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Deformation process and strength evolution in accretionary wedges are important factors that affect kinematics and dynamics at subduction zones. However, it is still challenging to understand the relationship between the short-term geodetic observations (coupling ratios or earthquakes) and the long-term geological structures (patterns of imbricated thrust sheets or fault networks) in natural systems. In this study, we performed 2-D, large-shortening (1 m) analog sandbox experiments to examine how the wedge deformation is affected by different décollement conditions including heterogeneities and numbers of weak layers in the incoming sediment. Four different settings (Types 1–4) of the incoming sediment layers were examined in this study. Serial side-view digital photographs were quantitatively analyzed with an open-source DIC software to characterize the accretion cycles, underthrusting/underplating, and reactivation of pre-existing thrusts (out-of-sequence thrusts).The reference models with single décollement (Type1) were dominated by periodic cycles of frontal accretion with landward propagation of strain, uplift, and reactivation of the pre-existing thrusts, which progressively increased in strength and then approached the critical state. Each cycle was composed of preparation (Phase 0), initiation (Phase 1), accretion (Phase 2), and reactivation (Phase 3). Through frontal accretion, the wedge accumulated the strain internally with landward migration of the basal coupled area along the plate interface, which caused uplift and reactivation of the landward preexisting thrusts in the wedge (hardening). When a new frontal thrust emerged at the deformation front (Phase 1), the basal coupling was suddenly lost (softening). Through this cycle, the entire accretionary wedge progressively increased in strength while experiencing hardening and softening and approached the critical state. The double décollement models (Type 2) showed a similar accretion cycle to Type 1 models, but it consisted of a combination of shallow-rooted and deep-rooted frontal thrusts, meaning that the décollement stepped up and down between the interbedded and basal weak layers. This promoted sediment underthrusting at the frontal part of the wedge during the early phase of the accretion cycle and favored the connection of pre-existing deep-rooted thrusts with shallow-rooted thrusts. A frictional interruption in the basal décollement (Type 3 or 4 models) produced a combination of a steep-taper inner wedge and a gentle-taper outer wedge, and disturbed the wavelengths of the accretion cycle. The single décollement models (Type 3) were dominated by high-angle out-of-sequence thrusts, while underplating was significantly promoted in the double décollement model (Type 4) where the interbedded décollement acted as a low-angle, smooth-surface megathrust.These results shed light on the impact of properties and homogeneity of the incoming sediment and the plate interface on the spatial and temporal evolution of internal structure and thrust activity in accretionary wedges through multiple accretion cycles. Comparisons of our results with natural subduction zones will contribute to understanding the mechanisms and dynamics of deformation process and strength evolution in natural subduction zones.

We propose a conceptual geological model for the collision of multiple basement topographic highs (BTHs; e.g., seamounts, ridges, and horsts) with a forearc accretionary wedge. Even though there are many BTHs on an oceanic plate, there are few examples of modeling the collision of multiple BTHs. We conducted numerical simulations using the discrete element method to examine the effects of three BTH collisions with forearcs. The typical geological structure associated with a BTH collision was reproduced during the collision of the first BTH, and multiple BTH collisions create a cycle of formation of BTH collisional structures. Each BTH forces the basal décollement to move up to the roof décollement, and the roof décollement becomes inactive after the passage of the BTH, and then the décollement moves down to the base. As the active décollement position changes, the sequences of underthrust sediments and uplifted imbricate thrusts are sandwiched between the décollements and incorporated into the wedge. The distinctive structural features observed in our model are comparable to the large faults in the Kumano transect of the Nankai Trough, Japan, where a splay fault branches from the plate boundary and there are old and active décollements.

Sandy trench-fill sediments at accretionary margins are commonly scraped off at the frontal wedge and rarely subducted to the depth of high-pressure (HP) metamorphism. However, some ancient exhumed accretionary complexes are associated with high-pressure–low-temperature (HP-LT) metamorphic rocks, such as psammitic schists, which are derived from sandy trench-fill sediments. This study used sandbox analogue experiments to investigate the role of seafloor topography in the transport of trench-fill sediments to depth during subduction. We conducted two different types of experiments, with or without a rigid topographic high (representing a seamount). We used an undeformable backstop that was unfixed to the side wall of the apparatus to allow a seamount to be subducted beneath the overriding plate. In experiments without a seamount, progressive thickening of the accretionary wedge pushed the backstop down, leading to a stepping down of the décollement, narrowing of the subduction channel, and underplating of the wedge with subducting sediment. In contrast, in experiments with a topographic high, the subduction of the topographic high raised the backstop, leading to a stepping up of the décollement and widening of the subduction channel. These results suggest that the subduction of stiff topographic relief beneath an inflexible overriding plate might enable trench-fill sediments to be deeply subducted and to become the protoliths of HP-LT metamorphic rocks.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.

