1 Department of Cell Biology and Anatomy, University of Tokyo, Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
2 Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Department of Cell Biology and Anatomy, University of Tokyo, Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Department of Cell Biology and Anatomy, University of Tokyo, Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
The motor protein kinesin moves along microtubules, driven by adenosine triphosphate (ATP) hydrolysis. However, it remains unclear how kinesin converts the chemical energy into mechanical movement. We report crystal structures ofmonomeric kinesin KIF1A with three transition-state analogs: adenylyl imidodiphosphate (AMP-PNP), adenosine diphosphate (ADP)–vanadate, and ADP-AlFx (aluminofluoride complexes). These structures, together with known structures of the ADP-bound state and the adenylyl-(β,γ-methylene) diphosphate (AMP-PCP)–bound state, show that kinesin uses two microtubule-binding loops in an alternating manner to change its interaction with microtubules during the ATP hydrolysis cycle; loop L11 is extended in the AMP-PNP structure, whereas loop L12 is extended in the ADP structure. ADP-vanadate displays an intermediate structure in which a conformational change in two switch regions causes both loops to be raised from the microtubule, thus actively detaching kinesin.
To move along microtubules, kinesins (1) must alternate rapidly between tightly bound and detached states. How both dimeric (2, 3) and monomeric (4, 5) kinesins achieve this remains unclear. Because the binding energy in the strong-binding state [10 to 20 kBT (3, 4), where kB is the Boltzmann constant and T is absolute temperature] is too large for rapid spontaneous release, the energy for fast detachment of kinesin from the microtubule must come from a step of the ATP hydrolysis cycle. Large change(s) in free energy are expected to occur during four steps: ATP binding, hydrolysis, phosphate release, and ADP release. Both conventional kinesin and KIF1A bind tightly to microtubules in the nucleotide-free state and in the ATP-bound state. In the ADP-bound state, conventional kinesin is detached from microtubules, whereas KIF1A is partially detached and diffuses freely along the microtubule. This is because loose binding of ADP-bound KIF1A is supported by the KIF1 family–specific K-loop at loop L12. A mutant KIF1A that lacks the K-loop detaches from the microtubule in the ADP-bound state, and the dissociation constant markedly varies depending on the type of bound nucleotide, as is true for conventional kinesin (4). For historical reasons, the tightly bound state is called the strong-binding state, and the fully or partially detached state is called the weak-binding state. Recent work detected the phosphate release from a mutant kinesin, which stalls before the detached state (6, 7). This means that detachment occurs just at or after the phosphate release. Thus, the active process to detach kinesin from the microtubule should occur at the transition from the strong-binding state to the weak-binding state.
The active detachment process can be detected in KIF1A because of its property of binding to the microtubule during adenosine triphosphatase (ATPase) cycling. The apparent dissociation constant of KIF1A in the presence of ATP is the weighted average of the equilibrium dissociation constant of various intermediate states during the ATPase turnover. Because the dissociation constant is not significantly different between two major intermediate states, the AMP-PNP–bound and ADP-bound states (Table 1) (fig. S1) (8), the apparent dissociation constant during the ATPase turnover was not expected to be fundamentally different from these values. However, the apparent dissociation constant in the presence of 2 mM ATP was twice the expected value (Table 1) (fig. S1). Considering that the duration of the intermediate states other than the AMP-PNP–bound and ADP-bound states is much shorter, this large apparent dissociation constant implies that KIF1A has another intermediate state with a considerably lower affinity to the microtubule, which likely corresponds to the actively detaching state.
(Apparent) equilibrium dissociation constants (Kd) for microtubules. Kd values are reported as means ± SEM of at least three independent experiments. Conditions: 2 mM nucleotide or its analog, 50 mM imidazole, 5 mM Mg-acetate, 1 mM EGTA, and 50 mM K-acetate, pH 7.4 at 27°C (nd, not determined).
View inline* ATP regeneration system was used to maintain ATP/ADP level.
View inline† L12: CK1 (4).
Because this detached state must occur between the ATP- and ADP-bound states, we examined the KIF1A-microtubule interaction in the presence of two ADP-phosphate analogs, ADP-vanadate (ADP-Vi) and ADP-AlFx (9). Interestingly, the two analogs had different effects. ADP-Vi markedly lowered the affinity of KIF1A to the microtubule, whereas ADP-AlFx did not significantly change the affinity (Table 1) (fig. S1). Thus, ADP-Vi and ADP-AlFx stop the ATPase cycle of KIF1A at two different substates of the ADP-phosphate state. The ADP-Vi state likely corresponds to the actively detaching state (10). Extremely weak binding in the presence of ADP-Vi is not specific to KIF1A. For example, conventional kinesin and the Drosophila kinesin-like proteins ncd and nod also show extremely low affinity for microtubules in the presence of ADP-Vi, whereas ADP-AlFx increases affinity (11, 12). Because the affinity of conventional kinesin in the ADP-AlFx state is closer to the affinity of the ATP-bound state than to the ADP-Vi or the ADP states (13), ADP-AlFx likely stops the ATPase cycle of kinesin at a state between the ATP-bound and ADP-Vi states (Fig. 1).
Kinesin (KIF1A)–microtubule hydrolysis cycle. Abbreviations: K, kinesin; M, microtubule; T, ATP; D, ADP; P, phosphate. Asterisks refer to the second ATP state (K*T) or the second ADP-phosphate state (K*DP) of kinesin. The main reaction pathway is enclosed (45).
Thus, biochemical analyses suggest that the affinity of kinesin-type motors to the microtubules undergoes a drastic change during the hydrolysis of ATP into ADP. In the ATP-bound state and in the early ADP-phosphate state (ADP-AlFx), kinesin has its highest affinity to the microtubules (the strong-binding state). This state is followed by a transient late ADP-phosphate state (ADP-Vi), at which point kinesin has its lowest affinity (the actively detaching state). After phosphate release, kinesin in the ADP state has a moderate affinity (the weak-binding state).
To understand the atomic details of these mechanical states, we solved the crystal structures of KIF1A in the ADP-phosphate (ADP-AlFx and ADP-Vi) states and compared them with known structures of the ADP-bound state (1I5S) (14) and the AMP-PCP–bound state (1I6I) (14), as well as with an AMP-PNP–bound form solved here. As reported for myosin (15), AMP-PCP blocks the ATPase cycle before an isomerization step, which precedes ATP hydrolysis. Thus, the AMP-PCP–bound form would represent a collision complex or a preisomerization state, rather than a prehydrolysis state, as suggested from the lack of interactions between the γ-phosphate of AMP-PCP and the two highly conserved residues in the switch regions (Ser215 and Gly251) (see below) (fig. S2). In this study, we solved the structure in the AMP-PNP–bound state in order to examine the prehydrolysis state.
The x-ray crystal structures of the motor domain of KIF1A with ADP-Vi, ADP-AlFx, and AMP-PNP were refined to values of 2.2 Å, 2.6 Å, and 1.9 Å, respectively (see table S1 for details of our crystallographic work). To identify the regions that change conformation during ATP hydrolysis, we superimposed these three structures and the previously solved ADP-bound structure with the use of the Cα atoms of the conserved nucleotide-binding loop (P-loop: amino acids 97 to 104), which remains unchanged throughout ATP hydrolysis (Fig. 2) (14). The overall architectures of the ADP-Vi, ADP-AlFx, and AMP-PNP forms are similar to the previously solved ADP and AMP-PCP forms. However, although the central β sheets and surrounding α helices hardly change their conformations [root mean square deviation (RMSD) < 0.6 Å], three loop regions do undergo marked changes (16). These are the switch I region (loop L9; amino acids 202 to 218), the switch II cluster (loop L11, helix α4, loop L12, helix α5, and loop L13; amino acids 248 to 324), and the neck-linker region (strand β9; amino acids 353 to 361), which are all thought to play a crucial role in the nucleotide-driven motility of kinesin-type motors.
Crystal structures of KIF1A. (A) The AMP-PNP form of KIF1A. The switch I, switch II, and neck-linker regions are highlighted in red. (B) Superposition of AMP-PNP, ADP-AlFx, ADP-Vi, and ADP structures. The AMP-PNP, ADP-AlFx, ADP-Vi, and ADP forms are shown in red, blue, green, and yellow, respectively.
The switch I loop L9 changes its conformation, along with the movement and release of the γ-phosphate, during ATP hydrolysis. Before isomerization, loop L9 has a tight β-hairpin structure (AMP-PCP form, Fig. 3A). This structure melts so that, in the prehydrolysis state, the conserved serine residue (Ser215) at the C-terminal end of the loop can approach the γ-phosphate (AMP-PNP form) (Fig. 3B) (fig. S2). After hydrolysis, the γ-phosphate moves toward the gap between the switch I loop L9 and the switch II loop L11 (ADP-AlFx form) (Fig. 3C) (fig. S3) (17), and the loop-to-helix transition of loop L9 likely supports the release of the γ-phosphate out of the nucleotide-binding pocket (ADP-Vi form) (Fig. 3D) (fig. S4) (18, 19).
The conformational changes that occur in the two switch regions and the neck-linker region during ATP hydrolysis. (A to D) AMP-PCP (A), AMP-PNP (B), ADP-AlFx (C), and ADP-Vi (D) forms are shown in light brown, red, blue, and green, respectively. These panels are seen from the upper right in Fig. 2A (indicated by the black arrow). Nucleotides and the coordinating residues around them are shown as ball-and-stick models. Missing C-terminal residues and loops are shown by dashed lines. The structural details around the nucleotide-binding pocket are also shown in figs. S2 to S4 (46). (E and F) The conserved salt bridge between Glu170 and Arg316 (enclosed by a red circle), shown in ball-and-stick models in the AMP-PNP (E) and ADP-Vi (F) forms. Loop L8 and the switch II cluster are shown in dark blue and dark red, respectively. Nucleotides are shown as space-filling models.
This dynamic structural change in the switch I loop L9 might explain the rapid hydrolysis and release of the γ-phosphate. The γ-phosphate is efficiently released through the "back door" formed by the highly conserved residues Arg216 and Glu253 (fig. S4). In myosin, the salt bridge between these two residues in the prehydrolysis structure closes this back door, which aligns the nucleophilic water with the γ-phosphate, and opening this back door generates a tunnel through which the γ-phosphate leaves the nucleotide-binding pocket (20, 21). KIF1A resembles myosin in the efficient release of the phosphate, which is generated by the swinging movement of the back door. The mutation of the back-door residue Arg216 significantly slows ATP hydrolysis, which also supports the functional importance of these back-door residues in fast ATP hydrolysis (22–25).
The conformational change of the back-door loop L9 not only contributes to the rapid ATPase turnover, but also triggers large conformational changes in the microtubule-binding loops in the switch II cluster. Before hydrolysis, the conserved Gly251 at the N-terminal end of the switch II cluster forms a hydrogen bond with the γ-phosphate (AMP-PNP form) (Fig. 3B) (fig. S2). The hydrolysis of ATP breaks this hydrogen bond and releases L11, the N-terminal loop of the switch II cluster (ADP-AlFx form) (Fig. 3C). The release of L11 triggers the rotation of the whole switch II cluster and the elongation of helix α4 from both ends by shortening and raising of both loops L11 and L12 during the phosphate release (Fig. 3, C and D). The raised conformation of loop L11 is stabilized by a salt bridge that forms between the conserved Glu267 in L11 and the conserved Arg216 in L9, and the hydrogen-bond network involving the γ-phosphate that connects switch I loop L9 and switch II loop L11 (fig. S4) (26, 27). Release of the phosphate breaks these bonds, which results in partial melting of the raised loops L11 and L12 in the ADP form. The rotation of the switch II cluster is supported by the salt bridge between the conserved Glu170 in loop L8 and the conserved Arg316 in helix α5 (Fig. 3, E and F) (28). This rotational movement also leads to the displacement of the neck, as we have proposed previously (14, 29).
Thus, apparently, the rotational movement of the switch II cluster is supported by two conserved salt bridges: that between Arg216 and Glu253 (back door), and that between Glu170 and Arg316. The back door might serve as a "latch" to keep the switch II cluster to the strained "up" position. The release of the latch triggers the rotation of this helix, which is pulled to the relaxed "down" position by the salt bridge between Glu170 and Arg316. The interaction between loop L8 and the switch II cluster, mediated by the salt bridge between Glu170 and Arg316, might serve as the mechanochemistry coupler that couples the ATPase chemical reaction to the conformational change of the microtubule-binding surface. Consistent with this hypothesis, mutation of Glu170 results in the decoupling of the ATPase turnover from the detachment from the microtubule (6). Interestingly, a recent structural study with another kinesin KIF2C suggested that L8 might serve as the sensor for the microtubule, triggering the closure of the back door (30). The conserved salt bridge between L8 and α5 might also contribute to closing the back door, because the mutation of either Glu170 or Arg316 considerably lowers the microtubule-activated ATPase activity (31).
