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Structures of the extracellular regions of the group II/III metabotropic glutamate receptors
Takanori Muto, Daisuke Tsuchiya, Kosuke Morikawa, and Hisato Jingami
PNAS March 6, 2007 104 (10) 3759-3764; https://doi.org/10.1073/pnas.0611577104
Takanori Muto
Daisuke Tsuchiya
Kosuke Morikawa
For correspondence: morikako@protein.osaka-u.ac.jp
Hisato Jingami
For correspondence: jingami@mfour.med.kyoto-u.ac.jp
Communicated by Shigetada Nakanishi, Osaka Bioscience Institute, Osaka, Japan, January 4, 2007 (received for review November 20, 2006)
Metabotropic glutamate receptors play major roles in the activation of excitatory synapses in the central nerve system. We determined the crystal structure of the entire extracellular region of the group II receptor and that of the ligand-binding region of the group III receptor. A comparison among groups I, II, and III provides the structural basis that could account for the discrimination of group-specific agonists. Furthermore, the structure of group II includes the cysteine-rich domain, which is tightly linked to the ligand-binding domain by a disulfide bridge, suggesting a potential role in transmitting a ligand-induced conformational change into the downstream transmembrane region. The structure also reveals the lateral interaction between the two cysteine-rich domains, which could stimulate clustering of the dimeric receptors on the cell surface. We propose a general activation mechanism of the dimeric receptor coupled with both ligand-binding and interprotomer rearrangements.
cysteine-rich region
ligand binding
G protein-coupled receptor
The metabotropic glutamate receptor (mGluR) is a G protein-coupled receptor (GPCR) that transduces extracellular (EC) signals into G protein activation through biomembranes. The mGluR molecule belongs to family C, which includes the GABAB receptor, the calcium-sensing receptor, and some taste and pheromone receptors (1). The family C GPCR protomer has a large EC region that recognizes a specific ligand molecule. l-glutamate (Glu) is a principal excitatory neurotransmitter in the central nerve system, where glutamate receptors play an essential role in regulating synaptic activity. The mGluRs are categorized into three groups, which comprise eight subtypes (2, 3). Each of the groups has a specific regional distribution in the brain and displays a distinct pharmacological profile. Therefore, structural information about the receptor–ligand interaction is essential for drug development.
An mGluR protomer consists of three distinct regions: the EC, transmembrane (TM), and intracellular regions (Fig. 1 A). The EC region is further divided into two parts: the N-terminal ligand-binding region, which is frequently called the "Venus flytrap module," and the cysteine-rich (CR) domain, which intervenes between the ligand-binding and TM regions. Previously, we reported the crystal structures of the ligand-binding region of group I mGluR subtype 1 (mGluR-I1) (4, 5). The structures revealed that dimeric molecules could undergo quaternary structure changes, depending on the bound ligands. Furthermore, we proposed that the structure is in dynamic equilibrium, where the ratio between the active and resting conformations is modulated by the presence/absence of ligand. In response to our structural analyses, the initial activation mechanism of mGluR has been investigated by several biochemical methods (6–15). However, many issues still remain unresolved. In particular, the absence of structural information about the CR domain obscures the concrete and conformational views of the coupling mechanism between the ligand-binding and TM regions.
Here we report the crystal structures of the entire EC region of the group II mGluR subtype 3 (mGluR-II3), complexed with various agonists. This x-ray analysis revealed the structure of the CR domain, which is unique to the family C GPCRs (16). We also describe the crystal structure of the ligand-binding region of the group III mGluR subtype 7 (mGluR-III7). A comparison among the known mGluR structures, including those of mGluR-I1, provides a structural basis for the discrimination of the group-specific agonists. Furthermore, the crystal structure of the group II receptor reveals interaction between the two CR domains, thereby tying up the two adjacent dimeric receptors with the R-conformation. Finally, the activation mechanism caused by both ligand-binding and receptor clustering is proposed, in accordance with the various agonist/antagonist-bound mGluR structures and previous experimental results.
Architecture of mGluRs. (A) Domain architecture of mGluRs. The red lines in mGluR-II3 and mGluR-III7 indicate the region used for the present crystallographic analyses. Similarly, the blue line in mGluR-I1 indicates the region analyzed in our previous studies (4, 5). (B) Two orthogonal views of the mGluR-II3 EC region complexed with Glu. The noncrystallographic two-fold axis runs on the paper plane in both of the drawings. Each domain is colored as in A. Cyan and blue stick models represent disulfide linkages and sugar molecules attached at N209, respectively. Bound glutamate molecules are illustrated by red space-filling models. The disordered segments are represented by broken lines. The two protomers are distinguished by dark/faint colors to depict the dimeric architecture. (C) Overall architecture of the mGluR-III7 ligand-binding region, as illustrated in B. Yellow space-filling models represent the bound 2-(N-morpholino)ethanesulfonic acid molecules.
Overall Architecture of the mGluR-II3 EC Region.
The crystal of the EC region contains two protomers in the asymmetric unit. Because of the noncrystallographic two-fold symmetry in the dimer, their internal structures are essentially identical. The overall architecture of the dimer complexed with Glu is shown in Fig. 1 B. The N-terminal part (residues 25–508) consists of the ligand-binding region. Its general architecture is similar to that of mGluR-I1 (4) and is divided into two domains, LB1 and LB2 (Fig. 1 A). Because the bound agonist intervenes between the two domains (Fig. 1 B), the entire ligand-binding region adopts the closed conformation (4). Although the agonist is bound to both of the protomers, the interprotomer interface resembles that of the R-conformation observed in mGluR-I1 complexed with an antagonist (5), rather than that of the A-conformation for the agonist-bound form (4). Therefore, the overall conformational state is designated as closed–closed/R, which was not observed in the previous analyses (4, 5).
CR Domain.
The present structure includes the CR domains (residues 509–575) at the C terminus, which is followed by the TM and intracellular regions in the full-length receptor (Fig. 1 A). The structure of the CR domain (Fig. 2 A) contains three β-sheets, each composed of two short, antiparallel β-strands. This domain possesses nine cysteine residues, which are all strictly conserved among the family C GPCRs (Fig. 2 D), except for the GABAB receptor. All of these residues are fully oxidized (Fig. 2 A). The four intradomain disulfide bridges contribute to stabilizing the internal architecture of the domain. In contrast, the remaining cysteine residue (C527) is bound to C240 in the LB2 domain (17). Notably, the short connection between the C terminus of the structure (E567) and the N terminus of the predicted TM (A577) contains nine residues, which should also restrict the relative position between the two regions. Thus, it is most likely that the CR domain plays a major role in transmitting the conformational change in the ligand-binding domain to the TM region. Furthermore, this domain prevents a direct interaction between the ligand-binding and TM regions, because the distance between the LB2 domain and the C terminus of the CR domain is too far (Fig. 1 B).
CR domain. (A) Stereo diagram showing the CR domain, colored as in Fig. 1 B. Each of the three modular structures is bracketed. (B) Interaction between the two neighboring CR domains along with the crystallographic c axis. The left molecule is drawn in faint colors to visualize the intermolecular interface. The red arrow indicates the noncrystallographic two-fold axis. (C) Close-up view of the interface. Stick models represent residues on the interface in addition to cysteine residues forming disulfide linkages. (D) Multiple sequence alignment of the CR domain in the family C GPCRs, including human calcium-sensing receptor (hCaSR), murine pheromone receptors EC1-V2R (mPhR1), and EC2-V2R (mPhR2); human mGluR subtypes 1–8 (hmGluR1–8); and rat taste receptors type 1 members 2 (rTR2) and 3 (rTR3). The primary and secondary structures of rat mGluR-II3 (rmGluR3) are shown on the top. The bottom line indicates the conserved residues among these receptors. Capital letters represent the specific amino acid type. Otherwise, a, b, h, and l represent aromatic residue, basic residue, hydrophobic residue, and residue carrying a large hydrophobic moiety, respectively.
The domain architecture could be divided into three modules (Fig. 2 D), as reported for the TNF receptor (18). The N-terminal module in the CR domain (C509–I532) significantly deviates from any known structures. Although the structural feature is reminiscent of the B module (18), the position of the disulfide bridge between C509 and C528 is different from the conserved position in the authentic B2 module. Therefore, we tentatively named this module B2′. The other conserved residues are located near the characteristic disulfide bond (Fig. 2 A). The hydroxyl group of S510 forms a hydrogen bond to the main-chain nitrogen atom of W529, and the large aromatic ring of this residue apparently maintains the local structure by van der Waals (VDW) interactions. The conserved architecture is close to both the interdomain boundary between Q508 and C509 and the interdomain disulfide bond between C240 and C527, implying that the B2′ module plays an important role in fixing the relative orientation between the CR and LB2 domains. Consequently, the CR domain could amplify the conformational change in the ligand-binding domains and thereby more effectively transmit the signal to the TM region. This role probably accounts for the uniqueness of the B2′ module in the family C GPCRs.
In contrast, the structures of the middle (P533–M547) and C-terminal (D548–E567) modules are categorized into the A1 module (18). The crystal packing implies their potential function. In the crystal, the A1 module at the C terminus forms intermolecular contacts at a noncrystallographic two-fold axis (Fig. 2 B). This contact site is composed of T556, D558, G561, and Y563 (Fig. 2 C). These amino acids, except Y563, exhibit weak sequence similarity among mGluRs (Fig. 2 D). This interaction tempted us to envisage a physiological situation in which mGluR may be capable of clustering in a one-dimensional array that cooperatively stabilizes the closed–closed/R structure. The tandem interactions are indeed possible on the cell surface, only when the dimer adopts the closed–closed/R structure [supporting information (SI) Fig. 6]. The buried surface area within the two CR domains (517 Å2) is smaller than the standard value for biological interaction (19). Although the two CR domains may be unable to dimerize in solution, the A1-module-mediated interaction could play a role in regulating the dynamic equilibrium of the EC region (4, 5) on the cell membrane, where molecular diffusion is highly reduced (20). Alternatively, the A1 module may be responsible for binding to other proteins, as observed for TNF receptor 1 (21).
Agonist Binding by the Group II Receptor.
We have determined the crystal structures of mGluR-II3 complexed with five different agonists: Glu, (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV), (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3S-ACPD), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), and (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC). All of these structures were crystallized with essentially identical packing. As a result, their overall structures are basically the same as that shown in Fig. 1 B, except for the CR domains in the 2R,4R-APDC-bound form, in which one structure was disordered in the dimer. These agonists were bound in the same interdomain cleft (SI Fig. 7). The relative positions of the LB1 and LB2 domains are less variable in the agonist-bound forms (data not shown). These fixed open angles strongly suggest that the primary effect of the agonist binding is domain closing, as mentioned previously (4, 5).
Fig. 3 illustrates schematic diagrams representing the agonist recognition by mGluR-II3. These agonists share a common structure of an α-amino acid with one carboxyl group at the δ-position. The ligand-binding pocket recognizes these chemical groups in an essentially identical manner. The residues involved in ligand binding agree with the previous mutational studies (7, 8). Surprisingly, mGluR-II3 copes with these different agonists by rearranging solvent molecules, instead of altering the protein conformation. The positions of the W2 and W3 water molecules in the Glu- and 1S,3S-ACPD-bound structures are occupied by the additional carboxyl group of DCG-IV (Fig. 3 A–C). Consequently, the hydrogen-bonding network around the ligand is maintained among the three structures. Furthermore, DCG-IV binding would cost less in terms of solvent entropy than the binding of glutamate or 1S,3S-ACPD to form similar hydrogen bonds. In addition, the VDW contact between Y150 and DCG-IV (Fig. 3 B) may also contribute to stabilizing the ligand binding. These interactions agree with the fact that DCG-IV displays higher affinity to mGluR-II3 than does Glu (22, 23). Other VDW contacts with Y222 and G302 are observed in the 1S,3S-ACPD-bound form (Fig. 3 C). Considering the lower affinity of 1S,3S-ACPD than that of Glu (22, 23), the conformation of the bound agonist might be energetically unfavorable. In contrast to the above three agonists, water molecules are invisible in the ligand-binding pockets complexed with 1S,3R-ACPD and 2R,4R-APDC (Fig. 3 D and E), due to the limited resolution of the x-ray analyses. Although the δ-carboxyl groups of these two compounds have different stereo configurations from those of the other three, the hydrogen bonds with R68 and K389 are formed but skewed. These configurations may partly explain their lower affinity than that of Glu (22, 23). In contrast, the invisible water molecules partly contribute to the binding of 2R,4R-APDC, because the agonist could bind to the receptors more strongly than 1S,3R-ACPD (22, 23). The nitrogen atom in the five-membered ring of 2R,4R-APDC (Fig. 3 E) may be hydrogen-bonded with solvent molecules.