Forearc basin stratigraphy is expected to record a detailed history of the deformation and growth pattern of an accretionary wedge. However, the relationship between syntectonic basin sedimentation...

Slow slip events (SSEs) at the northern Hikurangi subduction margin, New Zealand, are among the best-documented shallow SSEs on Earth. International Ocean Discovery Program Expeditions 372 and 375 were undertaken to investigate the processes and in situ conditions that underlie subduction zone SSEs at the northern Hikurangi Trough. We accomplished this goal by (1) coring and geophysical logging at four sites, including penetration of an active thrust fault (the Pāpaku fault) near the deformation front, the upper plate above the SSE source region, and the incoming sedimentary succession in the Hikurangi Trough and atop the Tūranganui Knoll seamount; and (2) installing borehole observatories in the Pāpaku fault and in the upper plate overlying the slow slip source region. Logging-while-drilling (LWD) data for this project were acquired as part of Expedition 372, and coring, wireline logging, and observatory installations were conducted during Expedition 375. Northern Hikurangi subduction margin SSEs recur every 1–2 y and thus provide an ideal opportunity to monitor deformation and associated changes in chemical and physical properties throughout the slow slip cycle. In situ measurements and sampling of material from the sedimentary section and oceanic basement of the subducting plate reveal the rock properties, composition, lithology, and structural character of material that is transported downdip into the SSE source region. A recent seafloor geodetic experiment raises the possibility that SSEs at northern Hikurangi may propagate to the trench, indicating that the shallow thrust fault (the Pāpaku fault) targeted during Expeditions 372 and 375 may also lie in the SSE rupture area and host a portion of the slip in these events. Hence, sampling and logging at this location provides insights into the composition, physical properties, and architecture of a shallow fault that may host slow slip. Expeditions 372 and 375 were designed to address three fundamental scientific objectives: Characterize the state and composition of the incoming plate and shallow fault near the trench, which comprise the protolith and initial conditions for fault zone rock at greater depth and which may itself host shallow slow slip; Characterize material properties, thermal regime, and stress conditions in the upper plate directly above the SSE source region; and Install observatories in the Pāpaku fault near the deformation front and in the upper plate above the SSE source to measure temporal variations in deformation, temperature, and fluid flow. The observatories will monitor volumetric strain (via pore pressure as a proxy) and the evolution of physical, hydrological, and chemical properties throughout the SSE cycle. Together, the coring, logging, and observatory data will test a suite of hypotheses about the fundamental mechanics and behavior of SSEs and their relationship to great earthquakes along the subduction interface.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.

Forearc basins are one of the fundamental sedimentary basins, and they preserve various geological phenomena arising from dynamic interactions between subducting and overriding plates along convergent plate boundaries. Previous studies have proposed descriptive classification schemes for such basins and performed analog experiments and numerical simulations examining basin formation and evolution; however, the great variability of forearc basins means that a comprehensive understanding of these features remains elusive. This paper proposes a new classification scheme for forearc basins from the viewpoints of material transfer between the two plates (accretionary or nonaccretionary) and the long-term strain field in the basin (compressional or extensional) by using characteristics of 41 modern forearc basins. Geometric characteristics were also analyzed in order to reveal the relationship to subduction zone dynamics, including material transfer at the plate boundary (accretion/erosion), plate convergence configurations and kinematics, and the mechanics of strain and its partitioning. Compressional accretionary-type basins, which are characterized by landward-tilting strata and the landward migration of depocenters, show a constant width/thickness, ratio indicating self-similar growth of the basin as the outer wedge builds up. Extensional accretionary-type basins develop normal faults in the basin, probably due to a gravitational instability of the outer wedge. An increase of sediment flux at the trench may grow the accretionary prism and thicken the subduction channel faster, leading to a reduction of basal and internal shear strengths of the outer wedge. Subsidence caused by crustal thinning characterizes the nonaccretionary-type basins, which have thin trench-fill sediments, large forearc slopes, steady widths of the outer wedge, and variable width/thickness ratios of the basins. From these results, the sediment flux at the trench and the plate boundary can be considered as a dominant factor that determines accretion or erosion of the outer wedge and uplift or subsidence of the outer-arc high, and that is also responsible for the style of deposition in the forearc basin. An increase or decrease of the sediment flux may change the type, geometry, and deformation manner of the forearc basin. The results of this study provide important clues to further our understanding of dynamic interactions between forearc basins and subduction zone processes.