Loop L11, helix α4, and loop L12 are the main microtubule-binding elements of kinesin (4, 31–33); thus, their structural changes alter the affinity of kinesin to the microtubules. To examine the effect on microtubule binding, we docked the atomic structures of KIF1A and tubulin (34) to a KIF1A-microtubule complex whose structure was determined by cryogenic transmission electron microscopy (Fig. 4B) (14, 33). In the AMP-PNP form, loop L11 of KIF1A is extended down to the H11′ helix of tubulin, and helix α4 of KIF1A is inserted deep into the intradimer groove of tubulin. KIF1A is tilted toward L11 so that L12 is extended up and away from the microtubule. During the hydrolysis of ATP, both loops L11 and L12 are raised from the microtubule, and only helix α4 supports the interaction between KIF1A and the microtubule (ADP-Vi form). The rotation of the KIF1A core around helix α4 and the melting of loop L12 into the flexible conformation then allow loop L12 to interact with the C-terminal E-hook of tubulin in the ADP form while loop L11 is still raised.
Hydrolysis-induced conformational changes on the microtubule-binding surface of KIF1A. (A) Schematic illustration of the conformational changes in KIF1A. The switch I region (blue) and the switch II cluster (amino acids 251 to 269 in red, 270 to 288 in yellow, and 289 to 305 in green) are shown as ribbon models. Nucleotides are shown as space-filling models. The residues important for γ-phosphate release (Ser215, Arg216, and Glu253) are shown as ball-and-stick models. (B) The KIF1A-microtubule complex seen from the minus end of the microtubule. The microtubules (gray) are shown as space-filling models, except for helices H11 and H12 and the E-hook (blue). See movies S1 and S2 for details.
These structural models suggest a third transient mechanical state, in which kinesin detaches itself from the microtubule, between the strong-binding and weak-binding states (Fig. 4B). In the ATP-bound state, kinesin is tightly fixed to the microtubule by interactions between loop L11 of kinesin and the H11′ helix of tubulin (the strong-binding state). ATP hydrolysis then generates the actively detaching state by raising the two main microtubule-binding loops L11 and L12. Thus, kinesin is only weakly supported by helix α4 and other minor binding elements. After phosphate release, the flexible loop L12 is extended down onto the tubulin C-terminal E-hook, and this flexible interaction allows one-dimensional diffusion in the weak-binding state (4, 5, 32). In short, three successive states of the kinesin-microtubule interaction exist during ATP hydrolysis, and kinesin uses the energy of ATP hydrolysis to detach loop L11 from the microtubule and to extend another loop (L12) to the microtubule.
We tested this proposal of alternating use of the two microtubule-binding loops by introducing mutations to these loops. The positively charged residues Lys261, Arg264, and Lys266 in loop L11 were mutated to Ala, and this L11 mutant (K261A/R264A/K266A) was compared with an L12 mutant (CK1) (4) and an L8 mutant in which Lys161, Arg167, Arg169, and Lys183 were mutated to Ala (K161A/R167A/R169A/K183A). Loop L8 was selected for mutation because it corresponds to the third microtubule-binding region and does not change its conformation or position relative to the microtubule during ATPase turnover (14, 33). Relative to the wild-type protein, all of the mutants showed similar ATPase turnover rates but a lower affinity to the microtubule. As previously shown (4), the mutation in loop L12 selectively weakened affinity in the ADP state but not in the AMP-PNP state (Table 1). By contrast, the mutation in loop L11 had a stronger effect in the AMP-PNP state than in the ADP state. The mutation in loop L8 affected both forms to the same extent. Thus, the mutational studies support the proposal that KIF1A uses two loops, L11 and L12, in an alternating manner during ATPase turnover.
This alternating use of microtubule-binding loops provides structural support for our model of KIF1A's motility (4, 5, 32, 35). The model assumes that KIF1A alternates between two different binding states: the rigor-binding state with the affinity biased toward the forward tubulin subunit, and the diffusive binding state that allows one-dimensional diffusion. The rigor-binding loop L11 is extended toward the forward tubulin subunit. This configuration of loop L11 gives directional bias, or asymmetric binding potential, to the rigor-binding state. The force and binding energy supported by this binding are more than 10 pN and 10 kBT (3, 4), respectively. This strong binding is broken by the energy of ATP hydrolysis. ATP hydrolysis causes conformational changes that first raise loop L11 from the microtubule and then bring loop L12 into contact with the microtubule. The flexible tether between loop L12 and the E-hook of tubulin allows diffusive binding in the ADP form. Thus, KIF1A kinesin takes three structures successively: L11 down, both L11 and L12 up, and L12 down. It is therefore possible to surmise that a fourth structure might exist: both L11 and L12 down (at the transition from the L12 down, ADP state, to the L11 down, ATP state). Bringing both L11 and L12 to the microtubule might open the nucleotide-binding pocket and accelerate ADP release. Further structural analysis of the nucleotide-free state or the ADP-release intermediate state of KIF1A will be required to examine this possibility.
Finally, we note that the design principle of KIF1A is similar to that of heterotrimeric guanine nucleotide–binding proteins (G proteins) (36, 37) and other proteins such as protein kinases (38). The binding energy of KIF1A to the microtubule is used to achieve a mechanical step of KIF1A (5). With G proteins and protein kinases, the binding energy to an effector molecule or substrate is used to cause structural changes. Nucleophilic attack by water molecules or serine residues on the γ-phosphate catalyzes hydrolysis. Hydrolysis triggers a conformational change at the binding surface (the switch II helix) that detaches the enzyme from the target molecule. The binding between a G protein and its effector molecule, or between kinase and its substrate, is so strong that energy is required for dissociation. The energy of hydrolysis is used for this active detachment, which is necessary to cycle the reaction. This conserved strategy might reflect the evolutionary pathway of these classes of proteins, and also suggests a design principle for nanomachines.
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Although the biochemically measured apparent dissociation constant is not significantly different among the AMP-PNP–bound, nucleotide-free, and ADP-bound states, each kinesin molecule behaves differently on the microtubule in the ADP-bound state (one-dimensional diffusion) relative to the other two states (rigor-binding) (4, 5). Biochemical analysis using [α-32P]ADP indicates that more than 90% of the active sites of kinesin molecules are occupied with ADP. These results, as well as previous results with the L12 mutant CK1 (4), support that the result with excess ADP (2 to 10 mM) reflects the behavior of kinesin with ADP in the active site.
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The RMSDs of the switch I region (amino acids 202 to 218) are 2.0 Å (AMP-PNP versus ADP-AlFx forms), 4.5 Å (ADP-AlFx versus ADP-Vi forms), and 4.0 Å (ADP-Vi versus AMP-PNP forms). Those of the switch II region (amino acids 248 to 324) are 0.8 Å (AMP-PNP versus ADP-AlFx forms), 1.4 Å (ADP-AlFx versus ADP-Vi forms), and 2.1 Å (ADP-Vi versus AMP-PNP forms).
Although the γ-phosphate is expected to be nucleophilically attacked by water, by analogy to myosin (20, 40), the γ-phosphate in our transition structure with ADP-AlFx coordinates with Ser215 in the switch I region. This coordination could possibly be an artifact due to the use of a nucleotide analog. However, the difference map of AlF3 indicates that Al3+ exists in trigonal bipyramidal configuration with partial bonds to the β-phosphate and the hydroxyl group of Ser215 (Fig. 3C) (fig. S3). This coordination suggests another possibility: that the γ-phosphate is nucleophilically attacked by conserved Ser215, as occurs in protein kinases. Further studies will be necessary to clarify this issue.
The conserved residue Arg216 in the switch I loop L9 has been suggested to be the important phosphate-binding site near the nucleotide-binding pocket (41).
The possibility that our structure of ADP-Vi form might only reflect a structural variation of ADP is excluded by the following results. First, ADP-bound KIF1A never takes an ADP-Vi like structure, even under conditions identical or similar to the crystallization condition for the ADP-Vi–bound KIF1A. Similarly, ADP-Vi–bound KIF1A never takes an ADP-like structure, even under the crystallization condition for the ADP form. This is very different from the case with the ADP and AMP-PCP forms (14). ADP-bound KIF1A can take an AMP-PCP–like structure (but not an AMP-PNP–like structure) under the crystallization condition for the AMP-PCP form. This reflects that the energy barrier for the transition between the ADP-Vi and ADP structures is much higher than that between the ADP and AMP-PCP structures. Second, only preformed ADP-Vi-KIF1A complex takes this ADP-Vi structure. We could not obtain a crystal of ADP-Vi form by soaking of vanadate solution to ADP-KIF1A crystals or by the addition of vanadate to the mother liquid with which ADP-bound KIF1A is crystallized. These results strongly suggest that our ADP-Vi structure reflects a structure of a stable intermediate state within the ATPase cycle, rather than another structural variant or an artificial vanadate adduct to ADP-KIF1A.
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Recently, a new model was proposed for myosin on the basis of a new structure (42). Our structures and model are not inconsistent with this new mechanism. As proposed for the new "trapdoor" mechanism, kinesin has two "doors" that open and close asynchronously. The door on the switch I side is opened and the door on the switch II side is closed ("O/C conformation") in the preisomerization state. This conformation might contribute to the holding of the entering ATP. Before hydrolysis, KIF1A takes a "C/C conformation." During hydrolysis, it transiently takes a "C/O conformation" for the effective nucleophilic attack. Then, it takes an "O/O conformation," which opens the route through which the phosphate is released. Further studies will be necessary to determine whether kinesin works by a back-door or a trapdoor mechanism.
Here, two differences between kinesins and myosins should be noted: (i) The nucleotide-binding pocket of myosin is enclosed, whereas that of kinesin is rather exposed to the surface; (ii) the back door in the prehydrolysis state of myosin is rigidly closed, whereas that of kinesin is only partially closed. These differences might affect the kinetics of kinesin ATPase much faster than those of myosins (32, 43). Further structural study of the KIF1A-microtubule complex will be needed to clarify these differences.
The possibility that the vanadate moiety on Arg216 only reflects an artificial coordination of the solvent ion in crystal can be excluded by the following reasons. First, the position of vanadate is analogous to that in myosin. With myosin, vanadate is found on the corresponding back-door residue through which the produced phosphate is thought to be released. Second, vanadate is located at the same or similar position even in solution. The position of vanadate in solution was determined by the photo cleavage experiment. With myosins, the cleavage site (P-loop) agrees well with its ADP-Vi structure (40). Similarly, KIF1A was cleaved at loop L11, as expected from our ADP-Vi structure. This confirms that our ADP-Vi structure actually reflects the solution structure.
This stabilization of loop L11 of the ADP-Vi form is also evident from the low temperature factors of the residues in loop L11 [mean B value of the main-chain atoms of loop L11 (amino acids 251 to 270), 39.5 Å2, overall mean B value, 32.0 Å2]. In the ADP form, the residues from Ala255 to Ala260 in loop L11 are disordered because of its flexibility.
This arginine is conserved among kinesins, although some kinesins have arginine at the residue corresponding to 313, a position just next to 316 on helix α5. For example, in conventional kinesin (3KIN), Arg313 forms a salt bridge to Glu170.
Before ATP hydrolysis, the neck-linker β9 (amino acids 353 to 361) is fully docked [except for the (His)6 tag at the C terminus] to the catalytic core (AMP-PCP and AMP-PNP forms) (Fig. 3, A and B). During hydrolysis, the rotational movement of the switch II helix α4 pushes the neck-linker β9 down through the hydrophobic interaction between the conserved Leu285 of helix α4 and the conserved Ile354 of strand β9 (ADP-AlFx form) (Fig. 3C). This leads to the complete detachment of the neck-linker from the catalytic core (ADP-Vi and ADP forms) (Fig. 3D).
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This active detachment mechanism is also applicable to dimeric kinesin, including conventional kinesin. Hydrolysis of one head triggers the conformational change of its switch II cluster, both the microtubule-binding loop raised and the switch II helix rotated. The rotation of this helix pushes the neck-linker by which two heads coordinate. Thus, our study provides structural evidence of the idea that the active detachment is coupled with the coordination of two heads (44). In other words, active detachment of one head precedes the hydrolysis of the second head, the second step.
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Both conventional kinesin and KIF1A share this pathway. The only major difference is the affinity of kinesin to microtubule in the ADP state (yellow). The K-loop of KIF1A increases its affinity in the ADP state (4), shifting the equilibrium to the associated state (MKD). With K-loop mutant KIF1A as well as conventional kinesin, the equilibrium is shifted to the dissociated state (KD).
We thank D. R. Tomchick, N. Ota, S. Wakatsuki, N. Igarashi, H. Sawa, Y. Wakabayashi, and their colleagues for technical suggestions; H. Fukuda, H. Sato, and M. Sugaya for technical and secretarial assistance; and H. Miki, M. Kawagishi, H. Yajima, T. Ogawa, E. Nitta, and our colleagues for discussions and technical assistance. Supported by a Center of Excellence Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (N.H.). Coordinates for the four new structures of KIF1A have been deposited in the PDB database and are available under the following accession codes: both 1VFV and 1VFW for the AMP-PNP form, 1VFX for the ADP-AlFx form, and 1VFZ for the ADP-Vi form.
Two loops of a cellular motor protein alternately bind to tubulin, propelling it along the microtubule.


