997, Simons and Ikonen (84) postulated that newly synthesized apical proteins accumulate in these microdomains in the TGN, while basolateral proteins are excluded from these lipid rafts. Small lipid rafts are then clustered, forming bigger rigid membrane domains that then bud from the TGN as apical transport containers (41, 81).
Certain apical integral glycoproteins, including influenza viral proteins hemaglutinin and neuraminidase, associate with lipid rafts via their transmembrane domains (4, 80). Although transmembrane domains of these proteins are important for both raft association and apical sorting, the signals for raft association and apical sorting are not identical (4, 49, 80). Raft association appears necessary, but not sufficient, for apical sorting of hemaglutinin (4, 49, 80). In contrast, raft association is not absolutely required for apical sorting of neuraminidase (4, 80).
GPI-anchored proteins associate with lipid rafts due to the favorable packing of the GPI anchor into ordered domains of the membrane (85). Stable association with rafts is required for apical sorting of several chimeric GPI-anchored proteins (18, 66, 75, 81, 85). However, raft association is neither necessary nor sufficient for apical sorting of a natural GPI-anchored glycoprotein, membrane dipeptidase (67, 88). Removal of a GPI anchor excluded the protein from lipid rafts but did not impair its apical distribution. On the other hand, removal of N-glycans from the protein resulted in basolateral sorting but did not affect the protein association with rafts (67, 88).
Oligomerization of apical glycoproteins appears to increase their affinity for rafts. For example, clustering of gp114 molecules in the plasma membrane induced by interaction with the gp114-specific antibodies increases association of gp114 with lipid rafts, as judged by increased detergent resistance of the glycoprotein (92). It has been postulated that intracellular multivalent lectins could cluster apical glycoproteins in rafts in vivo and thus facilitate their apical delivery (41, 81, 92).
However, direct evidence for the importance of N-glycans in clustering of apical N-glycosylated proteins in lipid rafts has not been presented. Furthermore, several pieces of evidence suggest that the presence of N-glycans does not facilitate raft association. First, many N-glycosylated apical proteins are not associated with lipid rafts (Table 3). Second, removal of N-glycans did not affect raft association of the membrane dipeptidase, while removal of a GPI anchor excluded this protein from lipid rafts (67, 88). Finally, apical pyrophosphatase/phosphodiesterase NPP3, but not its basolateral homolog, NPP1, associates with rafts, even though both NPP3 and NPP1 contain N-glycans. Specific positively charged amino acid residues in the cytoplasmic tail rather than N-glycans have been shown to be important for association of NPP3 with lipid rafts (19, 53).
Moreover, lectins that cluster N-glycosylated proteins in lipid rafts have not been found. Lectins of the galectin family were considered as candidates. They usually are multivalent and, therefore, binding of one lectin molecule to N-glycans that belong to different glycoprotein molecules can organize glycoproteins in clusters, bundles, arrays, and lattices (8). Indeed, galectin-3 causes clustering of apical glycoproteins, lactase-phlorizin hydrolase, transmembrane neurotrophin receptor p75, or gp114 (15, 17). However, none of these three proteins are present in rafts. Also, galectin-3 does not bind to sucrase-isomaltase, the apical glycoprotein that associates with lipid rafts (15). These results indicate that galectin-3 does not play a role in clustering of apical glycoproteins in lipid rafts.
Another lectin of the same family, galectin-4, is a major component of lipid rafts (14, 16). Depletion of galectin-4 impairs formation of rafts and affects apical sorting of several proteins in HT-29 cells. However, galectin-4 binds with high affinity to glycolipids but not glycoproteins (16).
Recent studies have shown that association of apical proteins with rafts occurs not only in the TGN (9) or late compartments of the Golgi apparatus (86) but also in the cis-Golgi or even in the ER (3, 78). It is possible that the mannose-binding lectin VIP36 facilitates apical sorting of glycoproteins by stabilizing them in lipid rafts in the early steps of the glycoprotein processing in the ER or cis-Golgi, when the mannose residues are exposed at the termini of the carbohydrate chains. This hypothesis is in agreement with the fact that VIP36 was originally isolated from rafts (23), as well as with the data showing that overexpression of VIP36 increases apical distribution of two raft-associated N-glycosylated proteins, clusterin and α-amylase (34, 35).
Conclusions and Future Directions
N-glycans are attached to the majority of membrane proteins. Besides the direct effect of N-glycans on the conformation and intrinsic properties of proteins, N-glycans play a role in intracellular trafficking that arises from specific interactions of N-glycans with intracellular lectins. The best studied of these are the interactions of N-glycans with the ER-resident lectins that are crucial to folding and quality control of newly synthesized glycoproteins and their export from the ER to Golgi. These glycan-lectin interactions ensure that only properly folded proteins exit the ER (Table 2).
Growing experimental evidence also suggests that N-glycans attached to a number of apical proteins are required for their apical distribution (Tables 3 and 4). Recent studies indicate that N-glycans are important for delivery of certain glycoproteins to the apical membrane (72, 73, 90) and for their retention in the apical membrane (90). However, apical localization of a number of membrane glycoproteins is not affected by changes in N-glycosylation. Moreover, several proteins that are specifically sorted to the basolateral membrane are, in fact, N-glycosylated.
Identification of specific lectins that recognize N-glycans and facilitate apical distribution of glycoproteins is a challenging task. So far, only two lectins have been identified as potential apical sorting receptors: the mannose-binding lectin VIP36 and the galactose-binding lectin galectin-3. It is remarkable that VIP36 has been found to facilitate apical distribution of two raft-associated proteins (34, 35), whereas galectin-3 has been shown to be critical for apical location of three non-raft proteins but not a raft-associated protein (15). Possibly, VIP36 and galectin-3 facilitate apical distribution of glycoproteins by two different mechanisms, raft dependent and raft independent. However, this hypothesis needs to be tested for other apical proteins. Also, given the highly diverse structures of complex N-glycans, it would be expected that other lectins facilitating apical sorting and apical membrane retention of glycoproteins will be identified.
In summary, N-glycans attached to many apical proteins are critical to their maturation, sorting, and trafficking to and retention in the apical membrane. As a consequence, defects in N-glycosylation can lead to cellular abnormalities in different tissues. Further investigations may reveal previously unsuspected roles of N-glycans in trafficking of glycoproteins which will provide insight into normal epithelial development and the pathogenesis of various diseases.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-077149, DK-58333, and DK-053642.
- Copyright © 2009 the American Physiological Society


