Magnetic properties induced by the Yb-valence inhomogeneity in the layered Kondo-lattice compound Yb4RuGe8.

We have successfully grown single crystals of a novel ytterbium-based layered compoundYb4RuGe8and studied its structural, magnetic, thermal, and transport properties. The magnetic susceptibility has a broad peak caused by the Kondo effect at approximately40 Kand is enhanced below15 Kowing to the development of additional magnetic correlations. An analysis with the grand-Kadowaki-Woods relation reveals that the low-temperature state except for the effect of the additional magnetic correlations is a heavy-mass Fermi liquid.

Association of Education and Depressive Symptoms with Tooth Loss.

Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between "≤9 y of education" and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between "≤9 y of education" and "depressive symptoms" in the general Japanese population.

Electronic and spin structures of CaMn4Ox clusters in the S0 state of the oxygen evolving complex of photosystem II. Domain-based local pair natural orbital (DLPNO) coupled-cluster (CC) calculations using optimized geometries and natural orbitals (UNO) by hybrid density functional theory (HDFT) calculations.

Domain-based local pair natural orbital (DLPNO) coupled cluster single and double (CCSD) with triple perturbation (T) correction methods were performed to elucidate the relative stabilities of ten different intermediate structures of the CaMn4Ox cluster in the S0 state of the oxygen evolving complex (OEC) of photosystem II (PSII). Full geometry optimizations of all the S0 intermediates were performed by the UB3LYP-D3/Def2-TZVP methods, providing the assumed geometrical structures and starting natural orbitals (UNO) for DLPNO-CCSD(T)/Def2TZVP calculations. The effective exchange integrals (J) for the spin Hamiltonian models for the ten intermediates were obtained by the UB3LYP/Def2-TZVP calculations followed by the general spin projections. DLPNO-CCSD(T) calculations followed by the CBS extrapolation procedure elucidated that the (II, III, IV, IV) and (III, III, III, IV) valence states in the CaMn4O5 cluster of the OEC of the PS II were nearly degenerated in energy in the S0 state, indicating an important role of dynamical electron correlation effects for the valence and spin fluctuations in strongly correlated electron systems (SCESs) consisting of 3d transition metals.

Generation of interspecies limited chimeric nephrons using a conditional nephron progenitor cell replacement system.

Animal fetuses and embryos may have applications in the generation of human organs. Progenitor cells may be an appropriate cell source for regenerative organs because of their safety and availability. However, regenerative organs derived from exogenous lineage progenitors in developing animal fetuses have not yet been obtained. Here, we established a combination system through which donor cells could be precisely injected into the nephrogenic zone and native nephron progenitor cells (NPCs) could be eliminated in a time- and tissue-specific manner. We successfully achieved removal of Six2+ NPCs within the nephrogenic niche and complete replacement of transplanted NPCs with donor cells. These NPCs developed into mature glomeruli and renal tubules, and blood flow was observed following transplantation in vivo. Furthermore, this artificial nephron could be obtained using NPCs from different species. Thus, this technique enables in vivo differentiation from progenitor cells into nephrons, providing insights into nephrogenesis and organ regeneration.

Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia.

Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3ach/SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3ach mice was significantly ameliorated in Fgfr3ach/SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic potential of CNP for treatment of midfacial hypoplasia and foramen magnum stenosis in achondroplasia.

An update on stem cell biology and engineering for brain development.

Two recent technologies, induced-pluripotent stem cells (iPSCs) and direct somatic reprogramming, have shown enormous potential for cell-based therapies against intractable diseases such as those that affect the central nervous system. Already, methods that generate most major cell types of the human brain exist. Whether the cell types are directly reprogrammed from human somatic cells or differentiated from an iPSC intermediate, the overview presented here demonstrates how these protocols vary greatly in their efficiencies, purity and maturation of the resulting cells. Possible solutions including micro-RNA switch technologies that purify target cell types are also outlined. Further, an update on the transition from 2D to 3D cultures and current organoid (mini-brain) cultures are reviewed to give the stem cell and developmental engineering communities an up-to-date account of the progress and future perspectives for modeling of central nervous system disease and brain development in vitro.

Comparison of human mesenchymal stem cells derived from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous tooth pulp.