Agonist recognition by mGluR-II3. Schematic drawings for the binding of Glu (A), DCG-IV (B), 1S,3S-ACPD (C), 1S,3R-ACPD (D), and 2R,4R-APDC (E). Hydrogen atoms attached at the Cα atom of the ligands are modeled with the corresponding ideal geometries. Only the residues/water molecules that directly interact with one of the agonists are drawn. Red and blue lines indicate hydrogen-bonding and VDW contact, respectively. Either of the two carboxyl oxygen atoms connected by the green line in B is likely to be protonated, as suggested from the short distance between them (2.4 Å).
The mGluR-III7 Ligand-Binding Region.
Fig. 1 C illustrates the overall architecture of the ligand-binding region of the dimeric mGluR-III7, which lacks the CR domain. The asymmetric unit contains one protomer, which forms the dimer related by crystallographic two-fold symmetry. As in the cases of mGluR-I1 and mGluR-II3, the ligand-binding region is divided into two domains (Fig. 1 A and C). The structure of each domain is essentially the same as those of the corresponding regions in mGluR-I1 (4) and mGluR-II3 (Fig. 1 B). In the crystal, the protomer adopts the open conformation, probably because of the binding of a buffer molecule, 2-(N-morpholino)ethanesulfonic acid (Fig. 1 C; see also SI Fig. 8), in the pocket. The open angle between the LB1 and LB2 domains is comparable with those observed in the mGluR-I1 crystals with an antagonist (5). The interprotomer interaction primarily occurs only between the two LB1 domains, which assume the R-conformation (4). Thus, the overall architecture is designated as open–open/R.
A structural comparison among mGluR-I1, mGluR-II3, and mGluR-III7 suggests that they recognize Glu in a similar manner. To elucidate the recognition mechanism, the closed protomer of mGluR-III7 was modeled with reference to the closed protomer of mGluR-II3 by least-square fitting. Fig. 4 A represents the ligand-binding pocket with the conserved residues among the three receptors. These residues belong to not only the LB1 domain (R78/68/78, S165/151/159, T188/174/182, and K409/389/407; each residue number represents that for mGluR-I1/mGluR-II3/mGluR-III7) but also the LB2 domain (Y236/222/230 and D318/301/314). These conserved residues form electrostatic interactions with the α-amino acid and δ-carboxyl groups of Glu in both mGluR-I1 (4) and mGluR-II3 (Fig. 3 A). The highly conserved structure strongly suggests that these interactions should also occur in mGluR-III7. The mutational studies of the group III receptor confirmed that these residues affect agonist binding (9, 10).
The ligand-binding pocket. (A) Conserved amino acid residues involved in ligand binding. Red, green, and blue stick models represent the structures for mGluR-I1, mGluR-II3, and mGluR-III7, respectively. The three closed protomers were superimposed by least-square fitting. The model of the closed mGluR-III7 was constructed as described in the text. (B) Difference in the open angle of the closed protomer between mGluR-I1 (purple) and mGluR-II3 (green). The yellow stick model represents the bound Glu. The black arrow indicates the view direction in A. (C–E) The ligand-binding pockets of mGluR-I1 (C), mGluR-II3 (D), and mGluR-III7 (E) as viewed in A. Each molecular model is colored as in Fig. 1 B. Red lines indicate the conserved surface shown in A. (F) Diagram representing the DCG-IV binding of mGluR-II3, viewed from directions similar to that in A. The structure of the closed protomers of mGluR-I1 (green) (4) is superimposed onto the mGluR-II3 structures (yellow).
Group Discrimination by mGluR Agonists.
Fig. 4 A shows the biased distribution of the conserved residues that participate in the agonist binding. The nonconserved residues are located near the entrance of the ligands in the open conformation. Despite harboring the same ligand (Glu), the ligand-binding region of mGluR-II3 is more closed than that of mGluR-I1, because W110 and E292 mutually block further closing (Fig. 4 B). As a result, the ligand-binding pocket is kept open to the bulk solvent through the two channels in the group I receptors (Fig. 4 C). On the other hand, the ligand-binding pocket of the closed mGluR-II3 is inaccessible from the outside, because of the barrier formed by Y150 and R277 (Fig. 4 D), specific for the group II receptors. These residues are responsible for creating the distinct shape of the ligand-binding pocket. Although a previous homology modeling study proposed that R277 might participate in direct hydrogen-bonding with DCG-IV (8), such an interaction is not observed in the crystal structure (Fig. 3 B). Instead, the residue most likely plays a role in supporting the rigid ligand-binding pocket. A similar effect may be produced by S154 and R189 (7). In contrast to the group I/II receptors, the LB1–LB2 interface of mGluR-III7 possesses residues with small side chains (Fig. 4 E). When the closed protomer is modeled with reference to the mGluR-II3 structure, the ligand-binding pocket is wider and more easily accessible to the bulk solvent than those of the other two. It is apparently difficult for mGluR-III7 to close the ligand-binding region further, because of the steric hindrance among the residues surrounding the ligand-binding site. Therefore, the widely opened ligand-binding pocket would be unique to the group III receptors. This environment partly accounts for the low affinity of Glu to mGluR-III7 (24).
DCG-IV displays high selectivity and potency for the group II receptors (25, 26). The structural differences between mGluR-I1 and mGluR-II3 suggest that the side chain of conserved W110 in mGluR-I1 blocks the binding of DCG-IV by steric hindrance at the contact position of the agonist with Y150 (Fig. 4 F). Furthermore, the widely opened binding pocket for the group III receptors (Fig. 4 E) is unfavorable for binding DCG-IV, because the VDW interaction with Y150 in mGluR-II3 (Fig. 3 B) is absent in the group III receptors.
Implications for Receptor Activation.
The mGluR-II3 EC complexed with various agonists adopts the R-conformation, which appeared in the ligand-free state (4) and the antagonist-bound state (5) for mGluR-I1. A comparison of the R-conformations among mGluR-I1, mGluR-II3, and mGluR-III7 indicates that the relative position between the LB1 domains is basically identical (SI Fig. 9). The hydrophobic residues in the LB1 interface are conserved among the three groups (4), in addition to the invariant local structures (data not shown). Thus, all of the mGluRs potentially perform the A-to-R conversion. Because the clear shift of the C helix in the LB1 interface (5) was not observed in the closed protomer of mGluR-II3, the previous hypothesis, which claimed the absence of the open–open/A state in the dynamic equilibrium (5), appears to be legitimate. The observation of multiple structures not only in the ligand-free state (closed–open/A and open–open/R) but also in the agonist-bound state (closed–open/A and closed–closed/R) implies that the receptor activation involves a complicated mechanism based on dynamic equilibrium, although the crystal packing may have caused biased trapping of certain conformations.
The structure of the CR domain and its spatial relationships with the ligand-binding region allow us to discuss the connection between the EC and TM region less ambiguously than before (4). We constructed the six structural models of the EC region (closed–closed/A, closed–open/A, open–open/A, closed–closed/R, closed–open/R, and open–open/R) and evaluated the distances between the two CR domains in the dimer (Table 1). Given these distances and the size of the TM region (≈35 Å), estimated from the structure of rhodopsin (27), these structural models could be classified into two groups. The two TM regions in the dimeric receptor could associate with each other only in the closed–open/A and closed–closed/A conformations. On the other hand, the spacing in the R-conformations is too large for them to associate directly with each other. The two TM regions within an mGluR dimer may not always contact each other, whereas the dimer itself can be retained through the interprotomer disulfide bridge in the EC region (SI Fig. 10) (28).
Distance between the two CR domains in the mGluR-II3 dimer
Although we speculated that the A- and R-conformations might represent the "active" and "resting" states, respectively (4), their actual involvement in receptor activation is still controversial (29). As a simple interpretation, the closing of the EC region may be sufficient to induce a conformational change in the adjacent TM region, which could be activated in a separated state. However, this idea neglects the A-conformations, despite the functionality of the Gd3+-binding site (5, 12). To allocate the roles for both the A- and R-conformations, the original hypothesis proposed in our previous report (4) should be reevaluated (Fig. 5). The former induces the direct association of the two TM regions, which could activate G protein, whereas they hardly associate in the latter. The structure of the dimeric receptor is likely to be in a dynamic equilibrium composed of the five components (5). The A-to-R transition could induce the rearrangement of the TM regions, as suggested by Tateyama et al. (13) (Fig. 5). It was also reported that the dimeric receptor could be activated by a single protomer closing (14, 15). These data are consistent with our mechanism, because closing of one protomer is sufficient to induce the A-conformation (4). Furthermore, the intermolecular interactions within the crystal lattice (Fig. 2 B) suggest that the closed–closed/R structure represents another structural state that insulates the receptors from equilibrium. Both the A- and R-conformations coexist in equilibrium, even if two protomers in the dimer are fully closed. Excess amounts of the closed–closed/R molecules on the cell surface should cause aggregation of the receptors, which could stabilize the R-conformation. This structural state might be related to the desensitized one, where the receptor responsiveness to the agonists is attenuated. The intermolecular interactions by the CR domains suggest another possibility that a cluster of proteins may cooperatively function for the receptor activation. Interactions with other proteins, including G protein and scaffold proteins, might induce unexpected conformational changes in mGluR. To test these possibilities, further studies of mGluRs are required.
Hypothetical model for mGluR activation. Three structural models represent the active (bottom, left), resting (bottom, right), and insulated (top) states, respectively. Each model, viewed in parallel to the membrane, was constructed by using the atomic coordinates of mGluR-II3 EC (present work) and rhodopsin (26). For clarity, the closed–open/A and open–open/R conformations are highlighted in the active and resting states, respectively, with dark colors, whereas the other possible conformations are drawn with faint colors. In all of these models, the C termini of the EC region (black arrowheads) are anchored to the same position at the corresponding TM. The position is separated by ≈12 Å from the N terminus of the first TM helix (white arrowheads). The distance is long enough for the nine residues to connect the two regions in mGluR (black broken lines). Yellow and green spheres indicate the Cα atoms of the residues representing loops I (K67; connecting the first and second TM helices) and II (R147; connecting the third and fourth TM helices), respectively. The interatomic distances for I–I (yellow lines) (66 Å in A; 54 Å in R), II–II (green lines) (42 Å in A; 55 Å in R), and I–II (purple lines) (53 Å in A; 53 Å in R) are consistent with the experimental data (13). The A-to-R transition in the dynamic equilibrium could induce lateral translation of the blue TM, as indicated by the gray arrows.
The recombinant proteins for the crystallographic analyses were produced with the baculovirus expression system and were purified to homogeneity. The EC region of mGluR-II3, whose two glycosylation sites (N414 and N439) were mutated with glutamine, was crystallized in a buffer containing 0.2 M NH4H2PO4 (pH 4.9–5.1) and 2.5–5.0% (wt/vol) PEG 6000. Crystals of the ligand-binding domain of mGluR-III7 were obtained in a mixture of the B2 and C3 buffers in Grid Screen ammonium sulfate (Hampton Research, Aliso Viejo, CA) in a 1:4 ratio. Both of the crystal structures were solved by the molecular replacement method using the atomic coordinates of mGluR-I1 (Protein Data Bank ID code 1EWK) and were refined to provide the final structures with reasonable crystallographic statistics. Detailed experimental procedures and statistics are described in SI Table 2 and SI Materials and Methods .
We thank Drs. T. Oyama and N. Shimizu for help with x-ray data collection; Ms. R. Sata, Ms. H. Kishi, and Mr. T. Tomura for technical assistance; and Dr. S. Nakanishi for valuable comments. This work was partly supported by the New Energy and Industrial Technology Development Organization.
‡To whom correspondence may be sent at the present address:
Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan.
E-mail: morikako{at}protein.osaka-u.ac.jp
§To whom correspondence may be sent at the present address:
Office of Graduate Courses for Integrated Research Training, Kyoto University Faculty of Medicine, Yoshida, Sakyo-Ku, Kyoto 606-8501, Japan.
E-mail: jingami{at}mfour.med.kyoto-u.ac.jp
Author contributions: T.M., D.T., K.M., and H.J. designed research; T.M. and D.T. performed research; T.M. and D.T. analyzed data; and D.T., K.M., and H.J. wrote the paper.
↵*Present address: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Company, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
↵ †Present address: Institute for Advanced Biosciences, Keio University, 403-1 Nipponkoku, Tsuruoka, Yamagata 997-0017, Japan.
Data deposition: The atomic coordinates and the structure factors have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 2E4U (mGluR-II3, Glu), 2E4V (mGluR-II3, DCG-IV), 2E4W (mGluR-II3, 1S,3S-ACPD), 2E4X (mGluR-II3, 1S,3R-ACPD), 2E4Y (mGluR-II3, 2R,4R-APDC), and 2E4Z (mGluR-III7)].
This article contains supporting information online at www.pnas.org/cgi/content/full/0611577104/DC1.
mGluR,
metabotropic glutamate receptor;
GPCR,
G protein-coupled receptor;
Glu,
l-glutamate;
extracellular;
TM,
transmembrane;
CR,
cysteine-rich;
VDW,
van der Waals;
DCG-IV,
(2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine;
1S,3S-ACPD,
(1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid;
1S,3R-ACPD,
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid;
2R,4R-APDC,
(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate.
© 2007 by The National Academy of Sciences of the USA
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You are going to email the following Structures of the extracellular regions of the group II/III metabotropic glutamate receptors
Takanori Muto, Daisuke Tsuchiya, Kosuke Morikawa, Hisato Jingami
Proceedings of the National Academy of Sciences Mar 2007, 104 (10) 3759-3764; DOI: 10.1073/pnas.0611577104