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Why doesn't the Doctor duplicate himself when he has multiple medical emergencies at the same time?
The Doctor in Star Trek: Voyager is a hologram. Voyager's Sick Bay is loaded with holo-projectors.
The episode "Living Witness" shows that the Doctor regularly makes backup copies of himself. After he gets his Mobile Emitter he is able to transfer his program completely to the device.
In a medical emergency with multiple patients, why doesn't the Doctor ever duplicate himself?
If it's a matter of the ship not having enough processing power, why not transfer his program to the Mobile Emitter and then launch his backup copy from the ship's emitters in Sickbay?
In the episode "Concerning Flight", the ship's main computer core is stolen. This cripples weapons, navigation, transporters, and propulsion yet the Doctor continues on in Sickbay unaware as if nothing has happened.
This suggests that the Doctor requires less processing power to sustain his program than the weapon targeting systems, which makes answers suggesting limited processing power seem less likely to be correct.
star-trek star-trek-voyager star-trek-emh
KalamaneKalamane
Probably the same reason people can't be cloned by the transporter (except Riker and Evil Riker). There would be no peril for people and holographic doctors who could simply be replicated if lost. – Chad Levy Nov 19 '11 at 4:24
In the episode Lifesigns the Doctor created a holographic body for a dying Vidiian while also loading the memories and synaptic patterns for them into the computer. This would seem to negate any supposed technological limitations in either the computer memory or the holo-emitters in-so far as not being able to run multiple "artificial" intelligences or complex holo-matrixes (yes, in this case I am considering any biological intelligence copied into a computer to be artifical). – Xantec Nov 19 '11 at 12:53
My question would be: If you copied the Doctor, would you then have two Doctors who could potentially become two different "people"? If so, killing the copy would be immoral. – Jeremy Heiler Nov 26 '11 at 4:05
EXEs can't run from a ZIP file. Just because there are backups doesn't mean those backups can be executed. – John Sensebe May 4 '16 at 15:02
@JeremyHeiler: You can bypass the morality by simply having all instances of the Doctor access and store their experiences in the same repository. Then, since all running instances of the Doctor will essentially have the same experiences and moralities, you can bypass the moral dilemma without concern. In fact, I'd leave it up to the Doctor's primary program to decide which copies to deactivate, so now the choice is entirely up to the Doctor. – Ellesedil May 19 '16 at 17:32
In "Basics: Part 1" when Voyager fights multiple Kazon factions, they created multiple holographic fighter ships to distribute the shots from the Kazon ships so that Voyager came under less fire. When they first initialise these holographic ships, the Doctor appears in space stating:
TORRES [OC]: Doctor, are you there? Are you all right?
EMH: I told you we should have run one last systems check.
Indicating that these holographic ships run under the same computer program as the Doctor. This proves that it is, in fact, possible for there to be multiple copies of a hologram running simultaneously. I assume that this never happens in the show for the same reason that transporters cannot create copies, or replicators cannot be used for cloning, yet they can be used to create organs.
There are tons of contradictions like this in the Star Trek series. Stuff like that is inevitable with science fiction, although Star Trek does a very good job at being scientifically accurate as often as possible (where the narrative allows anyways). In one episode of Star Trek (TNG I believe) they used a transporter to get rid of a virus in one of the crew's body using a backup from the transporter logs. If this was truly possible, don't you think they would have done this more often? Such as healing injured crew members, or even bringing them back from the dead?
ZacZac
Despite Living Witness, Voyager does not have enough memory to make a backup copy of the Doctor's program (see the note at the bottom of this Wikipedia article). If he were to create two Doctors using the mobile emitter and Voyager's own memory then both copies would be stuck where they were, since there would be nowhere that either of them could be transferred.
Mike ScottMike Scott
Considering that Voyager has nearly the complete Federation Database with it, plus multiple holographic programs with many characters (though none of them so complex, but the doctor is not that complex either, at least not in the beginning, he's just backed by a vast medical database) I consider this a excuse. Maybe in-universe correct, but a very unbelievable excuse. – Bobby Oct 14 '12 at 10:42
What's the opposite of Deus Ex Machina? Cause it seems like this is it ;) – Wayne Werner Aug 11 '15 at 16:02
"Stuck in the machine" – Kalamane Nov 2 '15 at 18:59
@WayneWerner: Excusatio ex stercore bovis? – ThePopMachine May 19 '16 at 14:39
Tom: Captain, there isn't enough memory to have two doctors! Janeway: Harry replicate & install enough computer memory for another doctor instance. Harry: Captain, the bandwith considerations, the paralellisations, it's just impossible! Janeway: (raised eyebrow™) Really? We're in a state of the art space ship and that's your best excuse? Mr Tuvok relieve Mr Kim of his command and get another doctor up and running? – Binary Worrier May 26 '17 at 16:15
I thought that it was Digital Restriction Management at work. It's probably much more pervasive in Voyager's time than even today and it wouldn't surprise me if even medical units and the military/Starfleet would not be exempt from this.
Andrew J. BrehmAndrew J. Brehm
Can you offer any evidence of this or was this just intended to be a funny answer? – Valorum Nov 6 '18 at 18:19
According to Star Trek technical manuals I've found, and other resources from various places, the Sick Bay systems are completely separate physically from the rest of the ship. It''s got its own power supply, it's got its own replicators, it's even got it's own Emergency Power. It is for all intents and purposes a complete separate system. The only reason the Doctor is at all aware of anything that goes on on the ship is because in Episode 01x02, Janeway has the Doctor's program linked to all logs for everything that happens ship wide. That way he can be made aware of any emergencies that could come up. So therefore the separate system is networked with the rest of the ship.
Also, Sick Bay's systems are mainly only capable of storing one maybe two EMH's at a time. Any other holograms are taken from the main computer's memory, or the holodeck's memory storage. Assuming the doctor needed a secondary back up, he could instruct the computer to transfer a copy of his program into the holodeck, and use It as a secondary Med bay. The only problem with that is that in emergency situations upon all starships, the first systems to be deactivated to reroute power is the Holodeck. Which is done by the computer. This can be seen in TNG Episode 3x06 when the power on the ship is waning and the computer shuts down the holodeck because of it was Standard Operating Procedure.
It must also be taken into consideration that the EMH by his own admission has the sum of almost all the Medical Knowlege known to Starfleet. In order to be able to serve a star ship in the event that something like him would be necessary, and considering the types of encounters most exploration ships have, this would be absolutely necessary.
The size of all of this information would be tremendous, not to mention the computer in Sick Bay most likely draws upon His programmed knowledge when asked a question by the standard medical officer who would normally be there. It would be a waste of space to have both his knowledge, and a copy of this knowledge in the system at the same time.
And since Sick Bay is as stated before a separate system designed to be able to sustain itself in case of a ship wide power failure, or computer failure, we must assume that the amount of space within the computer must be finite.
SmerrillsSmerrills
The only problem with that is that in emergency situations upon all starships, the first systems to be deactivated to reroute power is the Holodeck. - Not in this case, the power systems on Voyager's holodeck were incompatible with the rest of the ship. – Izkata Oct 13 '12 at 20:25
This could be the best answer. Can you provide some citations? – EleventhDoctor Jun 29 '15 at 14:37
The Doctors program is "transferred" - cut and pasted - into various places throughout the series, and never copy and pasted. This is, IMO, a mistaken approach, but at least it is consistent. It would suggest that copy an pasting the Doctor would not work, or it would have been done in many situations.
I understand that his memories would not be consistent if he made copies, but they certainly do some re-modelling of his memory on occasions. And I am not sure why missing a few memories is such an issue - one version would have some memories, isn't that enough?
Schroedingers CatSchroedingers Cat
This also, in my mind, raises the issue of why not using the transporter in a similar fashion. Need more engineers? Store La Forge's pattern and copy away. Need a bunch of redshirts for a suicide attack? Find the best and "clone" away. – erdiede Nov 19 '11 at 22:31
@erdiede See DS9 4x10 Our Man Bashir for why that would not work for humans: So much memory is required to store a person's neural patterns, an extremely volatile type of memory is used. – Izkata Nov 22 '11 at 4:20
@Izkata Still not sure that the real answer is that the writers don't know what RAID 1 is. – erdiede Nov 22 '11 at 5:44
In Living Witness (VOY, Episode 4x23) there is a back-up version of the doctor. – liftarn Jun 30 '14 at 13:42
Take your pick:
Voyager runs on limited resources. The holographic doctor program is supposedly a very big program, very demanding in memory (and presumably processing power too).
Holograms are usually confined to the holodeck. Having holo-emiters in sickbay was novel technology, might not support more than a single hologram (although this has been contradicted later on. Neelix had holographic lungs for a while in an episode (but even then it was "straining the resources").
The writers just didn't think that far ahead of the curve.
MPelletierMPelletier
Don't forget about the hologram of Denara Pel, which co-existed in sickbay with the doctor. – Timwi Dec 8 '11 at 1:07
@Timwi Also supporting your comment, in Voyager 5x8 Nothing Human A holographic copy of Crell Moset exists with the Doctor in sickbay as a consultant. – Kalamane Jan 13 '12 at 15:07
And now that I remember, Barclay showed up as a hologram to fix the Doctor, I think? – MPelletier Jan 13 '12 at 16:32
And Kim was tasked with creating a second EMH for a while (before Crell Moset, IIRC), so computer usage wasn't a constraint – Izkata Oct 13 '12 at 20:22
@Izkata IIRC at that time the EMH had been transferred off the ship. Maybe it was the episode in which they encountered the Hirogen sensor network? – a CVn Jan 9 '13 at 9:05
The question becomes one of ethics.
Let's say the Doctor could duplicate himself to the mobile emitter, and one to the ship. When it becomes time to 'unduplicate' himself, which one do you suppose gets deleted?
If they retain both, the issue is the Doctor's experiences become fragmented. The mobile emitter version would gain knowledge from away missions, and the medical bay version would be contained there forever (also implicitly unethical), but whatever knowledge he gained cannot be shared easily with the one on the away mission, because which parts do you include? Which parts do you cut out? Maybe there were a series of mundane events of minor breakthroughs before he makes one big breakthrough?
