Anisotropic Fully Gapped Superconductivity Possibly Mediated by Charge Fluctuations in a Nondimeric Organic Complex.

We investigate low-temperature electronic properties of the nondimeric organic superconductor ß^{''}-(ET)_{4}[(H_{3}O)Ga(C_{2}O_{4})_{3}]PhNO_{2}. By examining ultrasonic properties, charge disproportionation (CD) without magnetic field dependence is detected below T_{CD}∼8 K just above the superconducting critical temperature T_{c}∼6 K. From quantum oscillations in high fields, we find variation in the Fermi surface and mass enhancement induced by the CD. Heat capacity studies elucidate that the superconducting gap function is fully gapped in the Fermi surface, but anisotropic with fourfold symmetry. We point out that the pairing mechanism of the superconductivity is possibly dominated by charge fluctuations.

Aneuploid rescue precedes X-chromosome inactivation and increases the incidence of its skewness by reducing the size of the embryonic progenitor cell pool.

STUDY QUESTION: Do monosomy rescue (MR) and trisomy rescue (TR) in preimplantation human embryos affect other developmental processes, such as X-chromosome inactivation (XCI)? SUMMARY ANSWER: Aneuploid rescue precedes XCI and increases the incidence of XCI skewness by reducing the size of the embryonic progenitor cell pools. WHAT IS KNOWN ALREADY: More than half of preimplantation human embryos harbor aneuploid cells, some of which can be spontaneously corrected through MR or TR. XCI in females is an indispensable process, which is predicted to start at the early-blastocyst phase. STUDY DESIGN, SIZE, DURATION: We examined the frequency of XCI skewness in young females who carried full uniparental disomy (UPD) resulting from MR or TR/gamete complementation (GC). The results were statistically analyzed using a theoretical model in which XCI involves various numbers of embryonic progenitor cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 39 children and young adults ascertained by imprinting disorders. XCI ratios were determined by DNA methylation analysis of a polymorphic locus in the androgen receptor gene. We used Bayesian approach to assess the probability of the occurrence of extreme XCI skewness in the MR and TR/GC groups using a theoretical model of 1-12 cell pools. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 12 of 39 individuals (31%) showed skewed XCI. Extreme skewness was observed in 3 of 15 MR cases (20%) and 1 of 24 TR/GC cases (4.2%). Statistical analysis indicated that XCI in the MR group was likely to have occurred when the blastocyst contained three or four euploid embryonic progenitor cells. The estimated size of the embryonic progenitor cell pools was approximately one-third or one-fourth of the predicted size of normal embryos. The TR/GC group likely had a larger pool size at the onset of XCI, although the results remained inconclusive. LIMITATIONS, REASONS FOR CAUTION: This is an observational study and needs to be validated by experimental analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study provides evidence that the onset of XCI is determined by an intrinsic clock, irrespectively of the number of embryonic progenitor cells. Our findings can also be applied to individuals without UPD or imprinting disorders. This study provides a clue to understand chromosomal and cellular dynamics in the first few days of human development, their effects on XCI skewing and the possible implications for the expression of X-linked diseases in females. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Grants-in-aid for Scientific Research on Innovative Areas (17H06428) and for Scientific Research (B) (17H03616) from Japan Society for the Promotion of Science (JSPS), and grants from Japan Agency for Medical Research and Development (AMED) (18ek0109266h0002 and 18ek0109278h0002), National Center for Child Health and Development and Takeda Science Foundation. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Increase in the Magnetic Ordering Temperature (Tc) as a Function of the Applied Pressure for A2Mn[Mn(CN)6] (A = K, Rb, Cs) Prussian Blue Analogues.