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Reviews of Whatnot
What the hell is all this?
Justified – A Retrospective
I have this recurring tendency to never watch things right when they come out. I watched Breaking Bad years after it was off the air. Will probably go through Better Call Saul in about a year or two.
Why is this? If I had to put a name to it, life is short, and there is already too much content to consume in one lifetime. So, I have a strong predilection to wait. See what stands the test of time. What is worth coming back to.
I mentioned in my first write up on this that I was on the hunt for something new. I scratch that itch from a number of different sources. This time, a wiser man than myself guided my way to Justified. I had heard good things, so I decided to start.
And boy am I glad I did. Pulled me in from the first 5 minutes.
On its surface, the show is a procedure. There is a bad guy/event of the week and our hero stops him. However, much as I say about any genre of music, you can make any genre of anything work if it just has good writing.
My first big takeaway on this show is writing craft. This show is meticulously written. Not even just from a full season story arc perspective. Scene to scene just has time and effort put into it.
That kind of dialogue work doesn't spring out of the ground organically. That takes effort.
Another HUGE part of the show for me is the fucking casting. Lets put aside the leads for a minute, I want to give the casting director Cami Patton all the credit in the world of managing to pick up the strongest actors for the bad guy of the week parts. Pulling everybody from most of the cast of Band of Brothers to Mary Steenburgen to Stephen Tobolowsky.
Every episode is a treat to just see who they managed to pull in from episode to episode to act off this wonderful main cast.
But of course, all of those are just some of the reasons to watch the show. You know why you should watch this show.
Walton fucking Goggins
Look, Justified ran for six fucking seasons. They can't all be winners.
BUT, even in the series laziest hours, Walton fucking Goggins. Coming in to save the day. The writers only wrote one of the best TV villains for him to play and he fucking crushes it. Delivers 100% every time he is on the god damn screen.
Like it is worth just to see what shit Boyd Crowder gets into this week.
Much is made of gatekeeping things. Whether it be anime or a music scene, people are protective of a certain definition. To me, the worst offender is the Western. Justified is a Western with no fucking horses and set in eastern Kentucky. A lawman out to figure out what justice means. Dunno how much more western you can get.
It's the Atmosphere too that sells it as a western. Building this whole world out of this small coal mining county just lends it to a man wanders into town looking for justice, vibe.
This is a show I plan on revisiting over and over again. In a land of 8 episode streaming bullshit that feels 4 episodes too long, this thing is a breath of fresh air. Go watch it.
4/4 – You'll never leave Harlan alive.
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News & Opinion | January 8, 2020 9:28 am
20 Trends That Will Define the Lives of American Men in 2020
Your future involves electric trucks, tie-dye shirts and something called "technodildonics." We can explain.
Pictured: Some things you will probably try in 2020, whether you like it or not
By Walker Loetscher @rhymeswfletcher
It's a big year, 2020.
There's an election. An Olympiad. The UK is (allegedly) leaving the European Union. Voyager 1 and 2 — a pair of space probes that NASA launched back in 1977 — are expected to finally run out of power somewhere out in the Milky Way.
And those are just the things we know will happen.
As is customary this time of year, we also like to take a look at the things we think will happen, by making a number of well-informed but ultimately wildly speculative predictions about the way that men's lives will change over the course of the next 12 months.
This year, we've got great news for tie-dye enthusiasts, railfans and people who like to drink without getting drunk. But there's also some bad: for carnivores, guys who still sag their pants and anyone who thought streaming would fix the ills of cable.
So gather 'round our crystal ball. These are the trends that await you in 2020.
1. The biggest health trend of the year will be "plant-based" dieting
One of the most talked-about documentaries of 2019 was The Game Changers, which highlights the ways in which switching to a "plant-based" diet has led to measurable performance improvement for a number of elite athletes, from ultra-runner Scott Jurek to mixed martial artist Conor McGregor. Amid a booming alternative-meat industry, growing concerns over the climate crisis and a $4 trillion wellness industry that has humans paying closer attention than ever to what they put into their body, expect vegetarianism to finally shake free of the stigmas that have long characterized it, especially among men.
Cryotherapy is popular among pro athletes — and increasingly, the casual gymgoer as well (Getty)
Dan Mullan / Getty
2. Recovering from your workout will become as important as the workout itself
One of our favorite new products of 2019 was the Theragun, a "percussive therapy" device that massages the muscles after a workout. It's indicative of a far greater trend in the world of fitness, in which casual athletes and gymgoers are starting to take the "post" phase as seriously as professional athletes have for a long time. And we don't just mean saunas and hot tubs: high-tech facilities dedicated to recovery are popping up in cities around the country, with treatments that range from cryotherapy and compression to guided stretching and oxygenation.
3. Men's style will continue to become less binary
When we took a look back at our favorite men's outfits of 2019, we noticed a prevailing trend: the world's best-dressed gents are increasingly experimenting with garments and accessories traditionally thought of as feminine. Is this an invitation for you to go full-blown Harry Styles at the Met Ball? Not necessarily. But what you are going to see is that fashion as a whole is moving in a direction where more and more brands focus on gender-neutral collections — like Entireworld, the new label from Band of Outsiders founder Scott Sternberg that sells the majority of its styles without binary gender labels.
4. You will see a ton of high-waisted trousers
Plenty of other new menswear trends will litter your Instagram feed, but this will be the most conspicuous. You can look to Harry Styles (again) for this one, and then you can probably just keep looking at him for the next year or two, because everything the man puts on right now turns to gold.
Tie-dye socks from Anonymous Ism
5. … And also a ton of tie-dye
There is perhaps no item more indicative of fashion's cyclical nature than tie-dye, which seems to come and go in and endless blur of technicolor waves. With normcore icons like Ezra Koenig leaning on tie-dye as a staple and the world of streetwear increasingly looking to jam culture for inspiration, it is very much IN right now. The one must-have item? Socks.
6. Non-alcoholic beers will get the craft treatment
In 2019, all your favorite craft breweries were trying to crack the hard seltzer code. This year, the buzziest category in the craft world may be the one that doesn't give you a buzz at all: non-alcoholics. There are already a number of popular microbreweries — like Bravus, Surreal and Athletic Brewing — that specialize in non-alcoholic beer; this year, expect them to get competition from the big boys of the industry, with Brooklyn Brewery already out ahead of the pack.
7. Cocktails will introduce you to the world of low-ABV spirits
Given the continued success of low-ABV classics like the Aperol Spritz, we're seeing bartenders experimenting more with other low-ABV spirits — like aperitifs, sake or vermouth — as a base for cocktails. That trend, in turn, has opened up the market for a whole new category of low-booze spirits, with new brands like Haus and Portobello Road Temperance Gin fast becoming mixology standards.
The Ashland, from Chicago horology company Oak & Oscar, is made in collaboration with Wilson Sporting Goods
Oak & Oscar
8. Boutique watch brands will become household names
One of the more frustrating realities in the world of automatic watches is that the price of entry is getting higher and higher. The big-name brands are raising their prices year after year, even on their lowest-cost options, many of them making it so that you have to drop $3-5k for even their most basic offering. Which is why it's so refreshing that there's been such a significant uptick (sorry) in the number of independent brands popping up over the past few years, filling a notable void on the lower end of the pricing spectrum, specifically the $500 to $2,000 range. Brands like Oak & Oscar, Baltic, Farer and Monta make beautiful, solid watches that offer modern flourishes without straying too far from the traditional design language of horology, at price points that are welcoming to newcomers. As entry-level pieces from the big boys become more and more out of reach, it stands to reason that these startup brands will grab more of the market — and eventually be seen as more than just a stepping stone to something better.
9. The 35mm cinema will see a vinyl-like resurgence
There's a reason why Netflix and its ilk will never kill off the movie theater: because you don't just go to the movies to watch the movie — you go for the collective experience of watching the movie in a roomful of like-minded movie lovers. And that's exactly what you get at one- and two-room cinemas like Quentin Tarantino's New Beverly in LA or Alexander Olch's Metrograph in New York, where you're as likely to see an obscure French film as the latest big-budget superhero flick. These are places dedicated to building a community of movie lovers, and vitally, they tend to show movies as they were intended: on a crackling 35mm film projector. Physical media may be dying off in a popular sense, but that death is giving certain formats (see also: vinyl records) new life as niche cultural touchstones in a rapidly evolving digital era.
10. Major League Baseball will strike a deal with a streaming platform
In order to boost sagging TV ratings as well as put itself on the radar of a younger audience, expect MLB to (finally) dip their toes into the world of streaming, something that both the NFL and Premier League have experimented with already. It won't be carte blanche; rather, some basic version of MLB TV will be bundled into a Hulu or Amazon package, where bored Gen Z'ers might happen upon a game and remember that, oh yeah, baseball exists. Some proposed rule changes to make the game faster and more exciting (that won't work) will then follow.
At London's ATP Tour Finals, Stefanos Tsitsipas bested Dominic Thiem in a classic three-set final
11. The next generation of men's tennis greats will finally arrive
At the year-end ATP finals in London, Roger Federer, Rafael Nadal and Novak Djokovic did something they don't do very often: lose. The parties responsible for dispatching them? Stefanos Tsitsipas, Dominic Thiem and Sascha Zverev, the same brigade of talented young players who have long been derided as too mentally infirm to step up and take the mantle of tennis greatness from the ATP's three-headed monster. Is this the year that one of them finally tops a podium? Signs point to yes.
12. There will be huge breakthroughs in lithium-ion battery technology
We've already been over the biggest issue facing the long-awaited electric-vehicle boom: a lack of the urban infrastructure that's needed to keep them all adequately charged. But a prerequisite to that problem is making better, faster, cheaper, more durable batteries in the first place. Money is currently being poured into improving lithium-ion technology, and just last week, a university in Australia announced it had devised a lithium-sulfur battery that could theoretically power a car for more than 600 miles. With GM and LG recently announcing a $2.3 billion joint venture and Volkswagen, Tesla and Toyota already fast at work on similar projects, expect 2020 to be a banner year for batteries.
After Overland West, Rivian's R1T seems to be the most promising off-road vehicle of 2020
13. Electric trucks will finally become a reality
So far, attempts to build the world's first functioning, all-electric SUVs and pickups have been either kinda lame (the Tesla Cybertruck) or not very practical (also the Tesla Cybertruck, with which Elon Musk ran over a traffic pylon the first time he drove it in public). But in 2020, Ford and the Amazon-backed Rivian (among others) will be racing to get their very normal-looking e-pickups to market, thus kicking off what is sure to be a crowded market in the coming years.
14. All cars will have giant screens, not just Tesla
Jokes about their Lara-Croftian truck notwithstanding, Tesla has been responsible for plenty of design innovations that the rest of the auto industry will eventually plunder, if they haven't already. One of those? Their outsized infotainment screens, which will become something of a standard in 2020: everyone from Ford to Lexus to BMW to Mercedes has announced plans for 12"+ screens on upcoming models.
15. Streaming will become the thing it set out to destroy
Streaming was supposed to be a cure for what cable had become: rather than having to pay for bundled packages of channels that they probably didn't even want, consumers got to pick and choose the programming of their choice. But with the streaming industry more crowded than ever after the launch of Apple TV+ and Disney Plus last year, consumers are nearing a breaking point for how much they're willing to spend on it each month. The solution that Hulu, Disney and ESPN have come up with, with others sure to follow? Bundling, aka the exact thing that streaming was supposed to save us from.
The Dupont Circle Embassy Inn by FOUND is a new boutique hostel in DC
Hawkins Way Capital
16. You'll probably just book a hotel instead
One upside of Airbnb's emergence has been that it has inspired genuine innovation from its mortal enemy: the hotel industry. From low-cost boutique hostels to socially focused boho lodgings like Ace to a resurgence in old-school luxury, we've never had more options when it comes to booking a room. Couple that with the fact that cities around the world are now cracking down on the dubious legality of the home-sharing site (just last month, Airbnb was forced to remove thousands of listings in Boston), and even adventurous travelers may seek out the warm embrace of fluorescent lobbies and daily maid service.
17. Train travel will see a resurgence
You've probably heard of Greta Thunberg, the Swedish poster child for climate awareness and bane of airlines everywhere. She wants people to stop flying so much, and no matter how you feel about her personally, she has a point: on a single round-trip economy flight from LA to Paris, a person incurs more carbon emissions than they would if they stopped driving a car for a year. We don't think you should stop traveling out of a sense of climate guilt. But we do think you should consider exploring more locally, and doing so the old-fashioned (and most climate-friendly) way: on a train. High-speed rail construction is underway around the U.S. to make train commuting a more viable option, while sleeper trains like the UK's Belmond Royal Scotsman or Canada's Rocky Mountaineer are having a moment for well-heeled adventure seekers.
18. The music of the early 2000s will become classic rock
When Third Eye Blind — one of the seminal bands of my mid-'90s childhood — played Gov Ball in 2018, I was surprised at how well-attended their show was. The band was then about 20 years past their prime and playing a mid-afternoon set time, and yet when they launched into "Semi-Charmed Life," the entire crowd joined them in a raucous singalong. That's when I looked around and realized who was singing along with me: teenagers whose parents had raised them on a steady diet of '90s alt-rock anthems. Third Eye Blind was classic rock now. This summer, the bookend for what constitutes nostalgia will move even further forward, into the early 2000s. Green Day, Fall Out Boy and Weezer announced last year that they'd be joining forces for the "Hella Mega" stadium tour, and the featured "remember when?" artist at Bonnaroo this year will be Nelly performing 2000 album Country Grammar in its entirety.
The Eggbini, a Japanese-inspired breakfast sandwich at Manhattan's Konbini
19. You will get to know Japan's casual eating culture
Japanese food in America has stratified and proliferated in wonderful ways over the last decade. But most of that innovation has been at the finer end of the dining spectrum, with chef's-table-style omakase restaurants perhaps the biggest restaurant trend of 2019. This year, expect to see more options that celebrate the more democratic (but equally delicious) aspects of Japan's gastronomy, from Tokyo-inspired breakfast sandwiches to izakayas like Brooklyn's Maison Yaki to comfort-driven handrolls like the ones they serve at Manhattan's Nami Nori.
20. Technology will invade your boudoir
The big buzzword out of the annual Consumer Electronics Show in Vegas this week? Sex tech. The industry has its own dedicated area within the health and wellness section at the trade show this year, and venture capital is flooding into new technologies (e.g., "technodildonics") aimed at enhancing sexual pleasure for both individuals and couples. Just be sure you read the privacy policy before hooking things up to your wifi and connecting it with Facebook.
Additional reporting by Mike Conklin, Kirk Miller, Evan Bleier, Jason Diamond, Alex Lauer, Tanner Garrity and Danny Agnew.
For more travel news, tips and inspo, sign up for InsideHook's weekly travel newsletter, The Journey.
Baseball Hall of Fame Makes Lame Call With Election of Scott Rolen
Introducing: The New TAG Heuer Aquaracer Solargraph, 60th Anniversary Carrera and Monza Flyback Chronometer