This in turn burdens the systems of voyager. It has to maintain two EMHs (which have a history of going wrong), has to leave space for what is essentially duplicate knowledge, and has duplicate processing demands, in what is a power conservation situation where knowledge cannot be consistently shared.
Indeed, the Doctor hasn't been avoiding 'duplicating' himself, he just does it in a different way: he's been training Tom Paris as another medic to help out.
c1646091c1646091
This is a solvable technical problem. You assume that the experiences from the various Doctor's could not be stored in a single repository. If every copy of the Doctor shares the same store of experiences, then there's no additional systems burden (and no moral dilemma for "killing" off copies). In fact, that's what plenty of software systems do today: take the data from multiple instances, and store it all in one place. – Ellesedil May 19 '16 at 17:29
Note that playing around with the Doctor's memories has been seen to cause problems (S05E11 - Latent Image). And, of course, the Captain has chosen to treat him as a human, rather than as equipment, on multiple occasions - he might have problems with the idea. – RDFozz Nov 5 '18 at 23:37
First for context - For some reason this is one thing that was always being changed. At first the doc was so complex they couldn't have a backup or replace him and so it was vital to keep him from being damaged, then they like magic make Crell Maset into nearly as complex of a program, then somehow they manage to make a backup of the doctor only its lost and finally when the doctor is stolen all the sudden they cant make a backup or a new doc let alone a Crell Moset like hologram to be a stopgap.
Second to answer - At least two times more then one hologram was active in sickbay the love interest of the doc and Crell Moset one was an actual humanoid working through the comp. And the other almost as complex as the doc, so it's possible for him to do so but the issue with if he is too complex or not was retconned and retconned so many times it's hard to say anymore.
TrekFreakazoidTrekFreakazoid
It is quite common for a program to take up more memory when running than the program takes. As there are two types of memory as most people think of it hard disk space and RAM. Most browsers, for example, would take up maybe a couple of 100mb of disk space but can easily take more than a gig of RAM when running. It's not a perfect example as a browser can have multiple tabs windows open.
As someone who works in IT it seems to me that running a program as complex as the doctor would take up an enormous amount of RAM.
So the doctor's program might take up a relatively small amount of memory (even less if compressed but could be extremely resource intensive while running requiring a large amount of RAM.)
Thus, explaining how there could be a backup copy of the Doctor (as noted elsewhere, "Libing Witness"), but they couldn't run two copies of the Doctor at the same time. – RDFozz Nov 5 '18 at 23:25
At the beginning of the series, there was a limit in the resources available to the ship. Holograms are complex, the EMH especially so, and having a duplicate was probably too resource intensive when it was just as easy for him to supervise a number of trained assistants.
It wasn't until later on when they found out ways to be able to expand the doctors programming that they could figure out other resources for the buffers.
HorusKol
Timothy ReynoldsTimothy Reynolds
This really doesn't address the question. – Tango Jan 13 '12 at 7:40
It is never mentioned, but one problem with running multiple instances is concurrency: maybe Holodoc is not thread-safe. I.e., there are crucial data structures somewhere else that are shared between all EMHs, or something.
philosopher-animalphilosopher-animal
Speculative answers should be backed up with at least some sort of canon source. – Valorum Apr 25 '14 at 23:02
A key point not noticed so far: By Voyager's time, computing has long ago evolved into to quantum computing - i.e all major computer hardware exploits features of Quantum Mechanics - superposition, entanglement, etc - to perform computing tasks as effectively as possible (e.g quantum computers can perform searches vastly faster than classical computers because they can use superposition to inspect all search candidates simultaneously). Because of this, computing tasks - such as is needed to generate moving holograms - all run up against a fundamental limitation:
THE NO-CLONING THEOREM: Given a single particle in a specific quantum state, there is no physically possible process that can both leave that particle in its original state and produce a second particle in the exact same state.
The Doctor's hologram is a large assemblage of projected subatomic particles (and not just light, because it is 'solid') which are undoubtedly highly entangled, and so the entire hologram can be viewed as a large particle in a specific, very complicated, quantum state. Projecting a second instance of the Doctor would then require replicating that particle - which is not physically possible.
PMarPMar
Plenty of the technical manuals talk about optical computers and faster-than-light acceleration. Do you actually have any quotable reference for your quantum computing assertion? – T.J.L. May 4 '16 at 13:54
Also, if this were true then the doctor would have been lost when the backup that was used in the Living Witness episode was created. – Kalamane May 12 '16 at 0:13
No other answer seems to mention this, so I'll add it.
Throughout most of the run, the Doctor is treated (as much as possible) the same as any other member of the crew. As critical as he is, he's allowed to continue to expand his program, even though it's been shown to be dangerous (e.g., S03E18, Darkling, where he develops a split personality).
In addition to singing and holophotography, he's allowed to:
Create a holographic family (S03E22, Real Life)
Daydream (S06E04, Tinker Tenor Doctor Spy)
Participate in away missions (note that his holo-emitter is 29th century technology, and as far as we know cannot be replicated, so he risks both that technology and his program in these cases).
He's even granted permission to remain behind on a planet, leaving Voyager without his services (S06E13, Virtuoso), and to travel to the Alpha Quadrant, using a communication link that may not be entirely reliable, risking the permanent loss of his services, to treat his creator (S06E24, Life Line)
We've been reminded, on occasion, that he is a program, such as when the crew of the Equinox removed his ethical subroutines, and he was perfectly happy to experiment on Seven of Nine, even if it would permanently injure her (S05E26 - S06E01, Equinox).
We've also seen that monkeying around with his memories can cause problems (S05E11, Latent Image, where a patient died because of a triaging choice, but he blamed himself and became unable to function). And, the ultimate solution, in that story? Treat him like a biological crewmember, not a program; help him work through the issue until he can get back to work, where he'll probably be an even better doctor for the experience.
So, when he's in the Alpha Quadrant for a month, he's not replaced by a backup. As others have noted, that would leave them in the position of having two programs with unique experiences, and with potential difficulty in merging the programs together again. And, since he has been accepted as a member of the crew, it would be unthinkable to simply delete one copy.
Would a backup copy (assuming they exist, as indicated by "Living Witness") of the Doctor have been used if he had actually left the ship in "Virtuoso"? We simply don't know. He decided not to leave before such an eventuality would have been necessary. I will note that, apparently, he would have taken the one-of-a-kind mobile emitter with him if he left.
TL;DR - The fact that the Doctor is accepted and treated as a member of the crew, not merely a holoprogram, may ethically limit the uses for his program as much as it's limited by the technology on board.
RDFozzRDFozz
It is my opinion that this would be quite possible to copy the doctor and re-integrate his experiences after running double or even more instances, he is just a program with a database, but it would be too problematic to film the same actor in the same shot repeatedly and because of that they didn't do it.
You have to remember there are hundreds of EMH mark 1 running around scrubbing plasma conduits after the program was replaced by Mk II, many in the same facility. For example, in "Author, Author".
Granted they do not share the same database, but they are running multiple instances of the same program. (i.e the first day the Mk I's were started at the facility they were exactly the same, diverging from that point on).
Cyber TrecCyber Trec
Again, I note that the Voyager's EMH had expanded his program over the years; I don't know by how much, but we're told in Life Line that a small subset of his "extra" routines take up at least 12 "megaquads". – RDFozz Nov 6 '18 at 18:22
And, of course, that the facility mentioned isn't Voyager. That facility's ability to run multiple former EMH programs (possibly without the presumably huge medical database that still forms part of the Voyager's EMH's program. – RDFozz Nov 6 '18 at 18:29
people seem very preoccupied by the "huge medical database" taking up too much space... the entire collective size of every book written by every human throughout human existence if compiled into an efficient database would barely reach petabyte size. In Star Trek times you could probably fit a petabyte on a thumb drive. – Cyber Trec Nov 6 '18 at 18:34
I'm pretty sure that the people mentioning that are taking their cue from Voyager itself. Logically, your point is well taken, of course, it's just that the show has stated the medical DB is very large, in their terms. – RDFozz Nov 6 '18 at 20:43
It is just a story telling device. Since the doctor is a computer program youcan just copy him (hot or cold backup). If the RAM usage (as mentioned earlier) is a concern, you don't need to use RAM for a stored copy, only for a running version.
It is probably theoretically possible to use some sort of synchronisation to keep a sickbay and emitter version of the doctor in sync so that memories and experiences are copied over. Same would be to copy a version of the cooy as a data stream back to the alpha quadrant to treat dr Zimmerman.
The thing is, it makes it all a bit boring. If there is no risk of loss, there is not much of a story. So not being able to copy a holoprogram is imho just a plot device and not a pseudo-technical limitation.
As for copying people using the transporter: i am pretty sure there are moral/ethical reasons to not allow this. On a metaphysical level you could argue that you can copy the body and chemical processes, but not the soul of a person (if you believe in that kind of thing). But again... if you could revert to a backup of yourself as last stored in the teleporter, how boring would that make a scifi series? Bit like "go back to the last save point" in a game :)
Jeroen KeppensJeroen Keppens
Do you happen to have an in-universe answer? – Mithrandir May 26 '17 at 13:45
protected by TheLethalCarrot Nov 7 '18 at 11:47
Not the answer you're looking for? Browse other questions tagged star-trek star-trek-voyager star-trek-emh or ask your own question.
Why do they worry about losing the Doctor (EMH)?
Why didn't Seven of Nine assimilate the Voyager crew when she was separated from the collective?
Why does the Doctor need so much time to think and do research?
Why does the Doctor in Voyager tell everyone about his mobile emitter?
2x19 Lifesigns: Why does The Doctor give access to the medicinal database?
Why does the Doctor display such loyalty to the Equinox crew?
How did the EMH remain "solid" when beamed aboard the hologram ship?
Why did Captain Janeway feel that using the Doctor as an expendable messenger boy was more important than keeping him around to heal the crew?
Why did the Voyager Doctor have to scrub in?
Why doesn't the 29th century Starfleet intervene when Janeway travels back in time at the end of Voyager?

