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Objectives: MicroRNAs (miRNA) are functional RNAs that have emerged as pivotal gene expression regulators in cardiac disease. Although several cardiomyocyte miRNAs have been reported to play roles in heart failure progression among patients with idiopathic dilated cardiomyopathy (DCM), the role of circulating miRNAs has not yet been well-examined. Methods: After total RNA extraction from the peripheral blood samples of three control participants and six patients with DCM, miRNA profiling was performed using miRNA arrays. Based on the results of this initial screening, real-time polymerase chain reaction (RT-PCR) was used to perform a quantitative analysis of blood samples from a larger number of matched patients (DCM, n=20; controls, n=5). Finally, the correlations between specific miRNA expression levels and hemodynamic parameters were analyzed. Results: A primary screening of 2,565 miRNAs resulted in the identification of nine miRNA candidates. Quantitative RT-PCR results revealed significantly increased miR-489 expression levels in the DCM group. Moreover, there was a significant positive correlation between miR-489 expression level and left ventricular ejection fraction. Conclusions: Our results suggest that circulating miR-489 could be a potential noninvasive diagnostic biomarker for DCM. Additionally, the quantification of circulating miR-489 may have value as a potential prognostic marker for patients with DCM.

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury., 腎障害における線維化の正の側面の発見 --線維化が腎臓を修復する--. 京都大学プレスリリース. 2019-01-18.

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The phase separation behaviors from the single B2 ordered phase into the two separate B2 and L2$_1$ ordered phases in the X-Al-Ti (X: Fe, Co, and Ni) alloys are analyzed using the cluster variation method (CVM) with the interaction energies evaluated from the electronic band structure calculations. The cubic approximation of the CVM is employed for the X$_2$Al$_{2-x}$Ti$_x$ ($0 \leq x \leq 2$) alloys limiting an interchange between Al and Ti atoms on the $\alpha$- and $\beta$-sublattices of the L2$_1$ ordered structure with the X atoms fixed on the $\gamma$-sublattice. The phase stabilities of the B2 and L2$_1$ structures are examined, and the phase diagrams at the pseudo-binary section, XAl-XTi, are determined. The two-phase regions of B2 and L2$_1$ phases, i.e., phase separation behavior, are successfully produced in both Co- and Ni-Al-Ti alloy systems, whereas no phase separation is predicted in the Fe-Al-Ti alloy. The origin of the phase separation in the Co- and Ni-Al-Ti alloys is, respectively, attributed to the mechanical instability and the combination of mechanical instability and chemical repulsions of unlike pairs., Comment: 8 pages, 5 figures