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Should 'Dancing With The Stars' allow two gay men or women to perform a ballroom dance together on the hit show?
Controversial question which Blue Lou probably answered best. Well, closest to my understanding, anyway.
But your "should it be allowed" puts an interesting slant on the question.
Quite apart from the moral judgement implied, it makes very good sense from the producers' point of view. The object of commercial television is to sell products and the … Read more

subset: commoncrawl


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City-based firm Harris Hagan is the first UK law firm dedicated specifically to providing legal advice in all areas of the gaming industry in the UK and overseas.
"Hence our ability to attract work from other City firms that have clients who need help without any fear on their part of us trying to steal their corporate work, property work or whatever," comments senior partner Julian Harris, who along with managing partner John Hagan set up the practice in April 2004.
Both lawyers came from Pinsent Masons, and before that Biddle & Co, but decided to break away from the firm to focus on their specialist area in licensing law.
"Our area of work is highly specialised and it was quite easy for us to become slightly lost in an enormous firm," says Harris. "Of course, it also meant that Pinsents wouldn't be able to attract this specialist work from other firms that didn't have that capability."
They decided to leave with "the consent" of Pinsents as well as their clients on the basis that the new practice would be available to their old firm to fulfil its "licensing and gaming needs".
"Along with those of other firms hopefully," adds Harris.
Fours months after the niche firm was established, Elizabeth Southorn joined the team from Richards Butler, where she led the licensing department.
"They're the gaming and casino law experts, and I do the liquor licensing and betting side," she explains. "We appeal to the magic circle and the major City law firms that don't do this work and that can pass on their big clients to us, knowing they get them back without us poaching them for other work." All of her clients also followed her from her old firm. The formation of Harris Hagan also coincides with the UK's wholesale reform of its outdated gambling laws.
"Obviously, to a certain extent, we were in the right place at the right time," says Harris. "It's producing a huge amount of work, not only in terms of what the new Gambling Act will require of people already in the industry and those coming into the industry, but also the flood of work under the old legislation."
While the firm is a specialist outfit, it is also looking to grow in numbers.
"We want to grow and we need to grow. We're on the lookout for high-quality licensing lawyers, but it isn't easy because it's such a narrow field," says Harrison.
Senior partner: Julian Harris
Turnover: £1.2m
Total number of fee-earners: Seven
Main practice areas: Gambling, leisure law
Key clients: Coral Bookmakers, Conran Restaurants, Royal Opera House, Diageo, Marriott Hotels, Stanley Casinos, Kerzner International
Number of offices: One
Location: City of London


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Tower defense flash game
Tower defense is probably the most or one of the most popular game around these days. I'm sure some of you already thought on create something like that using your own graphics and concept.
Well, now you have your chance! Walter Reid has created a detailed 8 parts tutorial on how to create your own tower defense game using Flash.
How to build a tower defense flash game (Intro)


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Dean Robert Helsley, Grosvenor Professor of Cities, Business Economics and Public Policy has led UBC Sauder School of Business since July 1, 2012 when he returned to the University of British Columbia from the Haas School of Business at the University of California, Berkeley.
Read Dean Helsley's full bio >
UBC Sauder has launched the Parent & Family Network, an initiative that empowers parents and guardians to better support their students' university experience.
UBC Sauder's Dean Robert Helsley recently spoke at the Yale-led Global Network of Advancement Management's (GNAM) five-year anniversary symposium, which brought together 29 member schools to explore critical issues impacting business education.
UBC Sauder School of Business is expanding its programming for working professionals to offer a broader variety of career-focused non-degree programs, ranging from established courses for senior business leaders to new programs geared towards people in their early- to mid-career.
Responding to global demand for analytics professionals, the UBC Sauder School of Business is launching a new nine-month Master of Business Analytics (MBAN) program.
The University of British Columbia's extensive international connections and global mindset have pushed the university to rank 1st among North America's leading schools and 12th in the world in the Times Higher Education's "World's Most International Universities 2017" ranking.
$2-million gift supports advancement of women and diversity in business
Making better cities: New professorship for Sauder Dean to empower research into urban economics
Sauder's new leader: Dean Robert Helsley


text:
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Handpicked brands for you
Awwwww shit, it's Friday again! Time to enjoy some beers and sun! While you're loungin' make sure to check out our friends @hippydistractions for wonderful photos like this, and much more! #firewaterfriends #woods #weekend // And remember, everything...