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"The Other Side of COVID" – Tales From the Trenches
TWIN CITIES METRO AREA CHAPTER EVENT
"The Other Side of COVID" - Tales from the Trenches
Join us at the Hellmuth & Johnson on January 12th for "The Other Side of COVID" – Tales From the Trenches (7:45 am – 9:30 am). This will be a panel discussion with Business Owners and how COVID has affected their businesses. We will discuss how they adjusted and what they have learned.
How has COVID affected the Business Owners
What adjustments were needed to make
What did they learn, positives and negatives
Meet the Presenters:
Hear from Julie Keyes, Owner, Keye Strategies, Aleesha Webb, President, Village Bank, Jeff May, President, Solar Midwest, and Patrick Knight, CEO, Waymouth Farms.
This meeting will be held at Hellmuth & Johnson or via Zoom.
Address: 8050 W 78th St, Edina, MN 55439
Date: Wednesday, January 12th, 2022
Time: 7:45am CDT: In-Person Registration, Breakfast, & Networking
8:15am CDT: Welcome/Opening Remarks, Zoom Participants Login
8:20am CDT: A Word From Our Sponsers
8:20am-9:10am CDT: Main Room 50-min Speaker Presentation
9:10am CDT: Q&A, Wrap Up
9:10am-9:30am CDT: In-Person Networking
Location: Hellmuth & Johnson
Virtual: Zoom
Price to Attend: $39.00
To learn more about upcoming events, visit www.EPITwinCities.org.
The EPI Local Chapter is different than other groups because it brings together a diverse group of professionals from a wide range of specialties that can naturally work collaboratively on exit planning, succession planning, value growth, transaction or any engagement from both sides of the equation. The chapter meets regularly to network, reconnect, grow knowledge, and sharpen their skills with a common goal: Change the outcome for transitioning business owners. Make plans to join us for future events and connect with the local leadership by visiting www.EPITwinCities.org.
Julie Keyes
Owner, Keye Strategies
Meet Julie Keyes:
Keye Strategies is an advisory and public speaking firm, providing exit planning education and consulting to business owners of many sizes and types.
Julie Keyes is a national speaker, teacher, and Certified Exit Planner. As a life-long entrepreneur, and faculty member for the Exit Planning Institute, she brings an uncommon set of skills and talent to every speaking and consulting engagement. Her mission with every client or audience is to unpack the mystery of Exit Planning, explain the process, and provide a road map for succession. Her speaking engagements bring her across the country delivering her expertise to owner and advisor groups alike.
Aleesha Webb
President, Village Bank
Meet Aleesha Webb:
Aleesha Webb has "come home" as the new president of Village Bank, the Blaine-based community bank her father founded and where she began her banking career.
Webb, who started out as a Village Bank teller, returns with 14 years of industry experience. Her father, Don Kveton, chartered the bank in 1993 and continues as board chairman.
Between her first job at Village Bank and her return, Webb worked as a Senior Vice President as Sunrise Banks and a Vice President at Minnesota Bank & Trust.
"I wanted to figure out if I could do it myself and do it without Don," Webb said of working in banking. "I went from being a community banker to being a commercial banker.
"I got trained in what it means to manage the entire client relationship. … I got to build teams and see what social media strategies could help lift community banking."
Starting a family, Webb said, renewed her interest in community banking and making a difference locally.
Plans call for adding 15 new hires in 2019 to the bank's 70-plus employees, Webb said. Village Bank, with locations in Ramsey, East Bethel, St. Francis, and Blaine, may look to expand beyond its Anoka County base.
"We're looking for some very strategic roles that can help us grow," Webb said of the hiring plans. "Moving forward we see ourselves as a community bank for the Twin Cities."
Village Bank has more than $293 million in assets, according to the Federal Deposit Insurance Corp.
Q: Are any changes in store for Village Bank?
A: Don and I talked a lot about, "It's time to shake things up in community banking. It's time to get back to local business owners and back to the economic sustainability of the county, the state, the town in which we're doing business." There's a lot of opportunity out there.
Q: What's driving the hiring at the bank?
A: The commitment to community. Don has been a leader of this bank for almost 26 years. When Don and I made the decision for me to come home to Village Bank we looked at our values and [how they] aligned with earning what we have. We made the commitment to Village Bank, to have capital behind Village Bank and to help our community businesses earn what they have.
Q: Why do you like working in banking?
A: My favorite thing about banking is the people. There is nothing like watching someone's grandson getting his first savings account. There's nothing like watching a female client buy the businesses she's been the president of for seven years. There are all these life moments. Today banking is so commercialized. For me it's very, very personal.
Jeff May
President, Solar Midwest
Meet Jeff May:
In multiple CFO, COO, and President roles I have achieved superior results in middle market, large public, family-owned, and private equity backed businesses. My diverse experience and knowledge enables me to swiftly impact multiple functions across a company. By leveraging my finance and operations expertise, I drive critical enterprise improvements that achieve desired financial results. I use data to objectively understand all aspects of the business, prioritize issues and opportunities, and swiftly and effectively execute a multi-faceted plan to move a business to the next level.
My focus on teamwork, continuous improvement, and a drive for excellence is derived from a lifetime of playing and coaching sports. I provide the vision, leadership, and support to enable teams to achieve more than they imagined possible. By focusing on both individual and team development, I empower highly functioning teams to succeed. With a humble confidence, I listen, incorporate ideas, and leverage the diverse knowledge and ability throughout the organization and shape a culture where people feel valued and like to work.
– Data-driven decision making
– Developing high performing teams
– Achieving operational excellence across the enterprise
– Transforming middle market businesses
– Strategic and operational planning
– Turning business plans into results
Patrick Knight
CEO, Waymouth Farms
Meet Patrick Knight:
Patrick currently serves as Of Counsel to the Berns Knight Law Firm.
Patrick has experience helping Minnesota owners solve their problems and reduce their risks so that they can focus on running their companies. Based on his combination of extensive legal and business experience, Patrick has experience providing legal counsel on acquisitions and sales, contract review, employment issues, corporate governance and many other legal issues facing a business owner.
In addition to Berns Knight PA, Patrick has served as a judge advocate in the U.S. Marine Corps where he worked as trial counsel (prosecutor) and Special Assistant to the U.S. Attorney (Southern District, California) and worked as an attorney with Morrison Sund PLLC in Minnetonka, Minnesota.
Patrick currently serves as Chief Executive Officer of Waymouth Farms, Inc., a Minnesota food manufacturing company selling branded snack foods to national retailers.  Patrick previously owned and operated Kateri Foods, LLC, a start-up healthy snack food manufacturing company.
– US District of Minnesota
– Lieutenant Colonel, US Marine Corps (Reserve)
– Coach, Wayzata Youth Hockey Association
– Board Member, Riverland Bank
– Harvard Business School (MBA), 2000
– Georgetown Law Center (JD), 1994
– Holy Cross (BA), 1989, summa cum laude
– Patrick is married with four children and lives in Plymouth, MN.