Populations of pluripotent stem cells were isolated from bone marrow, synovial fluid, adult dental pulp, and exfoliated deciduous teeth and their multipotentiality properties compared. Osteogenic, chondrogenic, adipogenic, and neurogenic differentiation potentials were examined. Bone marrow mesenchymal stem cells (BMMSCs) and synovial fluid-derived cells (SFCs) showed the highest levels of osteogenesis as expressed by alkaline phosphatase (ALP) activity (0.54±0.094 U/mg protein and 0.57±0.039 U/mg protein, respectively; P=0.60) and by osteocalcin (BGLAP; determined by real-time RT-PCR). SFCs showed the highest levels of chondrogenesis as expressed by ALP activity (1.75±0.097 U/mg protein) and of COL2A1 and COL10A1 by real-time PCR. In terms of adipogenesis, lipid vesicles were observed in the BMMSCs and SFCs. Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) exhibited neurogenesis potential, as shown by increases in expression of class III ß-tubulin (TUBB3) and microtubule-associated protein 2 (MAP2) on RT-PCR. Variability was found in the differentiation potential corresponding to the tendency of the original tissue to differentiate. It is suggested that the cell type should be selected depending on the regenerative treatment regimen.

Generalized approximate spin projection calculations of effective exchange integrals of the CaMn4O5 cluster in the S1 and S3 states of the oxygen evolving complex of photosystem II.

Full geometry optimizations followed by the vibrational analysis were performed for eight spin configurations of the CaMn4O4X(H2O)3Y (X = O, OH; Y = H2O, OH) cluster in the S1 and S3 states of the oxygen evolution complex (OEC) of photosystem II (PSII). The energy gaps among these configurations obtained by vertical, adiabatic and adiabatic plus zero-point-energy (ZPE) correction procedures have been used for computation of the effective exchange integrals (J) in the spin Hamiltonian model. The J values are calculated by the (1) analytical method and the (2) generalized approximate spin projection (AP) method that eliminates the spin contamination errors of UB3LYP solutions. Using J values derived from these methods, exact diagonalization of the spin Hamiltonian matrix was carried out, yielding excitation energies and spin densities of the ground and lower-excited states of the cluster. The obtained results for the right (R)- and left (L)-opened structures in the S1 and S3 states are found to be consistent with available optical and magnetic experimental results. Implications of the computational results are discussed in relation to (a) the necessity of the exact diagonalization for computations of reliable energy levels, (b) magneto-structural correlations in the CaMn4O5 cluster of the OEC of PSII, (c) structural symmetry breaking in the S1 and S3 states, and (d) the right- and left-handed scenarios for the O-O bond formation for water oxidation.

Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1α expression in patients with glioma.

BACKGROUND AND PURPOSE: Hypoxic tissue evaluation in glioma is important for predicting treatment response and establishing antihypoxia therapy. In this preliminary study, (62)Cu-ATSM PET was used to determine its validity as a biomarker for distinguishing tumor grade and tissue hypoxia. MATERIALS AND METHODS: (62)Cu-ATSM PET was performed in 22 patients with glioma, and the (62)Cu-ATSM SUV(max) and T/B ratio were semiquantitatively evaluated. (62)Cu-ATSM uptake distribution was qualitatively evaluated and compared with MR imaging findings. HIF-1α expression, a hypoxia marker, was compared with (62)Cu-ATSM uptake values. RESULTS: The (62)Cu-ATSM SUV(max) and T/B ratio were significantly higher in grade IV than in grade III gliomas (P = .014 and .018, respectively), whereas no significant differences were found between grade III and grade II gliomas. At a T/B ratio cutoff threshold of 1.8, (62)Cu-ATSM uptake was predictive of HIF-1α expression, with 92.3% sensitivity and 88.9% specificity. The mean T/B ratio was also significantly higher in HIF-1α-positive glioma tissue than in HIF-1α-negative tissue (P = .001). Using this optimal threshold of T/B ratio, (62)Cu-ATSM PET showed regional uptake in 61.9% (13/21) of tumors within the contrast-enhanced region on MR imaging, which was significantly correlated with presence of a necrotic component (P = .002). CONCLUSIONS: Our results demonstrated that (62)Cu-ATSM uptake is relatively high in grade IV gliomas and correlates with the MR imaging findings of necrosis. Moreover, the (62)Cu-ATSM T/B ratio showed significant correlation with HIF-1α expression. Thus, (62)Cu-ATSM appears to be a suitable biomarker for predicting highly malignant grades and tissue hypoxia in patients with glioma.

Theoretical illumination of water-inserted structures of the CaMn4O5 cluster in the S2 and S3 states of oxygen-evolving complex of photosystem II: full geometry optimizations by B3LYP hybrid density functional.