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emma merial richardson
- 19 years old
- Date of birth: Sep 25, 1992
- Date of passing: Dec 16, 2011
|Let the memory of emma merial be with us forever
This memorial website was created in memory of our loved one, emma merial richardson, 19, born on September 25, 1992 and passed away on December 16, 2011. We will remember her forever.
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"miss you sis r.i.p have a good time and hope you dont miss me too much miss u loads so does ellie xxx
and so does mum love you loads and r.i.p"
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What a difference a day can make, particularly in the confused life of Aston Villa's Cameroon and former Manchester United midfield man, Eric Djemba-Djemba.
On Wednesday, Djemba-Djemba, so bad they named him twice, was widely quoted about his lack of first-team opportunities, saying: "I am very disappointed. It is unbelievable. I came from a big team and it is hard not to be in the side."
He then (allegedly) attacked his boss, David O'Leary, saying: "Whose fault is it that we have lost so many games? It is the manager's because he sometimes needs to change the team. So now we have lost a lot of games and it is too bad. If the manager doesn't try to do something to the team, then maybe we will go down."
The change the team needed, he seemed to be suggesting, was to bring in a bloke with a double-barrelled name in midfield, particularly one who proved such a powerhouse at Old Trafford that United manager Sir Alex Ferguson shipped him out. Come Thursday morning, however, when O'Leary demanded an explanation, Djemba-Djemba suddenly remembered that he did, in fact, work for the best manager in the Midlands, if not the world.
He said: "I was shocked when the manager showed me the newspapers, because they made me look like a troublemaker. I am definitely enjoying my time at Villa.
"Everyone is happy with me and I feel the same about them. As for this season, it is nowhere near finished." And he loves little puppies.
You can make up your own minds which version received the Alastair Campbell treatment. I prefer to believe that Djemba-Djemba's words were possibly lost in translation, since "crap" is apparently almost indistinguishable from "wonderful" in his mother tongue. Either that, or some white noise on a reporter's tape recorder was responsible for the offending words.
We all had a good yawn the other week when Frank Arnesen, Chelsea's director of youth development, explained how he would be central to the next stage of the great Roman Abramovich revolution by developing a new generation of young players at Stamford Bridge. He even told us that he would never get involved in a bidding war for young talent.
It seems, however, that his vision of a home-grown team of young Chelsea players running out at the Bridge, rather than multi-million pound buys, may have to wait another week or two. A few days ago, Arnesen was said to be talking to Feyenoord about buying striker Dirk Kuyt for £12 million. At 25, he seems a strange target for a director of youth development but he apparently looks young for his age.
Arnesen is apparently also excited by Atletico Madrid's teenage striker, Fernando Torres, who would also cost several million pounds. Oh, and Ajax's promising international full-back, Nigel De Jong, who would not be available on a free.
Meanwhile, manager Jose Mourinho is apparently unhappy that Abramovich is said to be demanding that some of the £100,000-a-week wasters at the Bridge are lobbed through the January transfer window. Is that not exactly the sort of meddling by Vladimir Romanov at Hearts that caused George Burley to walk out?
With the disrespect shown to opponents by England's supporters -note their witty chants about the Falklands in last Saturday's friendly against Argentina - one is always on dodgy ground criticising the fans of other nations. But it was particularly galling (Gaulling?) to hear our French friends booing God Save The Queen before the Under-21 European championship final play-off.
England's players could have less complaint about the penalty winner in a 2-1 defeat, even if that did not stop them bleating about a dive from Chelsea's Lassana Diarra. His fall may have been achieved with pike and tuck but that did not disguise the fact that he was caught by a clumsy challenge from Kieran Richardson.
England had taken the lead with a brilliant goal from Charlton's Darren Bent, loaned to the Under-21s after his spell in the full squad. Perhaps outclassed England should have gone the whole hog and asked Sven-Goran Eriksson to allow Wayne Rooney, who has only just turned 20, to play in the match. That would have silenced the French.
Whenever you hear the words European Commission, you think of another financial scandal in Brussels, another budget not signed off or a new directive on getting bananas straighter.
Sadly, you are rarely disappointed, as with the European Commission's ruling on Premiership TV rights for 2007-2010. Having insisted that they would smash the monopoly of Rupert Murdoch's evil Sky TV by bringing about a "viable and meaningful share" of live games, the commission have now come up with a compromise that makes their rulings on bananas look vaguely sensible.
The rights are to be split into six packages, with no television company able to win more than five of the bids. Wow! That is a full 23 games out of 138 that will be denied to Murdoch when the new contracts are decided. That will teach them at Sky, where they are already grieving over the cracking encounters they will lose -- Sunderland v West Brom, Birmingham v Fulham, Bolton v Blackburn...
It is wonderful news that the Government will back any Football Association bid for the 2018 World Cup finals. Only one concern - will the new Wembley be open by then?


