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Sulfotransferases (STs) catalyze the transfer reaction of the sulfate group from the ubiquitous donor 3 -phosphoadenosine 5 -phosphosulfate (PAPS) to an acceptor group of numerous substrates. This reaction, often referred to as sulfuryl transfer, sulfation, or sulfonation, is widely observed from bacteria to humans and plays a key role in various biological processes such as cell communication, growth and development, and defense. The cytosolic STs sulfate small molecules such as steroids, bioamines, and therapeutic drugs, while the Golgi-membrane counterparts sulfate large molecules including glucosaminylglycans and proteins. We have now solved the X-ray crystal structures of four cytosolic and one membrane ST. All five STs are globular proteins composed of a single ␣/␤ domain with the characteristic five-stranded ␤-sheet. The ␤-sheet constitutes the core of the Paps-binding and catalytic sites. Structural analysis of the PAPS-, PAP-, substrate-, and/or orthovanadate (VO 4 3؊ )-bound enzymes has also revealed the common molecular mechanism of the transfer reaction catalyzed by sulfotransferses. The X-ray crystal structures have opened a new era for the study of sulfotransferases.

In cells capable of entering the cell cycle, including cancer cells, ␤-catenin has been termed a master switch, driving proliferation over differentiation. However, its role as a transcriptional activator in terminally differentiated cells is relatively unknown. Herein we utilize conditional, cardiac-specific deletion of the ␤-catenin gene and cardiac-specific expression of a dominant inhibitory mutant of Lef-1 (Lef-1⌬20), one of the members of the T-cell factor/lymphocyte enhancer factor (Tcf/Lef) family of transcription factors that functions as a coactivator with ␤-catenin, to demonstrate that ␤-catenin/Tcf/Lef-dependent gene expression regulates both physiologic and pathological growth (hypertrophy) of the heart. Indeed, the profound nature of the growth impairment of the heart in the Lef-1⌬20 mouse, which leads to very early development of heart failure and premature death, suggests ␤-catenin/Tcf/Lef targets are dominant regulators of cardiomyocyte growth. Thus, our studies, employing complementary models in vivo, implicate ␤-catenin/Tcf/Lef signaling as an essential growth-regulatory pathway in terminally differentiated cells.

Estrogen sulfotransferase (EST) transfers the sulfate group from 3-phosphoadenosine 5-phosphosulfate (PAPS) to estrogenic steroids. Here we report the crystal structure of human EST (hEST) in the context of the V269E mutant-PAPS complex, which is the first structure containing the active sulfate donor for any sulfotransferase. Superimposing this structure with the crystal structure of hEST in complex with the donor product 3-phosphoadenosine 5-phosphate (PAP) and the acceptor substrate 17␤-estradiol, the ternary structure with the PAPS and estradiol molecule, is modeled.

Certain hydroxylated polychlorinated biphenyls (OH-PCBs) inhibit the human estrogen sulfotransferase (hEST) at subnanomolar concentrations, suggesting a possible pathway for PCB toxicity due to environmental exposure in humans. To address the structural basis of the inhibition, we have determined the crystal structure of hEST in the presence of the sulfuryl donor product 3´-phosphoadenosine 5´-phosphate and the OH-PCB 4,4´-OH 3,5,3´,5´-tetraCB. The OH-PCB binds in the estrogen binding site with the position of the first phenolic ring in an orientation similar to the phenolic ring of 17β-estradiol. Interestingly, the OH-PCB does not bind in a planar conformation, but rather with a 30-degree twist between the phenyl rings. The crystal structure of hEST with the OH-PCB bound gives physical evidence that certain OH-PCBs can mimic binding of estrogenic compounds in biological systems.

Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine.

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This paper investigates the Lamb wave generation by the surface bonded circular piezoelectric (PZT) actuator and wave propagation within the orthotropic Carbon Fiber Reinforced Plastic (CFRP) plate considering the anisotropy of the elastic and damping properties of the materials; existence of the adhesive layer; and dependence of the interfacial stress distribution on the surface between host plate and actuator, on the anisotropy of the plate material, and on the excited frequency, wavelength and plate thickness. This part of our investigation includes FE based study of the shear stress distribution on the interface between circular PZT actuator and surface of orthotropic CFRP plate, and its dependence on the excited wavelength and plate thickness. The anisotropic elastic and damping properties of the plate material, which are used in the implemented finite element (FE) model, have been preliminary determined in the first part of our investigation. We compare the behavior of the wave generation, propagation and attenuation that are studied using this model with the similar dependencies obtained at the simulation of the non-dissipating plate excited by the periodical radially oriented force, which is distributed along the circumference bounding the actuator, i.e. 3D pin-force excitation case. The proposed results can be used at the design of SHM for the composite structures with the structural anisotropy and damping, and at making a reasonable choice of the frequency, type, dimensions and optimum placement of the actuators and sensors.