Steepest-entropy-ascent quantum thermodynamics (SEAQT) is a mathematical and theoretical framework for intrinsic quantum thermodynamics (IQT), a unified theory of quantum mechanics and thermodynamics. In the theoretical framework, entropy is viewed as a measure of energy load sharing among available energy eigenlevels, and a unique relaxation path of a system from an initial non-equilibrium state to a stable equilibrium is determined from the greatest entropy generation viewpoint. The SEAQT modeling has seen a great development recently. However, the applications have mainly focused on gas phases, where a simple energy eigenstructure (a set of energy eigenlevels) can be constructed from appropriate quantum models by assuming that gas-particles behave independently. The focus of this research is to extend the applicability to solid phases, where interactions between constituent particles play a definitive role in their properties so that an energy eigenstructure becomes quite complicated and intractable from quantum models. To cope with the problem, a highly simplified energy eigenstructure (so-called ``pseudo-eigenstructure") of a condensed matter is constructed using a reduced-order method, where quantum models are replaced by typical solid-state models. The details of the approach are given and the method is applied to make kinetic predictions in various solid-state phenomena: the thermal expansion of silver, the magnetization of iron, and the continuous/discontinuous phase separation and ordering in binary alloys where a pseudo-eigenstructure is constructed using atomic/spin coupled oscillators or a mean-field approximation. In each application, the reliability of the approach is confirmed and the time-evolution processes are tracked from different initial states under varying conditions (including interactions with a heat reservoir and external magnetic field) using the SEAQT equation of motion derived for each specific application. Specifically, the SEAQT framework with a pseudo-eigenstructure successfully predicts: (i) lattice relaxations in any temperature range while accounting explicitly for anharmonic effects, (ii) low-temperature spin relaxations with fundamental descriptions of non-equilibrium temperature and magnetic field strength, and (iii) continuous and discontinuous mechanisms as well as concurrent ordering and phase separation mechanisms during the decomposition of solid-solutions. Ph. D. Many engineering materials have physical and chemical properties that change with time. The tendency of materials to change is quantified by the field of thermodynamics. The first and second laws of thermodynamics establish conditions under which a material has no tendency to change; these conditions are called equilibrium states. When a material is not in an equilibrium state, it is able to change spontaneously. Classical thermodynamics reliably identifies whether a material is susceptible to change, but it is incapable of predicting how change will take place or how fast it will occur. These are kinetic questions that fall outside the purview of thermodynamics. A relatively new theoretical treatment developed by Hatsopoulos, Gyftopoulos, Beretta and others over the past forty years extends classical thermodynamics into the kinetic realm. This framework, called steepest-entropy-ascent quantum thermodynamics (SEAQT), combines the tools of thermodynamics with quantum mechanics through a postulated equation of motion. Solving the equation of motion provides a kinetic description of the path a material will take as it changes from a non-equilibrium state to stable equilibrium. To date, the SEAQT framework has been applied primarily to systems of gases. In this dissertation, solid-state models are employed to extend the SEAQT approach to solid materials. The SEAQT framework is used to predict the thermal expansion of silver, the magnetization of iron, and the kinetics of atomic clustering and ordering in binary solid-solutions as a function of time or temperature. The model makes it possible to predict a unique kinetic path from any arbitrary, non-equilibrium, initial state to a stable equilibrium state. In each application, the approach is tested against experimental data. In addition to reproducing the qualitative kinetic trends in the cases considered, the SEAQT framework shows promise for modeling the behavior of materials far from equilibrium.

This is the peer reviewed version of the following article: Ohto, T., Tashiro, A., Seo, T., Kawaguchi, N., Numai, Y., Tokumoto, J., Yamaguchi, S., Yamada, R., Tada, H., Aso, Y., Ie, Y., Single‐Molecule Conductance of a π‐Hybridized Tripodal Anchor while Maintaining Electronic Communication. Small 2020, 2006709., which has been published in final form at https://doi.org/10.1002/smll.202006709. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving., Direct hybridization between the π-orbital of a conjugated molecule and metal electrodes is recognized as a new anchoring strategy to enhance the electrical conductance of single-molecule junctions. The anchor is expected to maintain direct hybridization between the conjugated molecule and the metal electrodes, and control the orientation of the molecule against the metal electrodes. However, fulfilling both requirements is difficult because multipodal anchors aiming at a robust contact with the electrodes often break the π-conjugation, thereby resulting in an inefficient carrier transport. Herein, a new tripodal anchor framework—a 7,7-diphenyl-7H-benzo[6,7]indeno[1,2-b]thiophene (PBIT) derivative—is developed. In this framework, π-conjugation is maintained in the molecular junction, and the tripodal structure makes the molecule stand upright on the metal electrode. Molecular conductance is measured by the break junction technique. A vector-based classification and first-principles transport calculations determine the single-molecule conductance of the tripodal-anchoring structure. The conductance of the PBIT-based molecule is higher than that of the tripodal anchor having sp3 carbon atoms in the carrier transport pathway. These results demonstrate that extending the π-conjugation to the tripodal leg is an effective strategy for enhancing the conductivities of single-molecule junctions.