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Gayal Anthony (Tony) Ellis
Dateline – Spartanburg, SC
Gayal Anthony (Tony) Ellis, 64, of Spartanburg, SC, passed away on March 22, 2019, surrounded by family and friends.
He was born to parents Gayal and Doris Ellis, on February 17, 1955, in Colorado Springs, Colorado. Tony graduated from Clinton High School, served as a paratrooper in the Army 82nd Airborne Division and went on to receive an associate's degree from Greenville Technical College. He spent most of his career as an instrumentation metrologist, working at Michelin, Fujifilm, Techni-Test and Norbord.
He married Marie in 1977, who survives him. Tony is also survived by daughters Leslie (Carlos) Casals, Amber (Henry) Bolen and Tess Ellis, grandchildren, Jose, Alex and Victor Casals and Megyn and Rachel Bolen; and two sisters, Mary Ann Edwards and Terry Powell; and his mother, Doris Ellis. Tony was predeceased by his father, Gayal Ellis, older brother, Bill Ellis, son, Craig Anthony Ellis and granddaughter, Adriana Casals.
The memorial service was held on Sunday, March 22, 2019, at 2 p.m. at Community Baptist Church in Clinton. Condolences can be sent to Marie Ellis, 106 Lakeview Drive, Laurens, SC 29360.