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Au 2 Maison D'hôtes 9.8Km
Welcome to AU 2, a unique guest house with the taste and color of the imagination and of a dream come true. In the small quiet village of Muidorge in the heart of the Oise in the Hauts de France, we welcome you in our authentic farmhouse proudly nestled on an acre of fantastic vegetation. Nice suites for happy guests! WIthin a theatrical atmosphere, our "suites" will surprise you by their generous volumes, their spectacular decor and elegant furnishings. Comfortably equipped, each Suite is provided with a boudoir and a great 'shower Salon" We value your comfort and well-being.!
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Le Carré aux Buis 26.8Km
Louvrechy, quiet village close to the D26 (Amiens Montdidier), 20 km south of Amiens, 2 guest rooms are furnished in a small house in the garden of 2000 m2 closed and trees. Parking in the yard and separate access to rooms.
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Les Clés d'Auriane 27.4Km
Guest house in the heart of the Pays de Bray, you will be charmed by its two completely renovated and tastefully decorated and independent lodging for up to four people.
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Les Chambres du Con.. 27.8Km
Just 90 km from Paris, 90 km from Dieppe, 50 minutes from Cergy Pontoise a breath of fresh air, walks in the countryside or in the forest await you. Lalandelle is 18 km from its airport and Beauvais Tille's, 15 minutes of Gisors, 18 km from Chaumont en Vexin and its golf courses. Our farmhouse, built in 1830, has been completely renovated. We wanted it warm, welcoming as a family home. A landscaped garden of 2500m2, surrounded the house and 3 cottages. A loss of sight, Thelle forest, crossed by the GR125 and hiking in the buttonhole. Enjoy with us the peace, nature and birds. It is also near, your activities, fishing, tennis, golf, paragliding, horse riding ... During your stay in our two cottages, you can sample a host table creative and generous. Gluttony will also go to breakfast. Because jams are my passion. Over the four seasons, I create amazing jams tastes: chocolate jelly with berries, zucchini ginger lemon, strawberry basil on sale at the jam ... During your stay with us, our house will be yours also. We tell you soon. (Mary, Leah, Thierry
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Les Chambres de La .. 27.9Km
Agnès welcomes you into this simple and cozy home in mind peasant houses of the Oise. Located in the Pay de Bray between Beauvais Rouen and Gisors. On the edge of the forest of Thelle natural sites in Picardy, the place is ideal for nature activities such as hiking, biking, running
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Les Chambres de l'A.. 28.0Km
Between Normandy and Picardy, 90 kms from Paris, a property with much character and charm, only 200 meters from a magnificent Roman Abbey.WIFI. Spa. Diner, on reservation les Chambres de l'Abbaye are on the cycle road London Paris
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La Chambre D'Emma 9.1Km
Saint Omer en Chaussée
A suite of 60m2 comprising: a chamber and antechamber, living room and open bathroom.
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Le Jardin de Marie-.. 9.1Km
Located in Achy, this guest house is surrounded by a flowered garden of 2.500 m² with a pond. It is just a 15-minute drive from Beauvais and its airport. Guests are invited to relax on the furnished terrace. All of the guest rooms at Le Jardin de Marie-Jeanne are elegantly decorated in light colours. The suite also features a seating area and a private bathroom. Breakfast is included and served every morning in the living room. Dinners with traditional dishes from the region are also available upon prior reservation. Free Wi-Fi is provided throughout the property. Free private parking is possible on site and the medieval village of Gerberoy is a 13-minute drive away.
Chez Francine et Xa.. 11.6Km
A traditional country house set in a well-kept garden, Chez Francine et Xavier offers a terrace and Wi-Fi is free of charge in the entire property. The B&B is 15 km from Beauvais Airport. With a view of the garden, the rooms at Chez Francine et Xavier feature wooden floors, a wardrobe and an electric kettle. The private bathrooms are complete with a bath tub or shower, toilet and hairdryer. A homemade continental breakfast is served daily and you can also share meals with other guests and sample regional specialities. Chez Francine et Xavier is 5 km from the A16 motorway and there is an amusement park in Saint Paul, which is 27 km from the property. Free private parking is provided on site.
Les Floralies 13.9Km
If you are looking for tranquility and conviviality, these you will find with us. 5 independent, warm and comfortable bedrooms are available for you, which you can access to from the yard. The decoration is very personalized with painted furniture by Catherine. Many definitely eye-charming varieties of flowers in the yard and in the garden, where youll be glad to walk or rest. Our chambres dhôtes 3 ears Gites de France are open all year. Each has an independant access. Rustic and contemporary furniture and decoration with wood painted furniture by Catherine. All of them are fitted out with a bathroom (basin, WC and shower). Were having our meals alltogether in our dining-room. We propose you a full meal (drink included). I do the cooking every evening of the week and all year. Familial cooking using the garden season products.
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Espace Troissereux .. 14.2Km
Great Townhouse, spacious rooms with ensuite shower and toilet, private secure parking, Lounge with TV
39Contact More info Add
La Treille 14.9Km
noyers saint martin
At 15 minutes of the airport of Beauvais. Charmed guest house situated on a quiet village.
55Contact More info Add
La Coulée Verte de .. 15.5Km
A studio of 20 m2 on the floor of the house above the owners
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La Coulée Verte 15.5Km
Recent house in a town dedicated to tourism and equestrian pêche.C is 20 minutes from Amiens and Paris time.
50Contact More info Add
La coulée verte 15.6Km
New construction in a tourist village dedicated to fishing and horse, located in a very quiet village.
45Contact More info Add
Chambres D'Hôtes 15.8Km
4 rooms with TV, shower, sink and toilet in each room. breakfast included. In a spacious house with panoramic views. Located in the valley of Evoissons, hiking site, near Poix de Picardie (shops, market on Sunday mornings). 30 minutes of Amiens and 40 minutes from Beauvais. Our animals (goats, Sheep, horses, parrots ...) as the only neighbors. Calm and serenity guaranteed.
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Au Nid de Tillé 15.8Km
Located in Tillé, 800m from Beauvais airport, the guest house Au Nid de Tille offers affordable quality accommodation. Upon arrival you are offered a bottle of still or sparkling water. Coffees, teas and chocolates are provisions to self-service. The continental breakfast is included in the room rate and nest also offers dinner service. WiFi access is free and good qualities but you will equally enjoy the company of cats in our nest. Ms. Florence Detroy the owner.
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Le Refuge des 3 Our.. 17.2Km
10 mn from Paris- Beauvais airport, WIFI, spa, old small wooden farm surrounded by a garden fields . All the first floor is for you: a family ensuite
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Aux 3 Bouleaux 18.5Km
Set in a converted farmhouse, this B&B is located in the picturesque village of Montreuil-sur-Brêche, just a 20-minute drive from Beauvais Airport. The property provides free Wi-Fi access, free on-site parking and a private terrace. All of the rooms at Aux 3 Bouleaux are provided with a private bathroom with shower and free toiletries. A continental breakfast including local and homemade products is served every morning. Other facilities offered include a shared lounge. Situated 90 minutes by car from central Paris, Aux 3 Bouleaux is the ideal base to plan outdoor activities and trips to the Somme region, Disneyland and Astérix Amusement Park.
Le Tilloy 18.6Km
In a beautiful house near airport
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Les Passereaux 20.2Km
Saint Paul
3 bedrooms separate buildingclose to the owner's house. Private shower room and toilets in each bedroom. Private car park.Garden and terrace at disposal. Internet Wifi.
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Au Nid du Thil 21.0Km
You'll stay in a room with two single beds (sheets, towels and bathrobes, television, wireless internet, a shower room with toilet in our home, access to the terrace and the garden to have breakfast in a family, while respecting your privacy. If you want dinner, maybe anticipated (13E/pers)
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Au Nid du Thil 21.0Km
you'll stay in two rooms of 54 m2, beds made, a welcome tray with coffee, tea and chocolate, and pastries. This studio can accommodate 5 / 6 people, close to a grocery store open from 7 to 1, a pizzeria, a 10 min. walk from downtown, 5 km from the airport. We can arrange transportation to the station or the airport if necessary.
350Contact More info Add
Chateau de Chaussoy 21.1Km
In the castle at one floor, 2 bed and breakfast to welcome you in a verdant and restful;
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Fl Arago 21.7Km
Les Jardins de Beau.. 23.4Km
Hericourt Sur Therain
Peaceful surroundings, Nature, and Well-being...only 1h30 from Paris, 1h from Rouen and Amiens, 30mn from Beauvais Airport. On the outskirts of a little village, a charming century-old farmhouse, restored respecting both tradition and ecology, with view upon the first rolling hills of the beautiful Pays de Bray. Two bedrooms dressed in clay, wooden and bright colors, 21 and 30 m2, with spacious bathrooms. Pascale welcomes you: a traditional indian Massages Therapist (ayurveda), I like hiking, horse-riding, I am a longtime biker. I enjoy sharing the produce of my garden and orchard.
65Contact More info Add
St Nicolas Les Hiro.. 23.5Km
On a former(ancient) Monastére, Brigitte and Patrick welcome you for a quiet stay in the countryside in the valley of Floods her(it)
90Contact More info Add
Domaine du Mont Hul.. 24.1Km
Villers Vermont
COTART family welcomes you to their family property in a pleasant and warm in a green area ... Located on the edge of Picardy and Normandy, VILLERS VERMONT is a small village quiet and charming.
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La Logerie du Val d.. 24.7Km
Come and relax at La Logerie du Val de Noye, an ancient farm of the beginning of 19th century, 15 minutes away from the centre of Amiens.
60Contact More info Add
La Grange de George.. 24.8Km
Located on the edge of Picardy and Normandy in the buttonhole of the Bray, LA GRANGE DE GEORGES offers apartments and rooms for lovers of the countryside and nature. In a green setting, near a park Leisure, 15 km from the international airport of Beauvais, and very easy access to a property of 1 ha, LA GRANGE DE GEORGES offers studios independent of 70 and 45 M ², with rooms totally surrounded by trees, away from the main house of the owner.
1Contact More info Add
La Chaumière entre .. 26.1Km
Cuigy En Bray
Great B & B in charming cottage, surrounded by animals, located near Beauvais, Gisord, Gournay and 80kms from Dieppe. Bedroom with double bed 160 + bed for young child, bathroom with shower and toilet just for you and for the long winter evening you can warm up by the wood pile, face to face in the room or meals on the terrace at night surcharge. A 150 deposit check will be requested and returned if everything is in order.
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Les Templiers Norma.. 27.2Km
Charming cottage combines the enchantment of medieval furniture for a modern upscale comfort.
210Contact More info Add
Les Clés D'Auriane .. 27.4Km
Completely renovated detached cottage, it has everything you need to spend several days. Try it.
390Contact More info Add
Le Cabray- Gite de .. 27.7Km
Gancourt Saint Etienne
This old oven independent 19th century bread near a farm, was restored with breathable materials (lime, hemp, flax wool). It will bring you comfort and well-being. You will have an enclosed garden of 1000m² with terrace. Located in the village center, you will have access to the coffee shop as well as hiking loops. Our organic farm will offer goat cheese and cider. Plus: you can watch the milking and discover the making goat cheese.
310Contact More info Add
Le Clocher du May 28.1Km
« Le Clocher du May » purpose a guest house with bed a breafast in Oise, inside the " Pays de Bray". Open all year long, the Bead and Breakfast suite is a typical house of the region. Independant house, with two floors, all confortable. Kitchen, bedroom and bathroom.
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Château d'Auteuil 28.8Km
Berneuil en Bray
BED AND BREAKFAST IN A CASTLE OF EXCEPTION. after 5 years of work, we are pleased to open three hotels in this charming family home. We restore this historic building while respecting its identity and its history with passion and a constant concern for aesthetics and wellness. Our guests enjoy the tranquility of this exceptional site in the countryside an hour from Paris. The scenery is guaranteed with large areas of meadows and woods, thoroughbred horses galloping around. Lovers of architecture and decoration will be filled by a staging mélant imagination and antique furniture. We look forward to welcoming our friends for a night or a weekend to stay out of time.
119Contact More info Add