Full geometry optimizations of several inorganic model clusters, CaMn(4)O(4)XYZ(H(2)O)(2) (X, Y, Z = H(2)O, OH(-) or O(2-)), by the use of the B3LYP hybrid density functional theory (DFT) have been performed to illuminate plausible molecular structures of the catalytic site for water oxidation in the S(0), S(1), S(2) and S(3) states of the Kok cycle for the oxygen-evolving complex (OEC) of photosystem II (PSII). Optimized geometries obtained by the energy gradient method have revealed the degree of symmetry breaking of the unstable three-center Mn(a)-X-Mn(d) bond in CaMn(4)O(4)XYZ(H(2)O)(2). The right-elongated (R) Mn(a)-X···Mn(d) and left-elongated (L) Mn(a)···X-Mn(d) structures appear to occupy local minima on a double-well potential for several key intermediates in these states. The effects of insertion of one extra water molecule to the vacant coordination site, Mn(d) (Mn(a)), for R (L) structures have also been examined in detail. The greater stability of the L-type structure over the R-type has been concluded for key intermediates in the S(2) and S(3) states. Implications of the present DFT structures are discussed in relation to previous DFT and related results, together with recent X-ray diffraction results for model compounds of cubane-like OEC cluster of PSII.

A new model of gastric bleeding induced in rats by aspirin plus clopidogrel under stimulation of acid secretion. Prophylactic effects of antiulcer drugs.

We set up a new model of gastric bleeding induced by the luminal perfusion of aspirin (ASA) in rats pretreated with clopidogrel under conditions where acid secretion is stimulated, and examined the effect of antiulcer drugs on the bleeding. Under urethane anesthesia, acid secretion was stimulated by i.v. infusion of histamine (8 mg/kg/h), and two catheters were inserted into the stomach, one from the esophagus and another from the duodenum. The stomach was perfused with 25 mM ASA at a rate of 0.1 ml/min using an infusion pump, and gastric bleeding was measured as hemoglobin concentration in the perfusate collected every 15 min. Clopidogrel (30 mg/kg) was given orally 24 h before the perfusion. Various antiulcer drugs were given intraduodenally 30 min before the ASA treatment. Perfusion of the stomach with ASA provoked little gastric bleeding or damage even when acid secretion was stimulated. Pretreatment with clopidogrel significantly increased the bleeding and damage caused by ASA. The bleeding and lesions produced by ASA plus clopidogrel were significantly prevented by pretreatment with famotidine and omeprazole. Mucosal protective drugs such as rebamipide, irsogladine and teprenone also prevented gastric bleeding response to ASA/clopidogrel under conditions of acid secretion, although the effect was less pronounced than that of the antisecretory drugs. We conclude that clopidogrel increases gastric bleeding induced by ASA when acid secretion is stimulated. Both antisecretory and mucosal protective drugs are effective in reducing gastric bleeding under such conditions. This model is useful for the screening of drugs that protect against gastric bleeding.

The use of induced pluripotent stem cells in drug development.

Induced pluripotent stem cell (iPSC) technology is revolutionizing medical science, allowing the exploration of disease mechanisms and novel therapeutic molecular targets, and offering opportunities for drug discovery and proof-of-concept studies in drug development. This review focuses on the recent advancements in iPSC technology including disease modeling and control setting in its analytical paradigm. We describe how iPSC technology is integrated into existing paradigms of drug development and discuss the potential of iPSC technology in personalized medicine.

Dental pulp cells for induced pluripotent stem cell banking.

Defined sets of transcriptional factors can reprogram human somatic cells to induced pluripotent stem (iPS) cells. However, many types of human cells are not easily accessible to minimally invasive procedures. Here we evaluated dental pulp cells (DPCs) as an optimal source of iPS cells, since they are easily obtained from extracted teeth and can be expanded under simple culture conditions. From all 6 DPC lines tested with the conventional 3 or 4 reprogramming factors, iPS cells were effectively established from 5 DPC lines. Furthermore, determination of the HLA types of 107 DPC lines revealed 2 lines homozygous for all 3 HLA loci and showed that if an iPS bank is established from these initial pools, the bank will cover approximately 20% of the Japanese population with a perfect match. Analysis of these data demonstrates the promising potential of DPC collections as a source of iPS cell banks for use in regenerative medicine.

[Mucosa-associated lymphoid tissue lymphoma in the thymus with multiple amyloid nodules in the both lungs].