text:
Graeme English (ur. 25 września 1964 w Kilsyth, North Lanarkshire, zm. 18 lutego 2021) – brytyjski zapaśnik walczący w stylu wolnym. Olimpijczyk z Seulu 1988, gdzie odpadł w eliminacjach w kategorii 90 kg.

Zajął siedemnaste miejsce na mistrzostwach świata w 1991 a dziesiąte miejsce na mistrzostwach Europy w 1988. Brązowy medalista Igrzysk Wspólnoty Narodów w 1986 i 1994. Drugi na mistrzostwach Wspólnoty Narodów w 1993, a trzeci w 1987, gdzie reprezentował Szkocję.

Dziewięciokrotny mistrz kraju w latach 1986-1988, 1990, 1992 i 1994 (90 kg); 1989 i 1993 (97 kg) i 2000 (120 kg).

 Turniej w Seulu 1988
Pokonał Tapha Guèye z Senegalu i Samba Adama z Mauretanii a przegrał z Gáborem Tóthem z Węgier i Amerykaninem Jimem Scherrem.

Przypisy

Bibliografia

Brytyjscy olimpijczycy
Brytyjscy zapaśnicy
Urodzeni w 1964
Zmarli w 2021
Uczestnicy Letnich Igrzysk Olimpijskich 1988

redpajama_set_name: RedPajamaWikipedia


text:
October 28, 2022 | Jason Perry
Report: Terrorists Kill Over 70 Christians in Nigeria
According to Morning Star News, over 70 Christians were killed in Nigeria this week in just two days. Islamic terrorists from the Fulani ethnic group are said to be behind the attacks. Geopolitical analyst Irina Tsukerman explains to NTD that terrorists, like the Islamic State–West Africa Province, have taken advantage of the unrest and are […]
September 22, 2022 | Charlotte Cuthbertson
Texas Governor Designates Mexican Cartels as Terrorist Organizations
Mexican cartels are officially terrorist organizations in Texas, according to a designation applied by Texas Gov. Greg Abbott in a Sept. 21 executive order. "Fentanyl is a clandestine killer. And Texans are victimized by Mexican cartels that produce and import it. So cartels are terrorists. And it's time that we started treating them that way," […]
August 15, 2022 | The Associated Press
Misfired Rockets May Have Killed Over a Dozen in Gaza Battle
Close to one-third of the Palestinians who died in the latest outbreak of violence between Israel and Gaza terrorists may have been killed by errant rockets fired by the Palestinian side, according to an Israeli military assessment. Forty-nine Palestinians were killed in the three days of heavy fighting, according to Gaza's Health Ministry. The Israeli […]
August 2, 2022 | Kevin Hogan
Zawahiri's Death Crushes Al-Qaeda: Analysis
NTD spoke with Bart Marcois, former deputy assistant secretary of foreign affairs, to hear his analysis on the strike that took out al-Qaeda leader Ayman al-Zawahiri. He discusses what this means for security from terrorists and for the Biden administration, as well as how the strike was different from the one that took out Osama bin Laden.
July 19, 2022 | Reuters
US Says It Kills 2 Al Shabaab Terrorists in Somalia Airstrike
NAIROBI—The U.S. military said it had killed two fighters from the al Shabaab terrorist group in an airstrike in a remote part of Somalia's southern Jubaland state on Sunday. The United States has been carrying out air strikes in Somalia to try to defeat al Shabaab, an al Qaeda franchise seeking to implement its interpretation […]
June 23, 2022 | Kevin Hogan
Rep. Higgins: Number of Terrorists Entering US Far Greater Than Official DHS Figures
During an unprecedented surge in illegal immigration, more suspected terrorists are being apprehended at the U.S. southern border. NTD spoke with Rep. Clay Higgins (R-La.), a decorated law enforcement officer, to learn more.
June 17, 2022 | Zachary Stieber
Number of Suspected Terrorists Nabbed at US-Mexico Border Spikes Under Biden
More suspected terrorists have been captured at the U.S.-Mexico border amid an unprecedented surge in illegal immigration under President Joe Biden. Fifty people with records in the FBI's Terrorist Screening Database have been nabbed by Border Patrol agents at the southern border between ports of entry between Oct. 1, 2021, and May 30, according to newly […]
April 18, 2022 | NTD Newsroom
23 Suspected Terrorists at Southern Border
Illegal immigrants are continuing to enter the United States through the southern border—some possibly with bad intentions. Customs and Border Protection has apprehended 23 individuals who are known or suspected terrorists.
October 23, 2021 | Naveen Athrappully
Israel Designates 6 Palestinian Organizations as Terrorists
The Israeli Defense Ministry has designated six Palestinian civil society groups as terror outfits operating as part of a network run by the left-wing militant Popular Front for the Liberation of Palestine (PFLP). The organizations are accused of funneling international donor aid to fund PFLP activities that include carrying out deadly attacks against Israelis. PFLP, […]
September 24, 2021 | Tiffany Meier
How Beijing Supports Anti-US Terrorists: Report
Twenty years ago, the terrorist attacks on 9/11 caused two former foes, the United States and China, to become friends in order to fight the war on terror. But just how sincere was the Chinese regime in its motivation? And what cost did the United States pay after taking the Chinese regime's word? In a […]


« Early-Life Pain May Lead to Obesity Risk.
When the research workers asked adults to price the children's productions for just how much they appeared as if English words and phrases, they discovered that the adults provided higher ratings, normally, towards the productions of old prephonological spellers than towards the productions of young prephonological spellers. The productions of older prephonological spellers were more word-like on many objective measures also, including length, usage of different characters within words, and combinations of words. For instance: A 5-year-old who writes fepiri when asked to create the term touch may seem to know nothing at all about spelling, but this attempt appears similar to a term than fpbczs as made by a 4-year-old.Scientists are getting in touch with for the de-stigmatizing of Truvada make use of, calling it a simple human right. Intimate wellness is vital for everyone. To permit for better intimate health, people have to modification their behaviour toward avoidance initial. You deserve to become properly educated on your own sexual health insurance and the privileges you have relating to the subject. You don't deserve to become ridiculed for attempting to prevent sexual illnesses. If people stood together to teach each other within the need for prevention, the world will be taking a step of progress. If individuals were quickly provided info concerning fresh medicine for HIV avoidance, the world will be taking a step of progress.


text:
Contact: Image Use
U.S. Stamp Images
The United States Postal Service's policy is that formal, written permission is not required to use stamp images that were issued prior to January 1, 1979.
When using pre-1979 stamps you must still follow the reproduction guidelines which are as follows:
Illustrations may be in color or in black and white, and may depict philatelic items as uncanceled or canceled. When depicting uncanceled items in color, illustrations must be less than 75% or more than 150% in linear dimension of the size of the design of the philatelic items as issued. Color illustrations of canceled philatelic items and black and white illustrations of uncanceled or canceled philatelic items may be in any size.
In many cases, particularly with older stamps including those released before 1979, the U.S. Postal Service does not have information about other potential third-party ownership interests. In these cases, you would be solely responsible for identifying and obtaining permission from any other third parties that may have an ownership interest in the image.
For additional information and to obtain stamp image files please contact the U.S. Postal Service Licensing Department
International Stamp Images
Permission for use of international stamp images (non-USA) should be obtained directly, before use, from the entity, or entities, to whom stamp copyright belongs.
Download Free Photographic Archives Images
View the museum's photo collection, People and the Post, on Flickr.com. The museum requests that National Postal Museum images be used with full attribution to National Postal Museum, Smithsonian Institution.
Rights and Reproductions and Contact Information
National Postal Museum Society
Donor Honor Roll 2022
Postal Museum Society Webinars
Annual Smithsonian Weekend 2020
Secrets of the Smithsonian and the NPM
Smithsonian Insider Series | Baseball: America's Home Run
Smithsonian Insider Series | Stephen Wong
Revisiting NPM Collections in Light of Covid
Stamps and Stamp Collecting
History of the US Postal Service
Items in the Collection