text:
Root Noun Synonyms: base, basis, foundation, source, seat, cause, fountain-head, origin, fount, well-spring
Root Verb Synonyms: rootstock, rootstalk, tap root, rootlet, tuber, radix, radicle, radicel, rhizome, rhizomorph
Business / Real Estate / Root Of The Title: The original grant (or root) of the title. MORE
Health / Dentistry / Root Planing: The process of scaling and planing exposed root surfaces to remove all calculus, plaque, and infected tissue. MORE
Science / Biology / Root System: Plant organ systems that anchors the plant in place, stores excess sugars, and absorbs water and mineral nutrients. That part of the plant below ground level. MORE
Technology / Home Audio / Root Mean Squared (RMS): A term used to indicate the average level of power that a receiver or amplifier can sustain over a given period of time. Average power ratings (ex: 100 watts RMS) provide a more realistic assessment o MORE
Science / Biology / Root Hairs: Extensions of the root epidermis that increase the roots ability to absorb water. MORE
Entertainment / Literature / Root Creation: Creating a new word by inventing its form from scratch--without reference to any pre-existing word or sound. MORE


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We don't have call display, so we can't see what number you're calling from nor can we find out. However, if you don't have any credit on your phone, you can leave us your number and we can call you back.
01223 744 444
available anytime during the CU full term. Answer within 48h.
Our email service automatically strips your email address from the email, so we cannot see your email address. However, please be aware that the service will not remove any footers or signatures at the bottom of your email.
Calls from Skype go straight through to our phones like any other call – we can't tell if a call comes from a phone or from a computer.


text:
I was checking out my statistics using Google Analytics and I came across this map of the United States. Apart from my abysmal readership south of the border, what else do you think is wrong with it?
For some odd reason the Great Lakes region states (Michigan. Illinois, Indiana, and Ohio) are completely out of perspective. I'm not sure if this is so the map of Canada and the map of the United States will fit together without a gap for the Great Lakes. Or if the engineers working on Google Maps don't talk to the engineers working on Google Analytics. Either way, it kinda threw me off when I first saw it.
This the age of search engine optimization. People in hosting business should actually start web design services as well as SEO services. Even advertising agencies are thinking of taking up additional services. Everyone now should have his own web hosting guide in this regard.


