Segregation of a QTL cluster for home-cage activity using a new mapping method based on regression analysis of congenic mouse strains.

Recent genetic studies have shown that genetic loci with significant effects in whole-genome quantitative trait loci (QTL) analyses were lost or weakened in congenic strains. Characterisation of the genetic basis of this attenuated QTL effect is important to our understanding of the genetic mechanisms of complex traits. We previously found that a consomic strain, B6-Chr6C(MSM), which carries chromosome 6 of a wild-derived strain MSM/Ms on the genetic background of C57BL/6J, exhibited lower home-cage activity than C57BL/6J. In the present study, we conducted a composite interval QTL analysis using the F2 mice derived from a cross between C57BL/6J and B6-Chr6C(MSM). We found one QTL peak that spans 17.6 Mbp of chromosome 6. A subconsomic strain that covers the entire QTL region also showed lower home-cage activity at the same level as the consomic strain. We developed 15 congenic strains, each of which carries a shorter MSM/Ms-derived chromosomal segment from the subconsomic strain. Given that the results of home-cage activity tests on the congenic strains cannot be explained by a simple single-gene model, we applied regression analysis to segregate the multiple genetic loci. The results revealed three loci (loci 1-3) that have the effect of reducing home-cage activity and one locus (locus 4) that increases activity. We also found that the combination of loci 3 and 4 cancels out the effects of the congenic strains, which indicates the existence of a genetic mechanism related to the loss of QTLs.

Clinical associations and risk factors for bleeding from colonic angiectasia: a case-controlled study.

AIM: A case-controlled study was performed to investigate the association of colonic angiectasia with other conditions and to identify risk factors for bleeding. METHOD: Information was collected from all patients who underwent colonoscopy at our hospital between January 2008 and December 2010. Data on 90 individuals with angiectasia [58 men; median age 69 (26-92) years] were compared with those of 180 individuals without angiectasia, matched for gender and age. RESULTS: Multivariate analysis showed that occult gastrointestinal bleeding [odds ratio (OR) 2.523; 95% confidence interval (CI) 1.238-5.142], liver cirrhosis (OR 13.195; 95% CI 3.502-49.711), chronic renal failure (OR 6.796; 95% CI 1.598-28.904) and valvular heart disease (OR 6.425; 95% CI 1.028-40.165) were identified as significant predictors of the presence of colonic angiectasia. Eight patients were diagnosed with bleeding from angiectasia. Cardiovascular disease (OR 22.047; 95% CI 1.063-457.345) and multiple angiectasias (P-value 0.0019) were identified as significant risk factors for active bleeding. Medication and a large size were not associated with an increased risk of bleeding. CONCLUSION: The presence of colonic angiectasia was associated with valvular heart disease, liver cirrhosis and chronic renal failure. Valvular heart disease and multiple lesions increased the risk of bleeding.

Perturbative expansion of irreversible work in symmetric and asymmetric processes.

The systematic expansion method of the solution of the Fokker-Planck equation is developed by generalizing the formulation proposed in [J. Phys. A: Math. Theor. 50, 325001 (2017)10.1088/1751-8121/aa7af4]. Using this method, we obtain an alternative formula to calculate the mean work perturbatively which is applicable to systems with degeneracy in the eigenvalues of the Fokker-Planck operator. This method enables us to study how the geometrical symmetry affects thermodynamic description of a Brownian particle. To illustrate the application of the derived theory, we consider the Fokker-Planck equation with a two-dimensional harmonic potential. To investigate the effect of symmetry of the potential, we study thermodynamic properties in symmetric and asymmetric deformation processes of the potential: the rotational symmetry of the harmonic potential is held in the former, but it is broken in the latter. Optimized deformations in these processes are defined by minimizing mean work. Comparing these optimized processes, we find that the difference between the symmetric and asymmetric processes is maximized when the deformation time of the potential is given by a critical time which is characterized by the relaxation time of the Fokker-Planck equation. This critical time in the mean work is smaller than that of the change of the mean energy because of the hysteresis effect in the irreversible processes.

Dissipative relativistic fluid dynamics: a new way to derive the equations of motion from kinetic theory.

We rederive the equations of motion of dissipative relativistic fluid dynamics from kinetic theory. In contrast with the derivation of Israel and Stewart, which considered the second moment of the Boltzmann equation to obtain equations of motion for the dissipative currents, we directly use the latter's definition. Although the equations of motion obtained via the two approaches are formally identical, the coefficients are different. We show that, for the one-dimensional scaling expansion, our method is in better agreement with the solution obtained from the Boltzmann equation.