Steepest-entropy-ascent quantum thermodynamics, or SEAQT, is a unified approach of quantum mechanics and thermodynamics that avoids many of the inconsistencies that can arise between the two theories. Given a set of energy levels, i.e., energy eigenstructure, accessible to a given physical system, SEAQT predicts the unique kinetic path from any initial non-equilibrium state to stable equilibrium by solving a master equation that directs the system along the path of steepest entropy ascent. There are no intrinsic limitations on the length and time scales the method can treat so it is well-suited for calculations where the dynamics over multiple spacial scales need to be taken into account within a single framework. In this paper, the theoretical framework and its advantages are described, and several applications are presented to illustrate the use of the SEAQT equation of motion and the construction of a simplified, reduced-order, energy eigenstructure., 18 pages

The kinetics of ordering and concurrent ordering and clustering is analyzed with an equation of motion initially developed to account for dissipative processes in quantum systems. A simplified energy eigenstructure, or pseudo-eigenstructure, is constructed from a static concentration wave method to describe the configuration-dependent energy for atomic ordering and clustering in a binary alloy. This pseudo-eigenstructure is used in conjunction with an equation of motion that follows steepest entropy ascent to calculate the kinetic path that leads to ordering and clustering in a series of hypothetical alloys. By adjusting the thermodynamic solution parameters, it is demonstrated that the model can predict the stable equilibrium state as well as the unique thermodynamic path and kinetics of continuous/discontinuous ordering and concurrent processes of simultaneous ordering and phase separation., Comment: 10 pages

Disruption of wild type acceptor site by the single nucleotide variants (c.853-2Aâ >â G) predicted from in silico programs. (PDF 184Â kb)

Creation of the new splice acceptor site by the three base insertion (NM_001204.6:c.1277-10_1277-9insGGG) predicted from in silico programs. (PDF 218Â kb)

Disruption of wild type acceptor site by the single nucleotide variants (c.853-2Aâ >â G) predicted from in silico programs. (PDF 184Â kb)

Possible pathogenic variants found in the intron of BMPR2 in family 4. A rare three base insertion (GGG) at 10 bases upstream from exon 10 creates identical sequences around the canonical splicing site (ACAGGG). By the insertion, an out-of-frame protein could be translated due to the new splice acceptor site. (PDF 411Â kb)

Summary of mapping statistics. (PDF 22Â kb)

Large deletion found in the patient in family 8. (a) The large deletion was supported by depth of coverage and discordant paired-end reads. (b) The length of the deletion was approximately 6.5 kilobases and spanned the entire region of exon 3. Breakpoints of the large heterozygous deletion were located in the Alu repeat sequences, which were supported by read depths and paired-end reads spanning the long region. (PDF 529Â kb)

Possible pathogenic variants found in the intron of BMPR2 in family 4. A rare three base insertion (GGG) at 10 bases upstream from exon 10 creates identical sequences around the canonical splicing site (ACAGGG). By the insertion, an out-of-frame protein could be translated due to the new splice acceptor site. (PDF 411Â kb)

Creation of the new splice acceptor site by the three base insertion (NM_001204.6:c.1277-10_1277-9insGGG) predicted from in silico programs. (PDF 218Â kb)

Chronic obstructive pulmonary disease (COPD) is a possible risk factor for cardiovascular disease. The association of COPD with the pathogenicity of infection with Chlamydia pneumoniae and Mycoplasma pneumoniae is controversial. We conducted a cross-sectional study to clarify the association between atypical pneumoniae seropositivity and COPD in a general population. We also investigated genetic polymorphisms conferring susceptibility to a pneumonia titer. The study included 9040 Japanese subjects (54±13 years). COPD was defined as a ratio of forced expiratory volume in 1 second to forced vital capacity of less than 70%. Serum levels of IgA and IgG antibodies to C pneumoniae were determined using an enzyme-linked immunoassay, and M pneumoniae seropositivity was assessed by a particle agglutination test. Subjects seropositive for C pneumoniae (26.1%) had a higher prevalence of COPD (seropositive, 5.8%; seronegative, 3.1%; P

