Modelling lead-rubber seismic isolation bearings using the unified mechanics theory

Lead-rubber seismic isolation bearings (LRB) have been installed in a number of essential and critical structures, like hospitals, universities and bridges, in order to provide them with period lengthening and the capacity of dissipating a considerable amount of energy to mitigate the effects of strong ground motions. Therefore, studying the damage mechanics of this kind of devices is fundamental to understand and accurately describe their thermo-mechanical behavior, so that seismically isolated structures can be designed more safely. Hitherto, the hysteretic behavior of LRB has been modeled using 1) Newtonian mechanics and empirical curve fitting degradation functions, or 2) heat conduction theories and idealized bilinear curves which include degradation effects. The reason for using models that are essentially phenomenological or that contain some adjusted parameters is the fact that Newton’s universal laws of motion lack the term to account for degradation and energy loss of a system. In this paper, the Unified Mechanics Theory – which integrates laws of Thermodynamics and Newtonian mechanics – is used to model the force-displacement response of LRB. Indeed, there is no need for curve fitting techniques to describe their damage behavior because degradation is calculated at every point using entropy generation along the Thermodynamics State Index (TSI) axis. A finite element model of a lead-rubber bearing was constructed in ABAQUS, where a user material subroutine UMAT was implemented to define the Unified Mechanics Theory equations and the viscoplastic constitutive model for lead. Finite element analysis results were compared with experimental test data.

Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine

Dysregulated circadian functions contribute to various diseases, including cardiovascular disease. Much progress has been made on chronotherapeutic applications of drugs against cardiovascular disease (CVD); however, the direct effects of various medications on the circadian system are not well characterized. We previously conducted high-throughput chemical screening for clock modulators and identified an off-patent anti-arrhythmic drug, moricizine, as a clock-period lengthening compound. In Per2:LucSV reporter fibroblast cells, we showed that under both dexamethasone and forskolin synchronization, moricizine was able to increase the circadian period length, with greater effects seen with the former. Titration studies revealed a dose-dependent effect of moricizine to lengthen the period. In contrast, flecainide, another Class I anti-arrhythmic, showed no effects on circadian reporter rhythms. Real-time qPCR analysis in fibroblast cells treated with moricizine revealed significant circadian time- and/or treatment-dependent expression changes in core clock genes, consistent with the above period-lengthening effects. Several clock-controlled cardiac channel genes also displayed altered expression patterns. Using tissue explant culture, we showed that moricizine was able to significantly prolong the period length of circadian reporter rhythms in atrial ex vivo cultures. Using wild-type C57BL/6J mice, moricizine treatment was found to promote sleep, alter circadian gene expression in the heart, and show a slight trend of increasing free-running periods. Together, these observations demonstrate novel clock-modulating activities of moricizine, particularly the period-lengthening effects on cellular oscillators, which may have clinical relevance against heart diseases.

Phenotypic proteomic profiling identifies a landscape of targets for circadian clock–modulating compounds

Determining the exact targets and mechanisms of action of drug molecules that modulate circadian rhythms is critical to develop novel compounds to treat clock-related disorders. Here, we have used phenotypic proteomic profiling (PPP) to systematically determine molecular targets of four circadian period–lengthening compounds in human cells. We demonstrate that the compounds cause similar changes in phosphorylation and activity of several proteins and kinases involved in vital pathways, including MAPK, NGF, B-cell receptor, AMP-activated protein kinases (AMPKs), and mTOR signaling. Kinome profiling further indicated inhibition of CKId, ERK1/2, CDK2/7, TNIK, and MST4 kinases as a common mechanism of action for these clock-modulating compounds. Pharmacological or genetic inhibition of several convergent kinases lengthened circadian period, establishing them as novel circadian targets. Finally, thermal stability profiling revealed binding of the compounds to clock regulatory kinases, signaling molecules, and ubiquitination proteins. Thus, phenotypic proteomic profiling defines novel clock effectors that could directly inform precise therapeutic targeting of the circadian system in humans.

RNA Splicing Factor Mutations That Cause Retinitis Pigmentosa Result in Circadian Dysregulation

Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindness, have a role in the brain circadian clock. In this study, we report circadian phenotypes in murine models of RP. We found that mice carrying a homozygous H2309P mutation in Pre-mRNA splicing factor 8 ( Prpf8) display a lengthened period of the circadian wheel-running activity rhythm. We show also that the daily cycling of circadian gene expression is dampened in the retina of Prpf8-H2309P mice. Surprisingly, molecular rhythms are intact in the eye cup, which includes the retinal pigment epithelium (RPE), even though the RPE is thought to be the primary tissue affected in this form of RP. Downregulation of Prp31, another RNA splicing factor implicated in RP, leads to period lengthening in a human cell culture model. The period of circadian bioluminescence in primary fibroblasts of human RP patients is not significantly altered. Together, these studies link a prominent retinal disorder to circadian deficits, which could contribute to disease pathology.

Generation of strong casein kinase 1 inhibitor of Arabidopsis thaliana

Casein kinase 1 (CK1) is an evolutionarily conserved protein kinase among eukaryotes. Studies on yeast, fungi, and animals have revealed that CK1 plays roles in divergent biological processes. By contrast, the collective knowledge regarding the biological roles of plant CK1 lags was behind those of animal CK1. One of reasons for this is that plants have more multiple genes encoding CK1 than animals. To accelerate the research for plant CK1, a strong CK1 inhibitor that efficiently inhibits multiple members of CK1 proteins in vivo (in planta) is required. Here, we report a novel strong CK1 inhibitor of Arabidopsis (AMI-331). Using a circadian period-lengthening activity as estimation of the CK1 inhibitor effect in vivo, we performed a structure-activity relationship (SAR) study of PHA767491 (1,5,6,7-tetrahydro-2-(4-pyridinyl)-4H-pyrrolo[3,2-c]pyridin-4-one hydrochloride), a potent CK1 inhibitor of Arabidopsis, and found that PHA767491 analogues bearing a propargyl group at the pyrrole nitrogen atom (AMI-212) or a bromine atom at the pyrrole C3 position (AMI-23) enhance the period-lengthening activity. The period lengthening activity of a hybrid molecule of AMI-212 and AMI-23 (AMI-331) is about 100-fold stronger than that of PHA767491. An in vitro assay indicated a strong inhibitory activity of CK1 kinase by AMI-331. Also, affinity proteomics using an AMI-331 probe showed that targets of AMI-331 are mostly CK1 proteins. As such, AMI-331 is a strong potent CK1 inhibitor that shows promise in the research of CK1 in plants.

Effect of Height Ratio and Mass Ratio on Structure—Soil—Structure Interaction of Two Structures Using Centrifugal Experiment

: In a megacity, structure response during an earthquake could be increased or decreased due to effects from neighboring structures, through structure-soil-structure interaction (SSSI). In the present study, a series of dynamic geotechnical centrifuge tests are carried out to investigate SSSI effects on responses of structure with various characteristics of mass, height, and natural frequency. Experimental observations are focused on the effects of the distance between two structures, type, and peak acceleration of input excitation. A period lengthening is observed in the soil-foundation-structure interaction (SFSI) effects of all structures. It is monitored that an increment in response of smaller structure and a decrement in response of larger structure, compared to isolated structure, due to SSSI effects. Unfavorable distance reveals that the most significant increment in response of S2 structure occurred at approximately one-fourth of wavelength transmitted from the vibrating adjacent structure. More severe SSSI effects are found under a lower input earthquake acceleration. It is found that both height and mass ratios, between two adjacent structures, are particular parameters on SSSI, resulting in increment or reduction of structure response.