Inhibition of DNA synthesis in chick embryo cultures by deprivation of either serum or zinc.

The rate of DNA synthesis in cultures of chick embryo cells is proportional to the concentration of serum added. The concentration of serum required to stimulate DNA synthesis increases with cell population density and with the duration of culture after trypsinization. The increase of the serum requirement with population density is not caused by the depletion of serum constituents. The requirement of cells for external zinc in DNA synthesis also increases with population density and duration of culture. The kinetics of inhibition of DNA synthesis by deprivation of serum or zinc are similar. Serum deprivation, however, inhibits 2-deoxyglucose uptake and cell movement, but zinc deprivation does not. The deprivation of either serum or zinc inhibits RNA synthesis about twofold. Very low concentrations of actinomycin D prevent the resumption of RNA and DNA synthesis upon restoration of serum or zinc to deprived cultures.

Raman scattering study of multiferroic Ho(3)Fe(5)O(12) thin films.

Ho(3)Fe(5)O(12) crystallizes in a body-centered cubic lattice and shows no ferroelectricity because of its highly symmetric (centrosymmetric) crystal structure. However, in heteroepitaxially grown thin films, Ho(3)Fe(5)O(12) may exhibit ferroelectricity because of lattice strains induced by the substrate. In this work, heteroepitaxial films of Ho(3)Fe(5)O(12) were grown with different thicknesses of 50-160 nm and studied by x-ray diffraction and Raman scattering. The results were compared with those of bulk polycrystals to characterize residual strains. At room temperature, Raman spectra of films revealed a phonon frequency shift from those of bulk samples, showing lattice distortion. There was a difference in the lattice distortion scheme between the thinner and thicker films. Results of x-ray diffraction were well correlated with the Raman data. Raman measurements at 300-800 K showed the existence of lattice strain up to ∼650 K. This suggests a remanent-polarization character of Ho(3)Fe(5)O(12) films up to this temperature. Closeness between the magnetic ordering temperature T(N) = 567 K and T(C)∼650 K may bring us the ideal multiferroic material with an enhanced magnetoelectric effect at room temperature.

Transport coefficients of non-Newtonian fluid and causal dissipative hydrodynamics.

A formula to calculate the transport coefficients of the causal dissipative hydrodynamics is derived by using the projection operator method (Mori-Zwanzig formalism) [T. Koide, Phys. Rev. E 75, 060103(R) (2007)]. This is an extension of the Green-Kubo-Nakano (GKN) formula to the case of non-Newtonian fluids, which is the essential factor to preserve the relativistic causality in relativistic dissipative hydrodynamics. This formula is the generalization of the GKN formula in the sense that it can reproduce the GKN formula in a certain limit. In this work, we extend the previous work so as to apply to more general situations.

Microscopic formula for transport coefficients of causal hydrodynamics.

The Green-Kubo-Nakano formula should be modified in relativistic hydrodynamics because of the problem of acausality and the breaking of sum rules. In this Rapid Communication, we propose a formula to calculate the transport coefficients of causal hydrodynamics based on the projection operator method. As concrete examples, we derive the expressions for the diffusion coefficient, the shear viscosity coefficient, and corresponding relaxation times.

Transplantation of human tumors in nude mice.

Ninety-one human tumors, including various common carcinomas, low-grade malignant tumors, and benign tumors, were transplanted into athymic nude mice. Tumor take was confirmed histologically for 22 neoplasms at the initial transplantation, and 14 serially transplantable tumors were established, including some hitherto unestablished or unreported, such as lung and hepatic cell carcinomas. Among the 91 tumors were 21, 14, and 13 carcinomas of the lung, stomach, and breast, respectively. Transplantability was highest in lung carcinomas (10/21), followed by gastric carcinomas (2/14) and breast carcinomas (1/13). Morphology of original tumors was retained well in most transplanted tumors, but desmoplastic or scirrhous tumors, such as gastric and breast carcinomas, tended to become medullary with a decrease in amount of tumor stroma. The ability to produce mucin in gastric carcinomas or melanin in malignant melanoma was maintained in serially transplantable tumors. In addition, ectopic production of adrenocorticotropin and beta melanocyte-stimulating hormone continued in a transplanted small cell carcinoma of the lung. Preliminary results were obtained on hormone dependency of the transplantable breast carcinoma and on alpha1-fetoprotein in the transplantable hepatic cell carcinoma.