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All posts tagged "Policy"
Rainwater harvesting a necessity to replenish groundwater
Rainwater harvesting is the solitary realistic option to counter the growing menace of rapid ground-water depletion.
Reaching out to tribals for more inclusive democracy
The Union tribal affairs ministry led by Jual Oram, created in 1999 during the Vajpayee regime, has a huge task of ameliorating...
Why we must make our smart cities gender sensitive
Women can't work beyond 10 pm in Maharashtra in retail sector whereas there are no such restrictions in the Sikkim, Maharashtra, Andhra...
Media campaign effective in combating heat wave mortality
Because a larger percentage of people have access to televisions (27% of the population own televisions as compared to only 11% who...
Economic Reforms : catching up speed!
With the passage of the GST Bill, the Indian democracy has once again reiterated that it has the necessary space for a...
Losing focus on basic issues
The Finance Ministry is not powerless in front of the RBI, however. It has complete and undisputed command of the tax policy.
Is Sheila Dikshit eyeing Uttar Pradesh CM post?
While we wait for the Congress to officially declare its CM candidate for UP later this year, here are 10 things you...
Cabinet clears Civil Aviation Policy: Highlights
The Narendra Modi-led NDA government had proposed a new draft for the National Civil Aviation Policy in October 2015.
How has the Modi government performed in the last two years?
The PM has completed this term but there will be plenty of reasons for him to find space in the pages of...
Drought management: Going beyond knee-jerk response
The court has pointed out a lot of loopholes in current drought management practices and shows how the existing mechanisms have failed...