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Irish FA vote against Sepp Blatter as Nelson admits it's time for change
The Irish Football Association say they will vote for Prince Ali Bin al Hussein of Jordan in today's presidential election in Zurich in an attempt to end Sepp Blatter's reign at Fifa.
Irish FA chief-executive Patrick Nelson has confirmed that they will unite with other European associations and back Prince Ali.
Blatter remains determined to win the election despite Uefa president Michel Platini calling on him to quit, however the 79-year-old may fail to secure a fifth term of office after seven Fifa officials were arrested and 18 people indicted by US authorities on corruption charges.
Nelson says the Irish FA are singing from the same hymn sheet of those who say it is time for change'.
"We have agreed to follow the Uefa recommendation which is to vote for Prince Ali because, like a number of European associations and others outside of Uefa, we believe that it is time for change.
"When you look at this week's events you conclude that Fifa has become a soap opera and we cannot allow the world's most important game to be this way. It's the most popular game in the world and deserves better, said Nelson.
"It should not be a soap opera and it's time for change."
During Blatter's 17-year tenure he has received the support of the Irish FA, but Nelson added: "The past is the past and we know what we need and want to do in this election."
Each of Fifa's 209 associations should have a vote, although a few can face disqualification for reasons such as not playing in competitions.
Nelson added: "It's a democratic decision and we will see what the outcome is but we are happy to support Prince Ali who we have met several times since 2012."
Platini said Uefa would unite behind Prince Ali and when asked if a boycott of Fifa competitions was a possibility, replied: "Uefa associations will meet in Berlin next week. We will be open to all options."
Pressed further on the prospect of a World Cup boycott, Platini added: "There may be proposals. I honestly don't wish that."
The FAI had earlier indicated they would be backing Prince Ali, with chief-executive John Delaney stating: "Regardless of the good he claims to have done during his tenure, he has to recognise Fifa has an incredibly bad brand image. We won't be voting for him."
One man relieved to be leaving Fifa is Jim Boyce who steps down as British vice-president today.
Boyce has dealt with uncomfortable questions in a dignified manner but he leaves the stage knowing many within Fifa should have conducted themselves differently - including Blatter.
The former Irish FA president believes Blatter's biggest mistake was not taking action against the likes of Jack Warner from Trinidad, Brazil's Ricardo Teixeira or former president Joao Havelange much earlier in his presidency.
He reflected: "The people who acted in an improper manner should have been away years ago, the action was not quick enough."
David Gill said he would refuse to take up Britain's Fifa vice-presidency if Blatter wins a fifth term as president. The FA vice-chairman and Manchester United director said it would be "futile" to serve under Blatter if he did not realise the "seismic" events of this week were a resignation issue.
Blatter tackled the crisis head on at the Fifa Congress opening ceremony, saying these were "unprecedented and difficult times for Fifa" and that corruption brought "shame and humiliation on football".
He added: "Actions of individuals bring shame and humiliation on football and demand action and change on us. We cannot allow the reputation of football and Fifa to be dragged through the mud any longer, it has to stop - here and now.
"I know many people hold me ultimately responsible for the actions of the global football community, whether it's the decision for the hosting of a World Cup or a corruption scandal. We or I cannot monitor everyone all of the time - if people want to do wrong they will also try to hide it."
Belfast Telegraph


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|Society News: Details
Computers at Manchester Central Library (Archives+)
If you are planning to come to the newly refurbished Central Library after it reopens on 24 March, PLEASE NOTE: You will require your Manchester Central Library library card to access the library computers. If you do not have a card, this is no problem as you can get one on the day. HOWEVER you will be asked to produce some form of identification, so make sure you bring a utility bill or similar to prove your name and address so as not to be disappointed.
This update was published on
01 Apr 2014.
For more information, please contact John Marsden at MLFHS
|Manchester and Lancashire Family History Society


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I know someone who quit school to get a job, ??? didn't receive a paper to state that ??? completed 40 hours of driving in Driver's Ed. DMV advised they will have to wait til age 19. Is there a class offered that this person can take to obtain a DL, subject has a job & vehicle but can not drive back and forward to wk without a DL. Also, would like to know if a subject needs to have a DL to tag & title subjects vehicle. Thank you
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Detalii loc de munca - Irlanda
Descrierea jobului - Irlanda
Description Bell Labs research located in Dublin (Ireland) has a vacancy for a senior manager to lead a high performing team of 16 in the areas of thermal management of electronics and photonics, energy harvesting and energy storage. The candidate will play a key role in ensuring the team delivers world leading research while also impacting Alcatel-Lucent products in the nearer term. The following are essential requirements for the role: - Proven people person: Ability to engage with people on all levels (researcher to CEO) both internally (across research centres and product lines) and externally (with suppliers and academic collaborators). - Excellent communicator: Ability to tailor communication style to academics, product developers, and executive level business leaders. - Excellent vision and impact: Proven record of formulating a research vision and delivering on that vision for impact. Strong track record of transferring research assets to product is critical. - Broad understanding: Understand a range of diverse topics from fluid dynamics to materials science, from thermal management to energy harvesting, and from people management/interactions to product impact. - Strong collaborator: The candidate must be able to foster a collaborative dynamic both within and external to the research team and between research locations and between product teams. The candidate must have a deep understanding of how to work with product partners, academia, and suppliers for long-term partnerships.
Likely qualifications, knowledge, and experience: · Deep appreciation for how research is performed and proven ability to productise research outputs and/or strong product development experience. · PhD (preferred but not essential) in any domain related to thermal science, mechanical engineering, electro-chemistry, advanced materials science etc. · Strong analytical skills and a flair for innovation. · Strong written and spoken communications skills. · Strong track record of bringing new products to the market and working with tier 1 suppliers and world leading academic research institutes.


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Re: Ross and Scioto County Records
In reply to:
Re: Ross and Scioto County Records
Philip Osen 12/07/06
These counties may have genealogy societies or genealogy libraries like Washington County has. Try checking online for genealogy in these counties. I have located sources in this way in other counties in various states.