Memory effect in the upper bound of the heat flux induced by quantum fluctuations.

Thermodynamic behaviors in a quantum Brownian motion coupled to a classical heat bath is studied. We then define a heat operator by generalizing the stochastic energetics and show the energy balance (first law) and the upper bound of the expectation value of the heat operator (second law). We further find that this upper bound depends on the memory effect induced by quantum fluctuations and hence the maximum extractable work can be qualitatively modified in quantum thermodynamics.

Ammonia sensing for enzymatic urea detection using organic field effect transistors and a semipermeable membrane.

Organic Field Effect Transistors (OFETs) are used to measure ammonia in solution via ammonia diffusion into the OFET channel. An increase in ammonia concentrations results in a decrease in transistor currents. The regeneration of the OFET current after ammonia uptake is slow, which allows us to read out the maximum ammonia dose which was applied. A 100 nm parylene-C layer serves as a semipermeable top gate dielectric. The parylene layer is functionalized with the covalently attached enzyme urease. The enzyme catalyses the hydrolysis of urea to ammonia and carbon dioxide, i.e. urea can be detected via its hydrolysis product ammonia. The sensitivity covers a range of physiological concentrations of urea, which are several mM.

Evidence that chicken antithrombin III is a developmentally regulated glycoprotein synthesized by hepatocytes.

Antithrombin III is the principal circulating active-site inhibitor of thrombin and other serine proteinases. We studied a protein synthesized and secreted by cultured chick embryo hepatocytes that has very similar immunological, structural and functional properties to adult antithrombin III. Its presence was demonstrated by; immunodiffusion analysis of a 100-fold concentrate of culture medium, which produced a single precipitin line of identity with adult and 1-day-old hatchling plasma antithrombin III; immunoprecipitation of a metabolically labelled protein from culture medium, having the same molecular size as adult chicken antithrombin III; conversion of antithrombin activity in culture medium to a faster acting thrombin inhibitory activity in the presence of heparin. Antithrombin III antigen levels were increased 3- to 4-fold in the presence of dexamethasone (2 nM) during a 3-day culture period. Plasma antithrombin III antigen levels from unhatched chicks increased from 26 +/- 6 micrograms/ml at 16 days of development to 104 /+- 6 micrograms/ml at 20 days, whereas 1-day-old hatchlings (21 days) had levels similar to that in adults (135 +/- 7 micrograms/ml vs. 143 +/- 24 micrograms/ml). In contrast to immunodiffusion and immunoelectrophoretic analysis of hepatocyte or hatchling plasma antithrombin III, which showed lines of identity with adult antithrombin III, 16- and 20-day-old embryonic plasma antithrombin III yielded lines of partial identity and migrated less anodally than adult antithrombin III. Consistent with this finding, embryonic plasma antithrombin III had no sialic acid (less than 0.01 residue/mol) in contrast with the adult form (3.5 residues/mol). These studies show that the increase in adult antigen levels and sialation of antithrombin III occurs rapidly after hatchling, suggesting developmental changes in expression at the transcriptional and translational levels in addition to post-translational carbohydrate processing.

Chemically modified thrombin and anhydrothrombin that differentiate macromolecular substrates of thrombin.

BACKGROUND: Thrombin is a primary inducer of thrombus formation by activations of coagulation cascade and platelet aggregation. Hitherto, several types of thrombin inhibitors have been developed for therapeutic purpose. OBJECTIVES: We prepared modified thrombin (M-thrombin) and modified anhydrothrombin (M-anhydrothrombin) by chemical modification of carboxyl groups of thrombin and anhydrothrombin, respectively, to present a new strategy for a potent antiplatelet-anticoagulant agent and new tools for investigation of thrombin functions. RESULTS: M-anhydrothrombin retained high affinity for factor VIII (FVIII), but demonstrated lower affinity than anhydrothrombin for fibrinogen and factor V (FV). Both M-anhydrothrombin and anhydrothrombin prolonged activated partial thromboplastin time (APTT) without affecting prothrombin time, and M-anhydrothrombin prolonged APTT much more than anhydrothrombin. M-anhydrothrombin also retained affinity for the recombinant extracellular domain peptide of protease-activated receptor 1 (PAR1). M-thrombin exhibited marginal clotting activity (4% of thrombin), but induced platelet aggregation in platelet-rich plasma without forming a fibrin clot, which was completely suppressed by anti-PAR1 antibody (ATAP2) and by M-anhydrothrombin, but not by anhydrothrombin. These results indicate that M-thrombin induced platelet aggregation through the activation of PAR1, and M-anhydrothrombin inhibited this process completely. In contrast, neither M-anhydrothrombin nor anhydrothrombin apparently inhibited thrombin-induced platelet aggregation. Only in the presence of the Gly-Pro-Arg-Pro (GPRP) peptide that inhibits polymerization of fibrin, M-anhydrothrombin completely inhibited thrombin-induced platelet aggregation. CONCLUSION: M-thrombin is PAR1-specific and M-anhydrothrombin is FVIII- and PAR1-specific derivatives, and thereby, are new tools as specific agonist and antagonist, respectively, of PAR1. Furthermore, M-anhydrothrombin may be an attractive model for development of a potent anticoagulant-antiplatelet agent.

Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG).

Histidine-rich glycoprotein (HRG) is a serum protein belonging to the cystatin superfamily. HRG may play a regulatory role in hemostasis and innate immunity. However, this role is uncertain because of a lack of rigorous testing in an animal model. We generated mice lacking the translation start point of exon 1 of the Hrg gene, effectively resulting in a null mutation (Hrg-/-). The mice were viable and fertile but had no HRG in their blood. Antithrombin activity in the plasma of Hrg-/- mice was higher than in the plasma of heterozygous Hrg+/- or wild-type Hrg+/+ mice. The prothrombin time was shorter in Hrg-/- mice than in Hrg+/- and Hrg+/+ mice. Bleeding time after tail tip amputation in Hrg-/- mice was shorter than in Hrg+/+ mice. The spontaneous fibrinolytic activity in clotted blood of Hrg-/- mice was higher than in Hrg+/+ mice. These findings suggest that HRG plays a role as both an anticoagulant and an antifibrinolytic modifier, and may regulate platelet function in vivo.

Retinoic acid induces down-regulation of Wnt-3a, apoptosis and diversion of tail bud cells to a neural fate in the mouse embryo.

The tail bud comprises the caudal extremity of the vertebrate embryo, containing a pool of pluripotent mesenchymal stem cells that gives rise to almost all the tissues of the sacro-caudal region. Treatment of pregnant mice with 100 mg/kg all-trans retinoic acid at 9.5 days post coitum induces severe truncation of the body axis, providing a model system for studying the mechanisms underlying development of caudal agenesis. In the present study, we find that retinoic acid treatment causes extensive apoptosis of tail bud cells 24 h after treatment. Once the apoptotic cells have been removed, the remaining mesenchymal cells differentiate into an extensive network of ectopic tubules, radially arranged around the notochord. These tubules express Pax-3 and Pax-6 in a regionally-restricted pattern that closely resembles expression in the definitive neural tube. Neurofilament-positive neurons subsequently grow out from the ectopic tubules. Thus, the tail bud cells remaining after retinoic acid-induced apoptosis appear to adopt a neural fate. Wnt-3a, a gene that has been shown to be essential for tail bud formation, is specifically down-regulated in the tail bud of retinoic acid-treated embryos, as early as 2 h after retinoic acid treatment and Wnt-3a transcripts become undetectable by 10 h. In contrast, Wnt-5a and RAR-gamma are still detectable in the tail bud at that time. Extensive cell death also occurs in the tail bud of embryos homozygous for the vestigial tail mutation, in which there is a marked reduction in Wnt-3a expression. These embryos go on to develop multiple neural tubes in their truncated caudal region. These results suggest that retinoic acid induces down-regulation of Wnt-3a which may play an important role in the pathogenesis of axial truncation, involving induction of widespread apoptosis, followed by an alteration of tail bud cell fate to form multiple ectopic neural tubes.

Microscopic derivation of causal diffusion equation using the projection operator method.

We derive a coarse-grained equation of motion of a number density by applying the projection operator method to a non-relativistic model. The derived equation is an integrodifferential equation and contains the memory effect. The equation is consistent with causality and the sum rule associated with the number conservation in the low momentum limit, in contrast to usual acausal diffusion equations given by using the Fick's law. After employing the Markov approximation, we find that the equation has the similar form to the causal diffusion equation. Our result suggests that current-current correlations are not necessarily adequate as the definition of diffusion constants.