A series of alleles of a particular gene. In theory probably all genes can exist in more than two alternative forms since mutations can occur at any number of points along their length. In practice, natural selection may eliminate all but one or two of these in wild populations. Examples of naturally occurring multiple allelism are found in the incompatibility systems of plants. For example, in Brussels sprouts (Brassica oleracea var. bullata) there are some 35-40 different incompatibility alleles, termed 5 alleles.


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Applying to Denver Jewish Day School
We are accepting applications for the 2023-24 school year for all grades!
Our application process is designed to ensure that our school's program and environment are a good fit for prospective parents and students.
Applications for admission to Denver JDS are accepted beginning in late October for the following academic year and are due by February 15. Post deadline applications are considered on a space available basis.
If you wish to apply for the current school year, begin with Step 1 Below.
Denver JDS is currently piloting a new Income Based Affordability Program that provides straightforward, predictable, and meaningful financial support for families across the economic spectrum. Click here to learn more and see if your family qualifies.
Step 1: Start Here
Step 2: Schedule Applicant Visit
Step 3: Apply for Financial Aid (if applicable)
Step 4: Decision Notification
The application window for the 2023-24 school year is open!
Click here to apply for the 2023-24 school year.
There are different visits for different grade levels! You will find information for all grade levels below. We ask that if you are feeling any symptoms of illness you refrain from attending. We will work with you to get visits rescheduled and wish everyone a school year of great health!
Please scroll to the appropriate grade level for your applicant:
Future Tiger Visits for Kindergarten applications will take place in January and February of 2023. Applicants will sign up for their visits with the Office of Admission beginning December of 2022.
Lower Division Grades 1-5
Students applying for grades 1-5 will schedule a half day visit to Denver JDS in their current grade. Visitors will shadow a student host for the morning, experiencing a day in the life of Denver JDS. The Office of Admission will work with you to schedule this visit after you submit your application. At the end of their visit, students will be sent home with a box lunch from our campus caterer (dietary laws observed).
Upper Division Grades 6-12
Students applying for grades 6-12 will schedule a half day visit to Denver JDS in their current grade. Visitors will shadow a student host for the morning, experiencing a day in the life of Denver JDS. The Office of Admission will work with you to schedule this visit after you submit your application. The Office of Admission will provide all testing instructions once the shadow visit has been scheduled. At the end of their visit, students will be sent home with a box lunch from our campus caterer (dietary laws observed).
Upper Division applicants are also required to interview with a member of the Upper Division Administration Team. The Office of Admission will contact you to schedule your interview after you submit your application submission. The interview can be in-person or conducted via Zoom.
View details about financial aid. The financial aid application window for the 2023-24 school year opens on October 15, 2022. Please check back here on that date to begin your application process. For all current and prospective families, the form and supporting documentation must be submitted by February 1, 2022. Post deadline applications are considered on a fund available basis.
Denver JDS will notify applicants of admission decisions via email in early March in accordance with the notification schedule set by the Association of Colorado Independent School (ACIS). Families that complete an application for tuition assistance by the February deadline will be notified of their award within two weeks of admission decision notification.
The notification deadlines for the 2023-24 school year are:
Grades 9 - 12: February 24, 2023 at 4 p.m.
Grades 6 - 8: February 24, 2023 at 4 p.m.
K - Grade 5: March 3, 2023 at 4 p.m.
Decision notifications could be an admittance, a decline, or a provisional admittance. (Provisional admission is an offer of admission that includes at least one provision. Provisions are individualized depending on the situation. A common provision is for students we are unable to meet in person in an observation period at the beginning of the school year. This ensures that Denver Jewish Day School is a good match for the student.)
The application window for the 2023-24 school year opens on October 15, 2022. Please check back here on that date to begin your application process. All students who wish to enroll at Denver JDS must complete our online application. The application is due February 1, 2023. Post deadline applications are reviewed on a space available basis. We require all teacher recommendations forms and school records for the applications to be considered complete.
For Kindergarten: Children must be five years old by October 1, 2023 to be eligible to apply to kindergarten for the 2023-24 school year.


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The Arkansas soybean industry contributes $2 billion annually to the state. Every soybean farmer pays into the commodity's Checkoff program. Those funds are administered by the Arkansas Soybean Promotion Board (ASPB), which invests in research, promotion and education.
In 2016, ComGroup conducted a content audit of commodity boards across the state. Our team discovered that many of the commodities presented facts about its industry and contributions to the state's economy in a video format. From that research, we proposed a short film that summarized the history and significance of the Arkansas soybean industry. During our research, we also discovered that soybeans were the only commodity not documented in the Encyclopedia of Arkansas, an authoritative source of information about the history, geography and culture of Arkansas.
As a result, our team authored and submitted a written history of the state's soybean industry in 2016. In 2017, we developed an accompanying short film to document the industry's history and significance to our state. It's an important endeavor because agriculture is our state's largest industry, annually contributing $16 billion to the state's economy.
During the annual planning session with the board, we presented the project for consideration. The objective of the film was to communicate the impact of the industry to Arkansas consumers and soybean producers. The secondary objective was to have a short film to show to international trade groups visiting the site to learn about and evaluate the state's soybean industry.
The goal was to earn at least 3,000 views within the first year of publishing the film. The creative concept was simple to show scenes from the agriculture process while mixing in important facts and statistics about the industry.
The team also planned to use the film to drive awareness for the industry through statewide media as a public relations tactic. We planned to launch the film in November, which our team worked with the governor's office to proclaim as Arkansas Soybean Month. The call-to-action was to visit the board's website or YouTube channel to watch the film. We also shared the film via the board's Facebook, Twitter and Instagram channels.
The Arkansas Soybean Documentary was produced with a combination of live shots and b-roll sourced from the United Soybean Board. All footage used in the film was shot in Arkansas. A challenge was sourcing harvest footage since production took place during the summer months, and harvest takes place in October and November. To address this challenge, the production team sourced existing footage made available to our team from the national checkoff organization.
Our team developed a content outline to be used during production, which ensured the most important information was communicated and the board's objective was included in every aspect of the film. We elected to forgo interviews and opted to include beautiful scenery with facts and statistics as the focus throughout the film. We chose to keep the film under two minutes based on research of viewership length for videos within the agriculture topic on YouTube. The video was produced in during the late summer and early fall of 2017 and we began distribution in November 2017, which is designated Arkansas Soybean Month\.
The tactics for promotion was the board's Facebook, Twitter and Instagram channels to drive traffic to the board's website. We also showed the video to international trade groups visiting the state on farm and facility tours.
Based on feedback we've received at trade shows, from farmers across the state, trade groups and consumers, the video series has been well received. The video has drawn more than 3,500 total views since it was published eight months ago. The documentary is the most viewed video on the board's Facebook page since it was published on November 1, 2017.


text:
Baekdudaegan o Baekdu Daegan (in coreano: 백두) è una catena di montagne e bacini con una lunghezza di circa 1400 km che costituisce la spina dorsale topografica della penisola coreana.