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Grandma's laid-back attitude was contagious.
(submitted by Faith)
My Mom, The Cougar
"This is a photo of my mom and her new boyfriend. They like to travel and take pictures of themselves. She is very proud to be with him and makes sure to post pictures like this one all over the internet for me and my sister's friends to see. So not embarrassing."
(submitted by Hayley)
Look At It
These two are considering having one of their own.
(submitted by Natasha)
The Fender Bender
"Lombard Street, San Francisco, CA, 1997. While touring the Crooked Street on foot we were witnesses to this fender bender that caused a traffic jam and uproar of tourists waiting for their chance to drive down the street. Our folks felt this was a perfect moment for a happy family portrait."
(submitted by Tiffani)
Down In The Dumps
"This is me, posing for my father on a Sunday morning, shortly after he separated from my mom. He let me wear whatever I wanted and do whatever I wanted with my hair (opportunities that I made the most of). For some reason, he thought it'd be a good idea to take pictures of me standing in front of a dumpster. I have a whole set of these. I guess he was a bit depressed…"
(submitted by Lucia)
She couldn't understand why Snuffy was always trying to smoke his treats.
(submitted by Jackie)
Family Ties
Every time she tries to get out, they keep pulling her back in.
(submitted by Nicki)
You've Got A Hold On Me
She was reconsidering the extensions.
(submitted by Anna)
Saturday Night Special: The Weathervane
"Bennie, we are sure, grows thumbs when we leave him. He has separation anxiety and he hates being left alone so he managed to push open a window on the second floor and scale up to the peak of the third floor. He was looking for his "people!"
(submitted by Cathie)
Saturday Night Special: Guys & Dolls
You should see their diagram for tomato and tomahto.
(submitted by Durby)


text: Ford Escape Routes Reality Competion Coming To NBC Ford is rolling out the new Escape SUV. What better way to get tons of publicity than by showing it off with a cross country challenge, driven by a bunch of hip coo youngsters. I for one am rooting for the brothers that form team black. ryancl 5 years ago 2 responses


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Apr. 21, 2017
Source: joint organization news release
Stockholders have approved a merger proposal bringing together two Farm Credit organizations serving Minnesota, North Dakota and Wisconsin. AgCountry Farm Credit Services and United FCS will merge under the name AgCountry Farm Credit Services beginning July 1.
The new organization will operate in 65 counties through 38 offices in parts of Minnesota, North Dakota and Wisconsin. Headquartered in Fargo, N.D., the Association will serve nearly 18,000 customer-members and have approximately $7.2 billion in assets.
"We believed from the beginning that the culture, values, and vision of both cooperatives made this a natural fit," said Greg Nelson and Brad Sunderland, who serve as board chairs for AgCountry Farm Credit Services and United FCS, respectively. "We would like to thank the stockholders from both organizations for their participation in the voting process and recognizing that this merger will help us better serve agriculture and rural America."
"Since merger discussions began last year, our goal has been to build on the strengths of both organizations to best serve the needs of our members," says Bob Bahl, AgCountry CEO. "In merging these two associations, we are positioned for even greater success and a strong, bright future."
About AgCountry Farm Credit Services:
AgCountry Farm Credit Services is an independently owned and locally governed lending association that provides credit and financial services to more than 12,000 farmers and ranchers in 18 counties in eastern North Dakota and 25 counties in northwest and west central Minnesota. AgCountry also provides agribusiness loans and leases nationwide. Offices are maintained in 26 locations throughout the territory, with nearly 400 employees. For additional information on AgCountry FCS, visit www.agcountry.com.
About United FCS:
United FCS is a member of the Farm Credit System, a nationwide network of banks and retail lending associations chartered to support the borrowing needs of U.S. agriculture and the nation's rural economy. Serving over 6,000 customer-members, United FCS has a primary focus in a 22-county service area in West Central Minnesota and North Central Wisconsin providing loans, leases and a wide array of financial services through 12 branch office locations and 190 locally-based employees. For additional information on United FCS, visit www.unitedfcs.com.


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Tang, X. and McBryde, D., "A Simple Test Method to Monitor Emission Control Operating State Space (Emission Control Failure & Defeat Device Recognition)," SAE Technical Paper 2016-01-2324, 2016, https://doi.org/10.4271/2016-01-2324.
Modern light-duty vehicles require well-controlled engine-out feed-gas and very high catalyst efficiencies to meet the US Environmental Protection Agency (EPA) Tier 2 & 3 standards. When a vehicle with either a gasoline or diesel engine is operating within its controlled state-space the exhaust emissions present at the tailpipe are extremely low. When it is not operating within its controlled state-space the combustion process and therefore its exhaust emissions characteristics will be different. This may occur when an emission control device fails or if a defeat device is employed. Moreover, different control technologies each have unique characteristics or signatures that could assist in identifying either emission control device failure or an existing defeat device.A simple exhaust extension apparatus equipped with a thermocouple for measuring exhaust temperature and a NOx / O2 sensor to measure tailpipe NOx and O2 concentrations can characterize this signature information for pattern recognition analysis. This device can be used both in a laboratory environment with conventional batch sampling systems or for on-road testing as a compact emission measurement system.If this information was acquired during conventional laboratory emissions tests it would provide valuable dynamic system information. This information could characterize events such as cold start open loop operation, engine transient fuel compensation, and high-speed load enrichment and emission control device status with minimal cost.