How are you doing today and how have you been? I went to get a manicure and pedicure over the weekend and stopped over at the ATM to withdraw some cash; I took out the usual amount that I pay but added some extras just in case. After getting my nails done, the lady was like, "Aunty, we don increase our price oh" so na extra N500 you go add"; I asked since when and why? Her response was "ah, you no dey dis Naija, dollar don increase and everything don cost for market". Even orange seller increased price of oranges because of dollar… haba!
Even a toddler in Nigerian knows the current financial situation of the economy and how everything is affected due to our over-dependence on oil, hence crippling the economic situation due to the reduced oil prices. But nevertheless, we still have to wear clothes every day as the weddings, social events, birthdays, child dedications; thanksgivings etc. seem to be on the rise during this period. In as much as we want to still look good and maintain our sense of style at these events and at our places of work, we also need to be careful with our fashion expenses so that we don't find ourselves in a financial hiccup that can be avoided. The jamb question now is – how do we balance our finances with fashion during this economic downturn? These 5 easy steps will help you.
Know you financial capacity – this is extremely important. You cannot be earning a low income and want to own the wardrobe of a high net worth individual. Knowing your financial capability helps you know how to spend and what to spend on; fashion & style is not solely dependent on how much you spend on an outfit but also on the way you wear it (the fitting). So don't live above your means because you want to look like the fashion aficionados on the blogs and magazines, create your own unique style, simple and sophisticated.
Scrap impulsive buying – many of us who are window shoppers give ourselves heart attack after window shopping. You often find yourself dreaming about the clothes and jewelleries you saw and that urge to buy it keeps hunting you until you satisfy its cravings. Dearest, you need to overcome that dream and curtail unnecessary spending; make purchases only when it is absolutely required, don't use money for a need to satisfy a want.
Buy Nigerian – majority of boutiques are stocked with imported London, Italian, American apparels; then when these clothes are sold, the prices are unnecessarily expensive because the increase in dollar and scarcity of foreign currencies (pounds & euros) means the items will definitely have some extra zeros added to the original price. But a Nigerian made outfit is sewn and styled in Nigeria by a Nigerian for Nigerians; these outfits will not be outrageously expensive as we have very good Nigerian outfits, foot wears and accessories at affordable prices. Visit Zinkata.com to find out the best Nigerian items to buy.
Re-rock – this is the ability to wear one outfit many times but styled in different ways to create a unique ensemble. Don't dump a good outfit after wearing it once just because you have posted pictures on Instagram with that outfit and you don't want to be seen wearing it again. It really doesn't make sense especially if you're doing this to impress social media at the expense of your finances. Do you know you can turn a dress to a skirt or top? You can also wear the same top, trouser, shirt etc. again but paired with different accessories from the first time you wore it. To get this right, you need to give at least 2 – 3 months gap between the first rocking and the re-rock. The ability to re-rock shows how creative your mind can be, give it a try – you could learn something in styling.
Minimalistic dressing – too much of fashion sometimes is not attractive; you can still look like a bombshell with minimal dressing, simple jewelleries and a light make-up. So buying too many things that will look like extra luggage on you may not be advisable.
With these simple steps, you can effectively manage your wallet and your wardrobe; fashion is important but not at the expense of your finances.
My Gwe, u re always on point. Please tell them ooo make dem hear.


text:
Tom Brady's dad suddenly has new take on Patriots drama
By Greg Joyce
March 28, 2020 | 2:43pm	| Updated March 28, 2020 | 3:07pm
Girlfriend's Instagram rant adds drama to Bill Belichick-Tom Brady divorce
Tom Brady's heartwarming moment with Drew Brees' son goes viral
Tom Brady still owns the big moments
Tom Brady may have just ended Drew Brees' career
Tom Brady Sr. may have predicted his son's unceremonious ending with the Patriots before anyone else, but now he is downplaying the drama that reportedly led to the quarterback's departure.
Brady left the Patriots after 20 years to sign with the Buccaneers last week. While multiple reports have indicated that a growing rift between Brady and coach Bill Belichick was at the heart of the stunning decision, Brady Sr. said he sees it as a "separation" instead of a "divorce."
"I think it's just change," Brady Sr. said on an episode of the "Raising Fame: Sports Edition" podcast with Dell and Sonya Curry, as transcribed by Boston.com. "I don't know that it's a divorce. Twenty years together is a long time. I can't tell you the hundreds of times Tommy has said, 'Bill [Belichick] is the best coach in football.' Tommy sings Bill's praises. Divorce sounds a little bit harsh."
Brady Sr. has been outspoken in the past, so much so that Brady reportedly once asked him to stop talking to the media. But it was Brady Sr. who said in a 2015 New York Times Magazine story that "it will end badly" for Brady and the Patriots.
The Patriots were reportedly unwilling to commit to the 42-year-old Brady beyond going year-to-year, but he was able to land a two-year, $50 million contract with the Buccaneers.
Tom Brady and Bill BelichickAP
"Bill's got a lot of responsibilities to keep the Patriots on track," Brady Sr. said. "That is a bigger responsibility than keeping Tommy under the hood. Both of them are mature individuals. I really respect Bill's decision and respect Tommy's decision as well. It's OK to take different paths. You don't have to stay joined at the hip."
All parties involved have taken the high road since Brady left the franchise with which he won six Super Bowls. Belichick released a glowing statement about Brady's tenure and Brady spoke in an equally complimentary manner about the Patriots during his Buccaneers introductory conference call on Tuesday.
Now, all eyes will be on Brady to see if he can win a Super Bowl without Belichick.
"Twenty years is about four lifetimes in the sports world," Brady Sr. said. "It's pretty unusual that people don't leave one franchise for another. After 20 years, I just kind of sense that this is going to be a new chapter.
"He wants another Super Bowl."
Filed under bill belichick	, new england patriots	, nfl free agency	, nfl free agency 2020	, tampa bay buccaneers	, tom brady	, 3/28/20
Giants signing Jets castoff to add much-needed depth


text:
Q: Tic Tac Toe - Turns C I've been turning around and around trying to figure out how to give my players turns. The questions is for there to be two players playing tic tac toe but I can't figure how to do that. Here's my code:
#include <stdio.h>
#include <stdlib.h>

void displayBoard(char [3][3]);enter code here
int playerType (int player, char boardArray[3][3]);
int selectLocation(char [3][3], int , int );
char setTurn(char [3][3], int , int , char );

int main()
{
    int player,location;
    char position;
    char boardArray[3][3]={{'1','2','3'},
            {'4','5','6'},
            {'7','8','9'}};

    player= playerType (player, boardArray);

    int i;

    for(i=0;i<9;i++)
    {

        if (player==3)
            break;
        else{

            location=selectLocation(boardArray, player, location);

            position=setTurn(boardArray, location, player, position);
        }

    }

    return 0;
}

void displayBoard(char boardArray [3][3]) //This displays the tic tac toe board
{
    printf("\t%c|%c|%c\n", boardArray[0][0], boardArray[0][1], boardArray[0][2]);
    printf("\t%c|%c|%c\n", boardArray[1][0], boardArray[1][1], boardArray[1][2]);
    printf("\t%c|%c|%c\n", boardArray[2][0], boardArray[2][1], boardArray[2][2]);

}
int playerType (int player, char boardArray [3][3]) //This decides who plays first
{

    player=0;

    printf("Enter 1 for Player X.\n");
    printf("Enter 2 for Player O.\n");
    printf("Enter 3 to Quit. \n");
    scanf("%d", &player);

    if (player == 1)
    {
        printf("You're player X.\n");
        displayBoard(boardArray);
    }
    else if (player == 2)
    {
        printf("You're player O.\n");
        displayBoard(boardArray);
    }
    else if(player == 3)
        printf("You Quit.\n");

    else
        printf("Invalid Entry.\n");

    return player;
}

int selectLocation(char boardArray[3][3], int player, int location) //This takes in the location
{
    printf("Pick a location from 1-9.\n");
    scanf("%d", &location);

    return location;
}

char setTurn(char boardArray[3][3], int location, int player, char position) //This outputs the location
{

    if (player == 1)
    {
        switch(location)
        {
        case 1:
        {
            boardArray[0][0]='x';
            break;
        }
        case 2:
        {
            boardArray[0][1]='x';
            break;
        }
        case 3:
        {
            boardArray[0][2]='x';
            break;
        }
        case 4:
        {
            boardArray[1][0]='x';
            break;
        }
        case 5:
        {
            boardArray[1][1]='x';
            break;
        }
        case 6:
        {
            boardArray[1][2]='x';
            break;
        }
        case 7:
        {
            boardArray[2][0]='x';
            break;
        }
        case 8:
        {
            boardArray[2][1]='x';
            break;
        }
        case 9:
        {
            boardArray[2][2]='x';
            break;
        }
        default:
            printf("invalid");
        }