Changes in stacking density of fluvial channel-belt sand bodies are one of the most obvious aspects of alluvial architecture. The proximity of sand bodies to each other has been used as a field criterion to suggest major changes in external factors, such as basin subsidence rates, relative changes in base level, and changes in climate. In places rapid changes in stacking density are found in vertical succession between very high to very low net sandstone. In the absence of an intervening unconformity such changes are not the result of two unrelated, but juxtaposed, fluvial regimes but represent a more transitional change of formative conditions or preservation style. To study whether a rapid change in stacking density was controlled by external factors rather than autogenic behavior, we sought to document other possible changes in deposition that took place in concert with changes in stacking pattern. The Morrison Formation, Upper Jurassic of eastern Utah and western Colorado, U.S.A., contains a rapid transition from the Salt Wash Member, with an average 63% net sand, to the overlying Brushy Basin Member, dominated by muddy floodplain deposits (10% net sand). We measured nine sedimentary characteristics related to fluvial system properties in both members along a down-paleoflow-oriented transect. The only significant change found between the two members is the composition and abundance of floodplain clay minerals. The transition in stacking density is coincident with a rapid increase in smectitic clay, interpreted to result from increased volcanic ash influx, at the expense of illitic clay. The ash was preferentially accumulated in the floodplain, either as airfall or carried in the wash load of rivers. Geometric calculations suggest that in order to generate the observed change in stacking pattern by the addition of volcanic ash alone, more than half of the flood-plain deposition would have to be composed of ash. An increase in ash supply would increase floodplain sedimentation rate and reduce the frequency of avulsion. Together these effects could reduce the stacking density by the requisite 50%. Dependence of stacking density on floodplain sedimentation rate highlights the danger in assuming changes in stacking density observed in alluvial sequences are mainly controlled by other external factors such as sea-level fluctuation, subsidence rate, or overall aggradation rates.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.

Slow slip events (SSEs) at the northern Hikurangi subduction margin, New Zealand, are among the best-documented shallow SSEs on Earth. International Ocean Discovery Program Expedition 375 was undertaken to investigate the processes and in situ conditions that underlie subduction zone SSEs at the northern Hikurangi Trough by (1) coring at four sites, including an active fault near the deformation front, the upper plate above the high-slip SSE sourc e region, and the incoming sedimentary succession in the Hikurangi Trough and atop the Tūranganui Knoll Seamount, and (2) installing borehole observatories in an active thrust near the deformation front and in the upper plate overlying the slow slip source region. Logging-while-drilling (LWD) data for this project were acquired as part of Expedition 372 (26 November 2017-4 January 2018; see th e Expedition 372 Preliminary Report for further details on the LWD acquisition program). Northern Hikurangi subduction margin SSEs recur every 1-2 years and thus provide an ideal opportunity to monitor deformation and associated changes in chemical and physical properties throughout the slow slip cycle. Sampling of material from the sedimentary section and oceanic basement of the subducting plate reveals the rock properties, composition, lithology, and structural character of material that is transported downdip into the SSE source region. A recent seafloor geodetic experiment raises the possibility that SSEs at northern Hikurangi may propagate all the way to the trench, indicating that the shallow thrust fault zone targeted during Expedition 375 may also lie in the SSE rupture area. Hence, sampling at this location provides insights into the composition, physical properties, and architecture of a shallow fault that may host slow slip. Expedition 375 (together with the Hikurangi subduction LWD component of Expedition 372) was designed to address three fundamental scientific objectives: (1) characterize the state and composition of the incoming plate and shallow plate boundary fault near the trench, which comprise the protolith and initial conditions for fault zone rock at greater depth and which may itself host shallow slow slip; (2) characterize material properties, thermal regime, and stress conditions in the upper plate above the core of the SSE source region; and (3) install observatories at an active thrust near the deformation front and in the upper plate above the SSE source to measure temporal variations in deformation, temperature, and fluid flow. The observatories will monitor volumetric strain (via pore pressure as a proxy) and the evolution of physical, hydrological, and chemical properties throughout the SSE cycle. Together, the coring, logging, and observatory data will test a suite of hypotheses about the fundamental mechanics and behavior of SSEs and their relationship to great earthquakes along the subduction interface.