Origine del nome
Baekdu Daegan si traduce letteralmente in una grande catena montuosa che si estende dal Monte Baekdu.

Geografia
La catena montuosa si estende da nord, dai confini tra Corea del Nord e Cina, con le sue montagne più alte. Prima a sud-sudest fino al Duryusan, poi a una distanza di circa 60 km a 80 km dalla costa orientale al Mar Orientale. Inseguito si allontana in direzione sud-ovest e poi segue l'arco di costa in direzione sud-sudest verso il confine inter-coreano dei due stati. La catena montuosa è divisa all'incirca per metà tra la Corea del Nord e la Corea del Sud. Sul lato sudcoreano, la catena montuosa è di 221 metri nel punto più basso e raggiunge i 1915 metri nel punto più alto. La catena termina con il monte Jirisan.

Un'area totale di 2750,77 km² delle montagne interessate è stata designata come area protetta.

Note

Collegamenti esterni

Geografia della Corea del Nord
Geografia della Corea del Sud

redpajama_set_name: RedPajamaWikipedia


Cardisys is a highly sophisticated cardiology management system built to empower practitioners and to improve patient care by streamlining all key aspects of cardiology operations. Cardisys improves clinical productivity by simplifying patient management, ward assignments, surgical schedules, staff rosters, inventory control, billing and reporting.
Cardisys is the only cardiology management system capable of fully integrated with the Hospital Authority's clinical, reporting, inventory and enterprise management systems.
In-patient management to cater in-patient logistics from admission to discharge and rehabilitation.
Full inventory management, either as a standalone system or integrated with hospital EPR and procurement systems.


Nitro snowboards is making a full length team video that breaks away from the standard snowboard movie format and focuses more on what snowboarding is really about. The Hyped! movie will be released fall 2012.
Get ready to see Austin Smith, Eero Ettala, Jon Kooley, Justin Bennee, Bryan Fox, Mark Swoboda, Markus Keller, Knut Eliassen, Anton Gunnarsson, Gjermund Braaten, Cheryl Maas, Benny Urban, Eric Botner, and many more like you have never seen them before.


