Giant Zincblende Structures Formed by an ABC Star-Shaped Terpolymer/Homopolymer Blend System

Giant Zincblende Structures Formed by an ABC Star-Shaped Terpolymer/Homopolymer Blend Syste

Clinical and neurophysiological data of patients having narcolepsy with and without cataplexy.

<p>Continuous values are expressed as mean±SD.</p><p>*p<0.05(t-test).</p><p>JESS: Epworth Sleepiness Scale, Japanese version.</p><p>MSLT: multiple sleep latency test.</p

Clusters showing significant main effects of group on ADC and FA values between the narcolepsy with cataplexy (NA/CA) and narcolepsy without cataplexy (NA w/o CA) groups.

<p>a) ADC value was higher in the right inferior frontal gyrus (Brodmann area 9) for the NA/CA group than for the NA w/o CA group. b) In the NA/CA group, the FA value in the right parietal lobe (precuneus) was higher than that in the NA w/o CAgroup. Results are significant at FWE-corrected p<0.05. Color scale is for F statistic.</p

Significant differences in the ADC and FA values for the NA/CA, NA w/o CA, and NC groups.

<p>Height threshold uncorrected p<0.001 in peak level on ANOVA.</p><p>Group main effects in cluster-level by multiple voxel-wise comparisons using P_FWE-corr: family-wise error, corrected p.</p><p>NA/CA: narcolepsy with cataplexy, NA w/o CA: narcolepsy without cataplexy, NC: normal controls.</p><p>ADC: apparent diffusion coefficient, FA: fractional anisotropy.</p

Clusters showing significant main effects of group on ADC value between patients having narcolepsy with cataplexy (NA/CA) and normal control (NC).

<p>1-1) ADC values were higher in the left parahippocampal gyrus (Brodmann area 34) and amygdala, and 1-2) in the left inferior frontal gyrus (Brodmann area 47/11) in NA/CA than in NC, while these values were lower in 2) the left postcentral gyrus (Brodmann area 3) in the former group. pone.0081059.Results.tifare significant at FWE-corrected p<0.05. Color scale is for F statistic.</p

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases