Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. ...Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.
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•2.1-, 2.1-, and 2.5-Å GLP-1R:Gs structures bound to GLP-1 and non-peptide agonists•Critical water networks stabilize peptide and small-molecule agonist binding•PF 06882961, but not CHU-128, closely mimics the GLP-1 signaling profile•Insight into how select non-peptide agonists mimic receptor activation by GLP-1
Zhang et al. show that the non-peptide GLP-1R agonist PF 06882961, but not CHU-128, was able to closely mimic the in vitro pharmacological fingerprint of GLP-1. These pharmacological activities could be rationalized from high-resolution structures that provide a novel template for the design of new agonists targeting the GLP-1R.
Lenses of eclogites (the Tulepsai complex) that formed at the peak of metamorphism at
P
= 15 kbar and
T
= 700–750°C and experienced decompression at 12 kbar (granulite-facies metamorphism) are ...located among the amphibolite sequences in the Eastern Mugodzhar Zone. The insignificant difference between the age of zircon cores, which, we believe, formed under the conditions of the eclogite-facies metamorphism (374 ± 4 Ma) at depths of 50–60 km (?) and the age of their rims (372 ± 6 Ma) formed during the isothermal decrease in pressure up to 12 kbar (25–35 km?) may indicate a rapid uplift of eclogites from considerable depths. Rutile extracted from eclogites yields a U–Pb age at 360 ± 2 Ma and reflects a later stage of rock transformation at 630–690 ± 40°C. The Maksyutov eclogite–glaucophane–schist and Tulepsai complexes are structural analogs of similar age and compose the lower allochthons on different branches of the Magnitogorsk synform. The complexes were formed in a similar geodynamic setting at the arc–continent collision.
The paper is devoted to the study of the general relations of the theory of torsion of rods from an ideal rigid-plastic anisotropic material. In this case, it is assumed that the rod is under the ...action of an external pressure that varies linearly along its generatrix. The stress-strain state of an anisotropic rod is determined under an arbitrary condition of plasticity. Equations for the characteristics of general relations and the stress and strain components along these characteristics are found.
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The ...genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal–contractile coupling.
At present, ontology is widely used for the formalization and systematization of knowledge and data in various subject areas. To facilitate and accelerate the process of developing ontologies, ...ontology design patterns have recently been used, which are formal descriptions of solutions to typical problems of ontological modeling proven in practice. The most popular type of ontology design patterns are content patterns that support a uniform and consistent representation of all the entities of the simulated subject area. The article gives a brief overview of ontology design patterns and proposes a methodology for constructing ontologies of scientific subject areas, the main feature of which is the use of basic ontologies and content patterns, and analyzes the experience of using this methodology in the construction of ontologies of various scientific subject areas.
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Vaterite particles are prospective biocompatible carriers for PDT.The proposed carriers are capable of cellular uptake.Encapsulation increases local PS concentration inside cells ...improving phototoxicity.Vaterite particles encourage reduction of PS therapeutic dose.
The elaboration of biocompatible and biodegradable carriers for photosensitizer targeted delivery is one of the most promising approaches in a modern photodynamic therapy (PDT). This approach is aimed at reducing sides effects connected with incidental toxicity in healthy tissue whilst also enhancing drug accumulation in the tumour area. In the present work, Photosens-loaded calcium carbonate (CaCO3) submicron particles in vaterite modification are proposed as a novel platform for anticancer PDT. Fast penetration of the carriers (0.9±0.2μm in diameter) containing 0.12% (w/w) of the photosensitizer into NIH3T3/EGFP cells is demonstrated. The captured particles provide the dye localization inside the cell increasing its local concentration, compared with ⿿free⿿ Photosens solution which is uniformly distributed throughout the cell. The effect of photosensitizer encapsulation into vaterite submicron particles on cell viability under laser irradiation (670nm, 19mW/cm2, 10min) is discussed in the work. As determined by a viability assay, the encapsulation renders Photosens more phototoxic. By this means, CaCO3 carriers allow improvement of the photosensitizer effectiveness supposing, therefore, the reduction of therapeutic dose. Summation of these effects with the simplicity, upscalability and cheapness of fabrication, biocompatibility and high payload ability of the vaterite particles hold out the prospect of a novel PDT platform.
The kinetics of atmospheric hydrochloric acid leaching of the iron-containing slime formed during quartz–leucoxene sandstone beneficiation is studied. The calculated activation energies indicate two ...temperature ranges of the slime leaching: a diffusion kinetic region at 40–70°C (
E
a
= 35.79–36.56 kJ/mol) and a kinetic region at 70–80°C (
E
a
= 48.68 kJ/mol). A steplike character of the development of slime during the leaching of iron-containing minerals from it is revealed, which is caused by the consecutive processes of siderite and hematite decomposition and a change in the process rate as the solution is saturated with iron ions.
The lead-free (1-x)Bi4Ti3O12/xBi4.5K0.5Ti4O15 composites (x = 0–0.4) have been synthesized by solid state reaction method. Evolution of microstructure and electric properties has been investigated ...with varying composition ratio. X-ray diffraction, Raman and IR absorption confirm the crystal transition tendency from orthorhombic to tetragonal phase. Evident texture along c-axis crystallographic orientation is observed in structure and morphology characteristics with x = 0.05 and 0.1. Through modulating the mole ratio of Bi4.5K0.5Ti4O15, coexistence of ferroelectric order and relaxor state is verified by the variation of ferroelectric hysteresis loops and polarization current density. This behavior can be attributed to the uncertain stability of discernable ferroelectric order induced by electric field among polar nanoregions during symmetry distoration. Temperature dependence of dielectric properties suggests an excellent thermal stability during a wide temperature range. Moreover, the detailed dielectric mechanism has been analyzed via various methods. Electrical conduction in grains and grain boundaries respectively plays the different role during the varying temperature process.
•(1-x)Bi4Ti3O12/xBi4.5K0.5Ti4O15 (x = 0–0.4) are synthesized by solid state reaction.•Crystal transition from orthorhombic to tetragonal phase can be observed.•Electric properties show a coexistence of ferroelectric order and relaxor state.•Electric response exhibits mixed conductivity mechanisms for varying temperature.
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