The new technique of measuring frequency by optical lattice clocks now approaches to the relative precision of $(\Delta f/f)=O(10^{-18})$. We propose to place such precise clocks in space and to use Doppler tracking method for detecting low-frequency gravitational wave below 1 Hz. Our idea is to locate three spacecrafts at one A.U. distance (say at L1, L4 & L5 of the Sun-Earth orbit), and apply the Doppler tracking method by communicating "the time" each other. Applying the current available technologies, we obtain the sensitivity for gravitational wave with three or four-order improvement ($h_{\rm n}\sim 10^{-17}$ or $10^{-18}$ level in $10^{-5}$Hz -- $1$ Hz) than that of Cassini spacecraft in 2001. This sensitivity enables us to observe black-hole mergers of their mass greater than $10^5 M_\odot$ in the cosmological scale. Based on the hierarchical growth model of black-holes in galaxies, we estimate the event rate of detection will be 20-50 a year. We nickname "INO" (Interplanetary Network of Optical Lattice Clocks) for this system, named after Tadataka Ino (1745--1818), a Japanese astronomer, cartographer, and geodesist., Comment: 11 pages, 4 figures; added references; to be published in Int. J. Modern Physics D

Hokkaido Island in northern Japan is located in a cool temperate to boreal climate zone influenced by summer monsoons and typhoons during summer–autumn, while its eastern area is influenced by the subarctic Oyashio Current. Palynomorph (pollen and spores) distribution was investigated in surface sediments from the shelf and slope (40–2300 m water depth) in the offshore area of Tokachi Plain, central-eastern Hokkaido Island. The objective of this study was to examine the source, transportation, and deposition of palynomorphs in marine environments. The majority of palynomorphs were transported from the Tokachi coastal plain by both strong local winds from the mountain areas during the spring–summer and the floods caused by heavy monsoon and typhoon rainfall. Approximately 10% of all palynomorphs were transported from both southwest and west areas by the wind. Palynomorph transportation by the Oyashio Current could not be discriminated because the same vegetation is present in Hokkaido and the islands in upper streams of the Oyashio Current. The total grain abundance was dependent on water depth. High concentrations were observed at depths of 700–1500 m, which is a region associated with high levels of fine silt and clay, suggesting that the transportation and deposition of palynomorphs are controlled by their grain sizes. This study supported a strong correlation between the distribution of sediments and the concentration of palynomorphs.

Summary Noda epileptic rats (NERs) present with clinico-pathological manifestations reminiscent of human generalized tonic-clonic epilepsy. Thus, this strain of rat has been a model of primary, generalized, tonic-clonic epilepsy. However, the infrequency of seizures in these rats makes the assessment of antiepileptic drugs (AEDs) difficult. Therefore, traditional AEDs have only been tested in NERs against audiogenic seizures evoked by weekly acoustic priming from 3 to 22 weeks of age or by using the kindling procedure in adult animals. Adult NERs are susceptible to changes in their environment, such as bedding replacement or unpleasant sensory stimuli. In the present study, traditional AEDs—phenobarbital (PB) and sodium valproate (VPA)—were evaluated against seizures evoked by strong environmental stimuli in mature NERs that had not been previously primed. The number of animals presenting with seizures decreased in a dose-dependent manner following administration of either PB (dose range 1.0–5.0 mg/kg) or VPA (50 and 100 mg/kg). Consequently, the utility of NERs as a model of generalized tonic-clonic epilepsy was confirmed. This type of protocol can be used to further evaluate AEDs and test effects of chronic administration of AEDs.

A graph is a mathematical representation of a set of variables where some pairs of the variables are connected by edges. Common examples of graphs are railroads, the Internet, and neural networks. It is both theoretically and practically important to estimate the intensity of direct connections between variables. In this study, a problem of estimating the intrinsic graph structure from observed data is considered. The observed data in this study are a matrix with elements representing dependency between nodes in the graph. The dependency represents more than direct connections because it includes influences of various paths. For example, each element of the observed matrix represents a co-occurrence of events at two nodes or a correlation of variables corresponding to two nodes. In this setting, spurious correlations make the estimation of direct connection difficult. To alleviate this difficulty, a digraph Laplacian is used for characterizing a graph. A generative model of this observed matrix is proposed, and a parameter estimation algorithm for the model is also introduced. The notable advantage of the proposed method is its ability to deal with directed graphs, while conventional graph structure estimation methods such as covariance selections are applicable only to undirected graphs. The algorithm is experimentally shown to be able to identify the intrinsic graph structure.