    }
    else if (player == 2)
    {
        switch(location)
        {
        case 1:
        {
            boardArray[0][0]='O';
            break;
        }
        case 2:
        {
            boardArray[0][1]='O';
            break;
        }
        case 3:
        {
            boardArray[0][2]='O';
            break;
        }
        case 4:
        {
            boardArray[1][0]='O';
            break;
        }
        case 5:
        {
            boardArray[1][1]='O';
            break;
        }
        case 6:
        {
            boardArray[1][2]='O';
            break;
        }
        case 7:
        {
            boardArray[2][0]='O';
            break;
        }
        case 8:
        {
            boardArray[2][1]='O';
            break;
        }
        case 9:
        {
            boardArray[2][2]='O';
            break;
        }
        default:
            printf("Invalid");
        }
    }

    printf("\t%c|%c|%c\n", boardArray[0][0], boardArray[0][1], boardArray[0][2]);
    printf("\t%c|%c|%c\n", boardArray[1][0], boardArray[1][1], boardArray[1][2]);
    printf("\t%c|%c|%c\n", boardArray[2][0], boardArray[2][1], boardArray[2][2]);

    return position;

}

A: Change player selection part player= playerType (player, boardArray); inside for loop like this -
int player,location;
char position;
char boardArray[3][3]={{'1','2','3'},
                       {'4','5','6'},
                       {'7','8','9'}};
int i;
for(i=0;i<9;i++)
{
    player= playerType (player, boardArray);
    if (player==3)
        break;
    else
    {
        location=selectLocation(boardArray, player, location);
        position=setTurn(boardArray, location, player, position);
    }
}

redpajama_set_name: RedPajamaStackExchange


text:
Q: mysql import script Is it possible to import csv data into mysql and automatically create the column names, as in can I create just the table, or must I create the table names as well?
Is it possible to check for duplicate entries upon importing? I have an identifier field, but dont know how to make it so it will not be imported twice.
How would you import a jpeg file on a website into a field? Assume the website has been stored locally, and has the same filename as an identifer with ".jpeg" added on to the end.

A: As tante said you'll have to handle the table creation yourself, but as far as importing csv is concerned you should have a look at LOAD DATA INFILE
LOAD DATA [LOW_PRIORITY | CONCURRENT] [LOCAL] INFILE 'file_name'
[REPLACE | IGNORE]
INTO TABLE tbl_name
[CHARACTER SET charset_name]
[{FIELDS | COLUMNS}
    [TERMINATED BY 'string']
    [[OPTIONALLY] ENCLOSED BY 'char']
    [ESCAPED BY 'char']
]
[LINES
    [STARTING BY 'string']
    [TERMINATED BY 'string']
]
[IGNORE number LINES]
[(col_name_or_user_var,...)]
[SET col_name = expr,...]

Duplicate entries won't be a problem if you have set primary keys on your table.
The jpeg question seems like a completely different issue (unless the data is in your csv)

A: Sure, but you'll probably have to write a few lines of code yourself, it can be done with very little code. Checking for duplicates is quite easy then, you can do that before inserting in your little script.
You could store the file as a combination of two fields, one Varchar for the name and a blob for the file contents.

A: *

*No

*You could add a unique
constraint - it really depends what
you want to do if a duplicate is
found

*Not using mysql - use a
scripting language to pull the image
data from the URL then insert that

A: Looks like the answers you got covers at least the first two items. For the Jpeg question, take a look at Storing a file in a database as opposed to the file system?.


If you are in the market for a new smartphone, then GearBest has quite a few options for you to consider. In particular, the UMi Z, the LeEco Le Max 2 and the Xiaomi Mi 5 are all currently available at discounted prices as part of various flash sales that GearBest is currently running. All of these smartphones look to offer a good level of specs and features, while maintaining a low and affordable price. Although, it is worth keeping in mind that all of these prices do reflect limited time and limited stock discounts.
In terms of the UMi Z, this smartphone is currently available to buy for $219.99. For that cost you are looking at a 5.5-inch display with 1920 x 1080 resolution, along with 4GB RAM, 32GB internal storage and a MediaTek Helio X27 deca-core processor. Cameras include a 13-megapixel camera on the back, as well as another 13-megapixel camera on the front. Additional features include dual-SIM support, a 3,780 mAh battery, Android 6.0 (Marshmallow), and more. In terms of network compatibility, the UMi Z is listed to work on 2G: GSM 850/900/1800/1900 MHz, 3G: WCDMA 900/2100 MHz and 4G: FDD-LTE 800/1800/2100/2600 MHz.
Alternatively, there is the LeEco Le Max 2 which is currently available to buy for only $199.99. This is a smartphone which comes with a 5.7-inch display with a 2560 x 1440 resolution. While inside you can expect to find 4GB RAM, 32GB internal storage and a Qualcomm Snapdragon 820 powering the show. Cameras include a 21-megapixel rear camera, along with an 8-megapixel front-facing camera. Additional features on offer include USB Type-C connectivity, a fingerprint sensor, VoLTE support, a 3,100 mAh battery and Android 6.0 (Marshmallow). In terms of network compatibility, the LeEco Le Max 2 is listed to work on 2G: GSM 850/900/1800/1900 MHz, 3G: WCDMA 850/900/1900 MHz and 4G: FDD-LTE B1/2/3/4/5/7/8/12/17/20/25/26.
Last but not least there is the Xiaomi Mi 5, which is currently available on sale for only $239.99. This is a smartphone that comes packing a 5.15-inch display with a 1920 x 1080 resolution, along with 3GB RAM, 32GB internal storage and a Qualcomm Snapdragon 820 processor. Cameras include a 16-megapixel rear camera, along with a 4-megapixel front-facing camera. While additional features include USB Type-C connectivity, a fingerprint sensor, NFC, a 3,000 mAh battery and Android 6.0 (Marshmallow). In terms of network compatibility, the Xiaomi Mi 5 is listed to work on 2G: GSM 850/900/1800/1900 MHz, 3G: WCDMA 850/900/1900/2100 MHz and 4G: FDD-LTE 1800/2100/2600 MHz.


19 easy & quick healthy recipes for kids mommies must know!
There are a lot of easy healthy recipes for kids mommies should learn that help to improve their children's health effectively, including simple and funny recipes they can make together! Growing up kids can help their mom in the kitchen and this will become one of their favorite to-do things.
In the article today, I would like to show you some of the best quick and easy healthy recipes for kids which will allow you to give your children better heath and fun. If you want to spend time with your little kids in the kitchen, you should learn these simple yet extremely delicious and healthy recipes for kids to make nutrition fun for them!
The first one in the list of easy healthy recipes for kids I want to show moms today is the funny chunky fish fingers – a nutritious and extremely delicious snack you can give your kids to eat at home or at school. Their friends will want to share with them this tasty "fingers".
3. Chicken Chow Mein This is one of the super tasty and healthy recipes for kids that take on your favorite takeout food! This recipe will be wonderful for your children's health with fresh garlic and ginger, plus healthy alternatives, such as reduced-salt soy sauce. Your children will have a lot of fun putting together the ingredients, especially the onions and peppers.
6. Pizzadillas With Red Sauce Most children love pizza, and they love making it themselves as well. This one out of the easy healthy recipes for kids is sure to be a big hit for any mom, especially because it mixes with quesadillas for mini pizzas. Your children will adore pretending like the kitchen is their own pizzeria, and you will feel satisfied with the healthy ingredients your kids will consume in this pizza, like spinach and whole wheat tortillas. Of course, quesdillas and pizza are both endlessly adaptable, so do not hesitate to let your kids experiment with their favorite additions.
9. Special Banana Smoothie This smoothie will be a greatly nutritious and healthy breakfast for your kids. You should give your kids this special banana smoothie with a granola bar or a handful of whole-grain dry cereal for a filling breakfast.
12. Blueberry Power Muffins With Almond Streusel We call these muffins "power" because they are jam-packed with heart-friendly monounsaturated fat from canola oil and almonds, B vitamins from whole-wheat flour, antioxidants from blueberries, and calcium from milk and yogurt.
15. Banana-Cinnamon Waffles Crown these lightly spiced waffles with sliced bananas, cinnamon sugar, and/or a drizzle of maple syrup.
17. Quick Breakfast Burritos This quick and healthy burrito is a wonderful breakfast for your kids, even if they are dashing toward the bus stop. This will help to boost your kids' metabolism and energy for good!
This is the list of 23 easy healthy recipes for kids that are very simple for moms to make with their children to have fun together. This list will help my readers who are visiting VKool.com improve their kids' health effectively without spending too much time, money, and efforts. If you think that my quick healthy recipes for kids are really useful for you and other moms your know, you should feel free to share this cooking sheet with them and let me see your feedbacks and comments below!


text:
UK Edition Of Holly Announced
Hodder & Stoughton has announced their edition of Holly.
A missing girl
Two serial killers with a savage secret
Only one determined woman on their trail . . .
Hodder & Stoughton is thrilled to announce the publication of Holly, a major new novel by international bestseller Stephen King. Hodder will publish in hardback, eBook and audiobook, and in trade paperback for Australia and New Zealand on 5th September 2023.
Holly marks the triumphant return of beloved King heroine Holly Gibney – one of his most compelling and ingeniously resourceful characters – as she uncovers the gruesome truth behind multiple disappearances in a Midwestern town.
Pre-order your copy here.