Here, we present a case of mucosa-associated lymphoid tissue (MALT) lymphoma in the thymus with multiple amyloid nodules in both lung. A 66-year-old woman was incidentally found to have an abnormal shadow on mass-screening chest roentgenogram. A chest computed tomography (CT) demonstrated a mass of 50 mm in diameter with a smooth margin adjacent to the heart in the anterior mediastinum and multiple small nodules in both lung. As a differential diagnosis, thymic carcinoma with multiple lung metastases was firstly considered from these clinical informations. To make a definite diagnosis, the operation via a thoracoscopy was done. As a result, it turned out that pulmonary nodules were amyloidosis and the thymic tumor was MALT lymphoma. Postoperative course was uneventful and she was treated with chemoradiotherapy. In addition, she was diagnosed with Sjögren's syndrome 1 and half years later. Four years later the patient has been well without recurrence.

Clinical characterization and long-term prognosis of neurological development in preterm infants with late-onset circulatory collapse.

OBJECTIVE: To characterize the risk factors for late-onset circulatory collapse (LCC) in preterm infants responsive to corticosteroid therapy and evaluate the long-term neurological prognosis. STUDY DESIGN: A retrospective case-control study for preterm infants (≤32 weeks' gestation) admitted to our neonatal intensive care unit from 1994 through 2002. RESULT: Sixty-five infants (11%) were diagnosed with LCC. Infants with a shorter gestation and lower birth weight had a higher incidence of LCC. LCC infants had a significantly lower 1-min Apgar score, significantly higher incidence of severe intraventricular hemorrhage, chronic lung disease, and postnatal periventricular leukomalacia, and significantly longer duration of ventilation use, oxygen use, and hospital stay. Somatic growth at 36 weeks' postmenstrual age was poorer in infants with LCC than without LCC (controls). LCC infants were significantly more likely than controls to have cerebral palsy at 3 years. CONCLUSION: LCC is associated with poor neurodevelopmental outcomes. Prevention of LCC can lead to improved neurological prognoses.

Symmetry and broken-symmetry in molecular orbital descriptions of unstable molecules. 3. The nature of chemical bonds of spin frustrated systems.

Symmetry and broken symmetry in the molecular orbital description of spin frustration systems have been investigated in relation to the resonating valence bond (RVB) theory of the spin liquid state and non-BCS superconductivity. Broken symmetry (BS) and resonating BS (RBS) molecular orbital (MO) methods have been employed to obtain resonating valence bond (RVB)-type explanations of spin frustrated systems. RBS MO solutions are expanded using the localized molecular orbitals (LMO) to elucidate a universal MO-VB description. The BS and RBS MO descriptions of triangular spin frustrated systems corresponding to transition structures for exchange-forbidden radical insertions were investigated in comparison with the RVB-type explanations of such systems. The BS and RBS calculations by the use of three different axial (SDW) solutions or three noncollinear GSO (helical SDW) solutions of a triangular hydrogen cluster were performed to obtain potential curves with and without resonance (quantum) effects. The resonating GSO (noncollinear) state responsible for short-range correlation was found to be the most stable for the system. The reliability of the approximate spin projection (AP) procedure to eliminate the high-spin component was also elucidated, comparing with the AP BS and RBS potential curves. The BS GSO (GHF) computations of several triangular systems, N(CH(2))(3), (CH(2))(3), and Mn(II)(3)O(4), were performed to obtain total energies and total spin angular momentums and effective exchange integrals (J) between local spins, which are crucial for construction of effective spin Hamiltonian models. The exact diagonalization of the Heisenberg models was also performed to depict the energy levels and magnetic susceptibility curves for triangular and kagome lattices to elucidate spin frustration effects and related quantum spin behaviors. Implications of the computational results have been discussed in relation to magnetic properties of several triangular and kagome systems synthesized recently and the superconductivity of triangular systems discovered recently.

[Metastatic ectopic cervical thymoma with prolonged survival; report of a case].

A 60-year-old woman presented with a palpable and painful nodule of her neck. Physical examination revealed that the anterior neck mass was enlarged without other positive findings. The tumor was not diagnosed with a fine needle aspiration biopsy, so that the excision of the tumor was underwent. The diagnosis at permanent section analysis revealed a non-invasive thymoma. The patient did not receive adjunctive postoperative therapy. For the duration of 6.5-year follow-up, metastasis of the left lobe of thyroid and right upper lobe of lung in twice have been sequentially detected and resected, and now she has been healthy with no known recurrence of the tumor. The recurrence of a non-invasive cervical ectopic thymoma has been reported as extremely rare, and this case indicates that the surgical control for recurrence lesion of cervical ectopic thymoma is effective when the tumor is resectable.