This paper describes a concept study of an optional kick stage system named “PLUS (for Planetary mission, Long-duration small-thrust Upper Stage)” equipped with a relatively small-thrust engine for interplanetary missions. The thrust force of PLUS assumed in this study is a maximum 29.4 kN, which is relatively small, used to inject a payload into interplanetary orbit with sufficiently low gravity loss i.e. less than 2%, although two split delta-Vs such as the Russian Proton/Breeze-M will improve performance efficiency (Proton Launch System Mission Planner's Guide, 2009 [1]). The orbital maneuvering capability of PLUS system is evaluated through Mars orbital maneuvering simulations. In this study, two types of PLUS systems are assumed. First, a 29.4 kN thrust force kicks stage system designated as “PLUS1” to inject the 3000 kg main payload into Mars transfer orbit. Second, a 9.8 kN thrust force small PLUS system designated as “PLUS2” to inject a 500 kg secondary payload into Mars transfer orbit. In the first case, the above-mentioned split delta-Vs are conducted to inject the main payload into Mars transfer orbit with sufficiently low gravity loss. In the second case, on the other hand, PLUS2 attached to the secondary payload is dual launched together with a primary payload into a geostationary transfer orbit, GTO, whereupon PLUS2 is initiated slightly before perigee to inject the secondary payload into Mars transfer orbit utilizing Electric delta-V Earth Gravity Assist, EDVEGA scheme via the on-board Ion Electric propulsion System, IES (Kawaguchi, 2001 2 and 3). Throughout the simulations, some optimized configurations of PLUS system covering a wide variety of space missions are suggested in this paper., 資料番号: PA1410024000

In Japan and South-East Asia Countries, Basketry is a heritage handcraft made with natural material such as bamboo strip and wheat straw. Shape and size of basketry products are depended on the basketry pattern and now FDM (Fused Deposition Modelling) 3D printer is used to a print the basketry pattern. This paper will present a bit further in epoxy coating on basketry products to make it more rigid and better shining appearance either while the coated basketry still have the 3D printing model inside as a structure or it will be taken off after coating epoxy. There are a lot of makers who try to use the 3D printed model for resin casting mold but many are fail to get the casted out of the 3D printed mold. Thus we do this preliminary study to investigate the adhesive strength of the casting epoxy resin holding on the 3D FDM printed model. An experiment was designed to find the effect of the curing time and the bamboo fiber adding for resin reinforce. In experiment, a flat dog-bone shape specimen for tensile testing is redesigned by separating into 2 identical parts and they are printed with ABS plastic filament. We glue epoxy resin on 12.5 X 10 mm. contact area in middle of the specimen. We left them cure and dry for 6, 12, and 24 hours before tensile testing then repeat the experiment again with bamboo strip added in between the contact area. The result of the experiment shows that bamboo strip reinforce and curing time affect the adhesive strength.

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor α, monocyte chemotactic protein-1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome.

[1] Mass transport is an important process of sediment redistribution from shallow to deep sea basins. It is vital to understand this process for disaster prevention and protection of economic interests in coastal and offshore areas. We describe mass transport-dominated sedimentation in an active foreland basin, the Hidaka Trough, which developed from collision between the northeastern Japan arc and the Kuril arc. The basin is deformed by east-west compression associated with large, frequent earthquakes. The trough is filled with thick (>4.5 km) sediments, ranging from coal-bearing Cretaceous terrestrial strata to modern diatomaceous hemipelagic mud and volcanic ash. Bottom-simulating reflectors and the distribution of mud volcanoes, pockmarks, and acoustic wipe-out zones on the seismic records suggest the presence of subsurface gases in the sediments. The basin features stacked mass transport deposits (MTDs), but no channel-levee systems have developed. The MTDs are relatively thin (

Background and aim. Sodium-glucose cotransporter (SGLT) 2 is a specifically expressed transporter in the kidney that plays an important role in renal glucose reabsorption, and its inhibition may present a novel therapeutic strategy for treating diabetes. Here, we pharmacologically characterized YM543, a newly synthesized SGLT2 selective inhibitor to test this theory. Results. In vitro studies revealed that YM543 potently and selectively inhibited mouse and human SGLT2 activities at nanomolar ranges. In vivo single oral administration of YM543 dose-dependently and significantly reduced blood glucose levels and improved glucose tolerance with a concomitant increase in urinary glucose excretion in KK/Ay type 2 diabetic mice, effects that were sustained even after 12 h. Repeated once-daily oral administration of YM543 for 5 weeks significantly reduced hyperglycemia in type 2 diabetic mice. In addition, combination treatment of YM543 with rosiglitazone or metformin additively improved diabetic symptoms. In con...