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Bonnie's Global Cafe on the Road!
CAMBODIA REPORT #1
First Day in Siem Reap…
Our first day in Siem Reap has stimulated our senses and provoked our thinking in profound ways. We spent the morning with Saren Sok, who was with the World Forum in Rotorua 2 years ago, working with educators, environmentalists, designers and architects to consider designs for a new school in the Samaky community. It was quite something to see him again, to visit New Hope Cambodia, where he is now principal, visit a government primary school together and then walk through Samaky, talking with community leaders, parents, and children. Our conversations focused on challenges in creating and sustaining healthy living environments for children and families and supporting children's rights to education. In the afternoon we were tourists, visiting the market, sitting in a café watching life go on around us, and getting a taste of both rural and urban life here.
Meeting with Global Leaders…
Global Leaders Asia-Pacific Region began their work together with personal stories and country reports. Mark Elliott, GL Program Coordinator and Sheldon Shaeffer, GL Regional Coordinator facilitated the introductions. Global Leaders: Temesia M Tuicaumia, Fiji; Torika Delailoa, Fiji; Jackie Bennett, Australia: Jessica Staines, Australia; Siva Prasad Behera, India; Savy Lach, Cambodia; Shabreen Nazmeen Nisha, Fiji. Analesia Tuicaumia and Karma Gayleg were there as Global Leaders graduates and cheerleaders and Evelyn Santiago, Executive Director of ARNEC, made a guest appearance.
Asia- Pacific Regional ECD
Cambodian Prime Minister Hun Sen opened the Asia-Pacific Regional ECD Conference with strong support for children's education and an impassioned highly political remarks on the causes of current problems for people in his country. You can listen to the Cambodian National Anthem as we heard it this morning:
Prime Minister Rails Against Deaths of Children in US Wars
Global Leaders posed for photos in front of the conference banner—you can tell we are all getting to know and enjoy each other.
We attended the most lavis
h banquet I've ever attended at the invitation of the Minister of Education to ARNEC conference delegates. Eight courses, beautiful flowers, hours of cultural dance and music performances, lovely service and sweltering temperature. We posed for photos framed by intricately carved watermelons—that's a first! Quite the evening and a grand time for all Global Leaders.
In between conference plenaries and sessions, Roger and I have been scheduling interviews to share with everyone in Bonnie's Global Café. We've been trying out our equipment and dedicating ourselves to be the most authentic, engaged listeners we can be. And then, of course, there are the random conversations that just happen. Two men sat down next to me at lunch, and we began talking about the presentation we had just heard about Laying the Foundations for a Healthy and Prosperous Society: Investing in Early Childhood Development by Professor Frank Oberklaid, University of Melbourne. "We have none of that here, we have nothing. The bad times have taken everything away from us," they shared. They continued, "The big problem is that parents go away to work in order to make enough money for their families. They go to Thailand or Philippines or Saudi Arabia, and they don't see their children for long periods of time. Children are left in the care of their grandparents. This is very hard on the grandparents. The children have no education and they are separated from their parents. Children can't study because they are malnourished."
"I left my family when I was 11 years old and traveled to get an education. I never saw my parents again." He struggled for his education and achieved his pharmaceutical degree. "I had the choice of joining the military, being a farmer or going to school. To get an education, children need the support of their families and of their communities and they need to want it for themselves."
"For a whole term I had one single piece of paper and a pencil. When I finished one lesson on the piece of paper, I erased it so I could use it again. And sometimes we had a chalk board and a bone."
"I was 8 when Pol Pot came to power. My father was killed, my uncle, many many people were killed. We have had very very hard times. People live for the present. People cannot live for the future, that was taken away with the hard times."
These men, both doctors, have children with strong ambitions and a commitment to education. "I have two children, my son is an engineer and my daughter will be a lawyer. They didn't want to be a doctor like me because they saw how hard I worked. So hard."
"We need people who can help us."
ARNEC finished with celebration and many delegates shared plans to join us for 2017 World Forum! We returned our attention to Global Leaders for a final meeting and dinner together. As we shared impressions about the week, I was struck by the pride expressed by several Global Leaders in the work happening for children and families in their countries. It's a great thing to own the good and to be proud of our individual countries. Savy Lach made an impassioned appeal for supporting the teachers who implement research yet continue to be tragically underpaid. Jessica Staines drew attention to the danger of losing the child in the statistics. Savy chose a restaurant outdoors with traditional Khmer food and entertainment. And we said our goodbyes until 2017 World Forum in Auckland.
Up early to watch the sunrise over Angkor Wat, we met Chan Roeurt (introduced to us by Kirsten Haugen) at 4:45 AM —Mark Elliott, Patti Smit, Shabreen Nazmeen Nisha. At the visitors' center where you buy your ticket there was quite the crowd, but Chan was proud of his plan for avoiding crowds, choosing time of day for best light and temperature, and taking breaks so we didn't get "templed out." So we sat on the bank of the moat, waiting for the sun. As the light grew, we enjoyed the waterlilies, the fish and birds, and the music from the nearby monastery. All of a sudden, you could see the red ball coming up behind the pineapple towers and the world begins to light up. It rises so quickly you feel like you can see it move. And it gets high enough so there is its reflection in the water of the moat, so there are two red balls. And then somehow there is another reflection in the ripples of the water, and there are three suns.
After the sunrise, we drove to Angkor Thom and walked around Bayon temple to see the base relief in the wall of the temple that tell the story of the Khmer people, as well as the towers with smiling faces of the Buddha. Approaching the Temple, we walked across the bridge lines with huge faces—on one side demons and on the other smiling faces. The sun was still rising over the river. It was beautiful. Chan gets so excited at every arrival that we are outwitting the tour buses and the other guides. His knowledge is a gift to us, as is his enthusiasm for sharing these places and his country, which he loves.
Chan was born en route to Thailand, his parents fleeing as refugees. His mother gave birth and they floated him in a basket across the river. When his mother was 11, she was with her family fleeing in helicopters. Somehow she got separated from them at the last second. She turned and an American ? bazooka blew up the helicopter. She was all alone. Recently she was reunited with an uncle who believed she had died with the others. He and Saren met in university, but both spent childhoods in refugee camps in Thailand.
After breakfast it was a 35 minute drive through the countryside, passing s
mall villages and markets and stands of produce, skinny cows, rice and sugar cane fields. Banteay Srey, the Lady Temple is made of pink sandstone that is intricately carved. It's spectacular. Monkey gods, bird gods, paisley-like elaborate, detailed designs.
Back to Angkor Wat to see inside the Temple this visit. Climbing to the third level was quite the challenge, but the view was something—old stone and trees. The builders of the temples carved their history into the walls, messages that can be read over a thousand years later.
Ta Prohm Temple, the Jungle Temple, was the finale. Raiders of the Lost Ark. Piles of stones, banyon trees, primal. There is a tiny room where you stand on a stone, pound your chest three times and make a wish. You can hear the pounding echoed in the space.
NEPAL REPORT #1
We arrived in Kathmandu late at night to the smiling faces of dear friends Kishor Shrestha and Bishnu Bhatta. Dhirendra Lamsal surprised us at the hotel with more smiles and a beautiful bouquet. The morning brought Dhirendra and Mukunda Kshetree for a day visiting schools, meeting teachers, playing with children and learning about the work of ICRI-Nepal at Early Childhood Development Centers in Shree Chandi and Tri-Padma School. "Head and Shoulders, Knees and Toes" seems to be known everywhere and is one of our favorite jokes to share with children as we go faster and faster and end up laughing together, whether we share language or not. We had a long conversation with Ishwar P. Pok
harel, Headmaster of Shree Chandi about the importance of children as the foundation of society. Deepak Raj Sopkota informed us of the work of Karuna Foundation, dedicated to preventing disabilities and serving children who are disabled and their families. Learn more about their amazing work at http://www.karunafoundation.nl/overons/in_nepal_uk.html. Deepak and Dhirendra took us on shattered dirt roads to a vista of the city for sunset. We were near tigers and leopards, but didn't encounter any. Probably a good thing, but still a bit disappointing. Deepak invited us to his home for dinner with his family, wife Neelu, daughter Spandan and son Deeptak.
Our drive to rural areas near the city was challenged by dust, potholes, horns and traffic "rules" we could not understand. Kishor Shrestha and Bishnu Bhatta joined us in being silly with beautiful boys who live in Samaj Kalyan Orphanage operated by PSD-Nepal in rural Nepal. These boys raise huge cabbages and potatoes, have some cool dance moves, and, of course, go to school. We met two very personable young men who will soon be attending University. We talked about Mud Day, because this is one of the
places where it began, and of the ongoing connection between Bishnu and Gillian McAuliffe. Every year 8-10 families from Gillian's program visit the orphanage to work on garden and be with boys.
Our next stop was the Pipaltar Integrated Project and the 87 houses Bishnu's team is building with Habitat for Humanities funding. The houses are replacing 87 houses destroyed by the earthquake. The project got delayed when India blocked the border so supplies could not come into the country. We met one of the families moving in.
We then drove down the mountain nearly avoiding 3,000 accidents, stopping on the way to eat at Dhulilchel Lodge's beautiful hotel/cafe – with a great view of Himalayas — which was blocked by the pollution. Then back in the city we met with Mr. Hari Khanal, Deputy Director and Head of ECD Section at the Department of Education. We talked about how ece is provided, monitored and supported in Nepal. He attended the ARNEC meeting in Cambodia, so we compared notes on that and ureged him to attend 2017 WF.
Next we toured Bhaktapur, the cultural center of Nepal with many temples, a royal palace (without royalty) and lots and lots of tiny shops.
Finally we had dinner with Bishnu, Dhirendra along with his daughter Anusha, and his wife Susan Risal, CEO Nagarik Aawaz for Peace at a restaurant where servers are hearing and speech impaired
Occluded skies meant no flight to see Mt Everest, so Dhirendra took us to Pashupatinath, a holy Hindu site for cremations, meditation and marking milestones. Monkeys would pop in now and then. Agatha Thapa, founder of Seto Gurans organized a meeting of Movers and Shakers at her office. Members of Parliament and the Early Childhood Caucus, Representatives from UNICEF, SAVE, and ICRI, as well as old friends who have created a strong community of World Forum family in Kathmandu. A quick walk with Agatha through Patan Durbar Square, lunch at the Red Mud Cafe, then off to UNICEF for a meeting with Dr. Rownak Khan and Dr. Dipu, United Nations Children's Fund, sharing the work of the World Forum and the work of UNICEF, Kishor and Bishnu in Nepal. We walked through Hanuman-dhoka Durbar Square where we caught a glimpse of the Living Goddess, did an interview with Mahen Shrestha, Global Family Village-Nepal, a bit of a race to see the view from Shoyambhu Stupa (Monkey Temple), and then a fine evening to reflect on this visit, the future, and life with Nepalese food and dancing at Bhojan Griha. It struck me during all of these meetings, that when we are with people we are always talking and thinking about children, which brings visibility to children and to the advocates who work with and for. These precious conversations are filling us up.
Airline snarls gifted us an extra day in Kathmandu and a morning visit with Agatha Thapa. We celebrated International Women's Day together, even though it was the day after because we just wanted to—we are women, after all, and women drive the world! Agatha shared her story of a lifelong commitment to bring attention and care to disadvantaged children in Nepal, her work founding Seto Gurans. Mukunda Kshetree of ICRI came to say goodbye and Dhirendra picked us up for the drive to Junkiri. The path to the home and school was steep and windy and offered panoramic views of the countryside. From quite a distance we could hear the sounds of children. When we reached the top we were greeted by beautiful children gifting us flowers of welcome to Junkiri (firefly) Children's Home, a residential program for children whose mothers are in prison. It enables them to go to school and to experience love and home and community. Our camera was handed over to Krishna Rana who recorded our visit. We spent time talking and playing and drinking tea together, met with teachers, sampled dinner, visited goats and most of all just enjoyed being with the children. See his photo story of life (in the gallery below!). Back to Kathmandu through villages rebuilding from the earthquake . . . piles of bricks and building debris, dust, dirt, hard labor. . .in such a beautiful natural setting. Dinner with Agatha, Shashi, Manu, Dhirendra began with a puppet farewell — fyi no children were at the table. And finally, a short introduction to Indira Ranamagar and her powerful work, Prisoners Assistance Nepal, which includes the program we visited today.
Krishna Photos
BHUTAN REPORT #1
At 6 AM the general strike over the Constitution began in Kathmandu; we left early for the airport, so Dhirendra could return home in safety. And then, in spite of many challenges we arrived in Paro, Bhutan, and were welcomed by Karma Gayleg and the traditional white scarves of welcome.
The drive to Thimpu wound around the mountains dotted with pine trees, the river roaring below. Karma's wife Jigme greeted us with white scarves, home brewed wine, and a traditional lunch.
We met with Rudolf Schwenk and Sangay Jamtsho from UNICEF about unifying services among government agenciesand NGOs and requested support from UNICEF for the Global Leaders program.
Our last meeting of the day, with Karma Tshering, Director General, Department of School Education and Sherab Phuntshok, focused on the King's commitment to providing early childhood services to every village in Bhutan by 2028. We shared perspectives on the impact of Karma Gayleg in creating the Early Childhood initiative in Bhutan and the impact his being a Global Leader has had on Karma and therefore Bhutan and, of course, all of us involved in the World Forum.
Bhutanese tea around the fire-burning stove with Karma, Jigme, and son Tila and dinner at a traditional restaurant—with, of course, some karaoke, finished off an amazing day. Zamen, Karma's daughter was there to wish us good night.
SNOW! We awoke to a winter wonderland and nature's gift of a holiday (it hasn't snowed like this in Bhutan since 2012). So the plan for visiting programs just didn't happen. Instead we had snow ball fights, snow angels in the plaza in front of the world's largest Buddha at Shakyamuni, bought vegetables in the market, and again, sat around the wood stove talking and drinking tea. Late afternoon we drove with a leaking tire around boulders to Paro, picked up cousins Tenzi and Jimmy and arrived at Namsay Choling Resort. The electricity was out so it was VERY cold. Dinner in the restaurant was by candlelight and we slept in our clothes and under at least four quilts.
Today was our day to see Tsatsang Monestery, the Tiger's Nest, but it didn't happen. Too much snow and ice and chilly slop made such an adventure foolhardy, so instead Karma took us to the end of the road, Drukgyen. We did see Tsatsang at great distance, tucked precariously to the snowy mountainside. And the view from Drukgyen was beautiful. Tila took us on a walk around Paro while the tire was being repaired. Then all of us went to Karma's sister's home for butter tea and rice snacks. We walked through the dormant rice fields to meet his parents who live in their traditional Bhutanese farm house. He showed us how they all lived in the house growing up and how they enjoy it when they arrive with children for times together. It was a great honor to meet Karma's parents and to be given this window into rural farm life. Karma's sister made lunch for us, several members of the family gathered, the cousins whooped it up—and we got to be part of it all. We celebrated the sunshine, the return of electricity, and warmth.
Time to leave. Karma's car wouldn't start. He tried for 45 minutes and then we had to rush by taxi to the airport, and leave Tila and Karma to sort the car. At immigration the officer challenged me because my passport and visa numbers didn't match! And then we were flying over the Himalayas, one range shadowing into the next.
Our Bhutan wasn't the Bhutan of tourist posters, monasteries and peaks, or trekking. It was the Bhutan of family life and daily pleasures and challenges. We spent many hours sitting on mats on the living area floor, circling the wood stove. We played Rats and talked about our lives, adults and children—getting hot on one side and then turning to take in the warmth. A big kettle on the stove heated water for baths, kept our cups of tea warm, and humidified the air. Tila and Zamen talked about school, dancing for the King, sports and they asked questions: Where do you live? How did you meet? What do you do in your day? Karma talked about the farm where he grew up, about teaching in a remote area and creating the Red Panda Festival. Jigme talked about being principal of her school and growing up in a village of weavers. Every now and then people would turn to their phones or iPads for updates. We ate several meals sitting this way as well—rice from each of their villages, greens, rotis delivered to the door, dal, curries, mushrooms and cheese.
Dinner with Vashima Goyal was the finale of our adventures. We had a grand time talking, eating, appreciating this city that she loves so much. Our conversation was authentic, honest, and reinforced what such conversations mean for friendship and work.
Full Picture Gallery:
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