Padi2 and Padi4 are expressed in the spleens of wild-type mice. (a–e) Immunofluorescence staining (×40) shows that Padi2 is expressed ubiquitously in the spleen. Spleens were probed with anti-Padi2 (green fluorescent signal) and cell surface markers (red fluorescence signal; a, CD3; b, B220; c, Gr-1; d, CD56; e, F4/80). The nuclei were stained with DAPI (blue fluorescence signal). The arrows indicate the colocalization of Padi2 and each cell surface marker. (f–k) Immunofluorescence staining (×40) shows that Padi4 was expressed in splenocytes. The spleens were probed with anti-Padi4 (green fluorescence signal), and cell surface markers (red fluorescence signal; f, CD3; g, B220; h, Gr-1; i, CD56; j, F4/80). Nuclei were stained with DAPI (blue fluorescence signal). (K) Immunofluorescence staining (left, ×40; right, ×280) shows that Padi4 was localized in both the nuclei and cytoplasm of macrophages, which expressed F4/80. (PDF 286 KB)

Padi2 and Padi4 expression in NK1.1+ cells. mRNA levels were determined by real-time TaqMan RT-PCR using NK1.1+ cells as a reference for GAPDH normalization. Padi2 and Padi4 mRNA expressions were not different between wild-type collagen-induced arthritis (CIA) (n = 10) and control (n = 8) mice spleens. (PDF 209 KB)

Cytokine mRNA expression in CD11b + macrophages in the spleen. CD11b + wild-type (n = 19) and Padi4−/− CIA mice (n = 17) were used for 10 days from the day after booster injection. The cells were analyzed by real-time TaqMan RT-PCR for mRNA levels of (a) tumor necrosis factor alpha (TNF-α), (b) CSF-2, (c) IL-1β, (d) IL-6, and (e) IL-10. *P

Generation of a Padi4−/− mouse. (a) Genomic structure of A Padi4−/− mouse. A 5837-bp fragment containing exon 1 and intron 1 of Padi4 was inserted to the targeting vector. We constructed the targeting vector to replace exon 1 and intron 1, including the transcription initiation site, using mouse PGK-1 promoter and the neomycin-resistance gene. We confirmed the knockout condition by Southern blotting (b) and RT-PCR (c). (d) Distributions of immune cells in the spleen of wild-type (n = 3) and Padi4−/− (n = 3) mice were analyzed by FACS. (e) Hematoxylin and eosin (HE) staining of Padi4-expressed tissues from the wild-type (WT) mouse, Padi4+/− (Heterozygote) mouse, and Padi4−/− (KO) mouse. (PDF 458 KB)

Rheumatoid arthritis (RA) is a joint-destructive autoimmune disease. Three composite indices evaluating the same 28 joints are commonly used for the evaluation of RA activity. However, the relationship between, and the frequency of, the joint involvements are still not fully understood. Here, we obtained and analyzed 17,311 assessments for 28 joints in 1,314 patients with RA from 2005 to 2011 from electronic clinical chart templates stored in the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. Affected rates for swelling and tenderness were assessed for each of the 28 joints and compared between two different sets of RA patients. Correlations of joint symptoms were analyzed for swellings and tenderness using kappa coefficient and eigen vectors by principal component analysis. As a result, we found that joint affected rates greatly varied from joint to joint both for tenderness and swelling for the two sets. Right wrist joint is the most affected joint of the 28 joints. Tenderness and swellings are well correlated in the same joints except for the shoulder joints. Patients with RA tended to demonstrate right-dominant joint involvement and joint destruction. We also found that RA synovitis could be classified into three categories of joints in the correlation analyses: large joints with wrist joints, PIP joints, and MCP joints. Clustering analysis based on distribution of synovitis revealed that patients with RA could be classified into six subgroups. We confirmed the symmetric joint involvement in RA. Our results suggested that RA synovitis can be classified into subgroups and that several different mechanisms may underlie the pathophysiology in RA synovitis.