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Quick Reference
Related content in Oxford Index
Reference entries
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(1875—1951) surgeon
Gask, George Ernest (1875-1951), surgeon
GASK, George Ernest (1875 - 1951), JP; Officer of the Legion of Honour, 1937; Emeritus Prof. of Surgery in the University of London; Consulting Surgeon St Bartholomew's Hospital; ex-Chairman Medical Advisory Cttee Oxford Regional Hospital Board; late Regional Adviser in Surgery EMS; late Member of Medical Research Council; late Vice-President Royal College of Surgeons, England; late Member of Governing Body of British Postgraduate School; late President of Medical Society of London; Hon. Fellow of American College of Surgeons; Corresponding Member of Academy of Medicine of Rome; Hon. member Académie de Chirurgie de France; Membre d'Honneur Société Chirurgicale de Lyons; Late Surgeon and Director of Surgical Unit to St Bartholomew's Hospital; Late Examiner in Surgery to Universities of London, Oxford, Cambridge, Bristol
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+91-11-45679615Post Your Requirement
Price Per Person
On Request
Description :
Desert Safari and BBQ: You will get picked up from your hotel for the desert safari, a ride over the sand dunes followed by a barbeque dinner and belly dance performance in the desert- another Dubai essential! The Desert Safari begins early evening with dune bashing, and is followed by barbeque dinner at a traditional Bedouin campsite.
Description :
City Tour: Take a half day city tour of Dubai on SIC basis. Visit the Dubai Museum, and stop to take pictures at Burj Al Arab, Jumeirah Mosque, Burj Khalifa and Dubai Mall, among others.Dhow Cruise: Spend the evening cruising the Dubai Creek on a dhow cruise, with music and lights- a signature experience that cannot be missed while in Dubai. This is a one hour evening cruise that includes dinner on the Dhow itself.
Description :
Ferrari World: Visit the famous Ferrari World at Yas Island, a one-of-its-kind Ferrari theme park! Experience exciting rides, drives, games and shows for a true F1 experience.Abu Dhabi City Tour: Drive around Abu Dhabi City on a tour bus, and pay a visit to the Grand Mosque while you're in the city.
Description :
Burj Khalifa : Take the elevator to the Observatory on the 124 floor of the Burj Khalifa, and witness the beauty of Dubai from the highest building in the world. The city is a beautiful sight from up there, and one that truly embodies everything Dubai is all about .Leisure :Spend the day at Leisure. You can spend the day visiting the various places covered by the bus, or shop to your heart's content at the magnificent malls in Dubai. We recommend the Mall of Emirates and the Dubai Mall.
Description :
Leisure: Spend the day at your leisure.
Departure: Leave for the Dubai airport in a seat in coach bus.
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CEBU, Philippines - A person with TB infection will have no symptoms. A person with active TB disease may have any or all of the following symptoms:
● A persistent cough
● Constant fatigue
● Weight loss
● Loss of appetite
● Fever
● Coughing up blood
● Night sweats
These symptoms can also occur with other diseases so it is important to see a doctor to find out if it is TB. A person with TB disease may feel perfectly healthy or may only have a cough from time to time. To be sure, it is important to have a TB test if any or a combination of the mentioned symptoms is observed.


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View other listings in Kensington, Potts Point, Darling Point, Darlinghurst, Alexandria.
Online about 1 year ago
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My name is Shaun, I'm an early 30's kiwi who is house trained, know my way around the kitchen as well as house hold cleaning tools and products.
Ive been in Sydney for a little over 5 years, work in the Automotive industry (don't worry I'm not a used car sales person) which is 9 to 5ish with a little bit of travel.
Im looking to live in a house with people who are happy to share a drink/meal but dont need to live in each others pocket.
All people looking in Sydney or more in Kensington, Potts Point, Darling Point, Darlinghurst, Alexandria


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General Question
How do I become a chaplain for a mental instuite?
Asked by talljasperman (21739) December 12th, 2013
I was told to have a masters of divinity, I don't know where it is taught, Can you transfer from a bachelor of arts in philosophy and religion. My religion is non denominational Christian. I have the first year of Bachelor of arts in Philosophy and Psychology.
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Billionaire businessman Donald Trump is the quintessential capitalist. He is a man who has found the successful formula for how to mix conservative fiscal principles with the reality of an increasingly liberal society, and in doing so has become enormously wealthy.
In short, Trump's business success has allowed him to accumulate a fortune.
Beyond his personal financial success, he has taken the national stage by storm after beginning his anti-establishment run for the Republican nomination for president. While campaigning, he has not shied away from putting his vast wealth and knowledge of the economy on center stage.
In fact, there isn't a stage that Trump has avoided, and America has seemed more than enthusiastic to come along for the ride.
Donald Trump recently decided to allow cameras onto his private luxury jet, according to the U.K. Daily Mail.
Take a look inside of Trump's private Boeing 757, and see what it is like when someone who unabashedly supports capitalism becomes wildly successful from it and lives in the lap of luxury that is only possible through the greatest economic system ever devised.
The massive jet contains a double bed in a separate bedroom, a spacious lounge with overstuffed chairs and a curved sofa, large TVs throughout, a marble bathroom with a stand-up shower and hidden toilet, and luxurious leather and gold inlay everywhere.
Check out the 24-carat gold seatbelt buckles and the plush white leather. The seats have the famous Trump seal emblazoned on the headrest.
That is a comfortable looking bedroom with a comfortable recliner. Note that desk — no doubt to make some epic deals.
Click NEXT PAGE To see more amazing photos of Donald Trump's jet.
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0 points
Recent Activity
Question Asked: There is some problem with the shocks,some noise that comes off the left side.
July 13, 2013, 02:59 PM
I am planning to buy a Used Mit' Gallant which has 105k miles on it and the car's engine sounds good. No noise, no leaks. The A/c works good and the interior is clean. Except the owner tell's me there is some problem with the shocks to the left side which makes some noise when it goes over a bump. I test drove it and also hear the noise but wasn't entirely sure what it was. It didn't last long it was no recurrent. I like the car and want to buy it but the scare off replacing the shocks is keeping me from buying the car. I was told it might cost 1000$ for replacing the shocks. is that True? also much would new brakes cost? I felt the brakes were not efficient on the freeway as it was slipping in gaps!!! HELP! Am I making the wrong choice?
Question Asked: Is the Dodge Intrepid a good choice for a student? In terms of cost of spares?
June 25, 2013, 11:44 AM
I am an international student planning on purchasing a car, I have a few options laid out for me with my limited budget and I would like some help from your experiences about what would be a good car for a student to buy without hitting the mechanic shop every month. Thanks a ton in advance.
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On a disc Azure, issuant from base a demi-globe of the field, gridlined Argent, surmounted by an American bald eagle stooping Proper, lifting in its talons a cross Gules, all within a narrow border Or.
Attached above the disc, a Blue scroll edged with a narrow Yellow border and inscribed "BRINGING THEM HOME" in Yellow letters.
Attached below the disc, a Blue scroll edged with a narrow Yellow border and inscribed "775 EAES" in Yellow letters.
Ultramarine blue and Air Force yellow are the Air Force colors. Blue alludes to the sky, the primary theater of Air Force operations. Yellow refers to the sun and the excellence required of Air Force personnel. The American bald eagle, as the national bird of the United States, symbolizes strength and freedom. The red cross represents the medical and support professionals tasked with the transportation and care of wounded warriors. The globe denotes the global capability of the unit whose primary mission is to evacuate the wounded from the battlefield to a military airfield closest to home base. "Bringing Them Home," the unit motto, emphasizes the mission.
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