Magnetization measurements under pressure reveal that the external hydrostatic pressure significantly increases in the ferrimagnetic transition temperature, Tc, for A2Mn[Mn(CN)6] (A = K, Rb, Cs). In the case of monoclinic A = K and Rb, dTc/dp values are 21.2 and 14.6 K GPa-1, respectively, and Tc increases by 53 and 39%, respectively, from ambient pressure to 1.0 GPa. The cubic A = Cs compound also shows a monotonous increase with an initial rate of 4.22 K GPa-1 and about 11.4 K GPa-1 above 0.6 GPa, and an overall Tc increase by 26% at 1.0 GPa. The increase in Tc is attributed to deformation of the structure such that the MnII-N≡C angle decreases with increasing pressure. The smaller the alkali cation, the greater the decrease in the MnII-N≡C angle induced by pressure and the larger the increase of dTc/dp. This is in accordance with the ambient-pressure structures for A2Mn[Mn(CN)6] (A = K, Rb, Cs), which have decreasing MnII-N≡C angles that correlate to the observed increasing Tcs as K > Rb > Cs. The large increase in Tc for the A = K compound is the highest class among several cyano-bridged metal complexes. The tuning of the transition temperature by such a weak pressure may lead to additional applications such as switching devices.

Usefulness of subtraction of 3D T2WI-DRIVE from contrast-enhanced 3D T1WI: preoperative evaluations of the neurovascular anatomy of patients with neurovascular compression syndrome.

BACKGROUND AND PURPOSE: High-resolution 3D MR cisternography techniques such as 3D T2WI-driven equilibrium radiofrequency reset pulse (DRIVE) are used preoperatively to assess neurovascular anatomy in patients with neurovascular compression syndrome, but contrast between vessels and cranial nerves at the point of neurovascular contact is limited. The postprocessing technique subtraction of 3D T2WI-driven equilibrium radiofrequency reset pulse from contrast-enhanced 3D T1WI (sDRICE) provides both high spatial resolution and excellent contrast in depicting the neurovascular contact. We evaluated the usefulness of sDRICE compared with 3D T2WI-DRIVE. MATERIALS AND METHODS: Twelve patients who underwent microvascular decompression for hemifacial spasm or trigeminal neuralgia were examined preoperatively with 3D T2WI-DRIVE and sDRICE. Two neuroradiologists retrospectively analyzed and scored lesion conspicuity, defined as the ease of discrimination between offending vessels and compressed nerves or the brain stem at the neurovascular contact. They also quantitatively analyzed the contrast and contrast-to-noise ratio at the neurovascular contact. RESULTS: The lesion conspicuity scores of sDRICE images were significantly higher than those of 3D T2WI-DRIVE for all 12 patients (P = .006) and the 6 cases of hemifacial spasm (P = .023) but were not significantly higher in the 6 trigeminal neuralgia cases alone (P = .102). For all 12 patients, the contrast-to-noise ratio between the offending vessels and the brain stem and between the vessels and nerves on sDRICE images was significantly higher than that on 3D T2WI-DRIVE (P = .003 and P = .007, respectively). Among these structures, the contrast values were also significantly higher on the sDRICE than on the 3D T2WI-DRIVE (P < .001) images. CONCLUSIONS: The postprocessing technique sDRICE is useful to evaluate neurovascular anatomy and to improve contrast and the contrast-to-noise ratio in patients with neurovascular compression syndrome.

Pretreatment with buthionine sulfoximine enhanced uptake and retention of BSH in brain tumor.

To determine the influence of buthionine sulfoximine (BSO) on boron biodistribution after sulfhydryl borane (BSH) administration for boron neutron capture therapy, the effectiveness of the combination of BSO with sulfhydril- (BSH) and non-sulfhydril (B12H12 and BNH3) boron compounds, and the interval between BSO and BSH administration, the retention of boron in tissues have been evaluated using a 9L rat tumor model. Simultaneous administration of BSH and BSO showed significantly higher boron accumulation compared to that without BSO, however there was no difference in tissue boron level between B12H12 and BNH3 administration with BSO or without BSO. The longer interval (6h) between BSH and BSO administration related to the highest boron concentration in the brain and subcutaneous tumors compared to shorter intervals (0.5, 3h). Boron concentration in subcutaneous and brain tumors was maintained for 6 and 12h after the administration of BSH following BSO pretreatment.

Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors.

Cancer stem cells (CSCs), a small and elusive population of undifferentiated cancer cells within tumors that drive tumor growth and recurrence, are believed to resemble normal stem cells. Although surrogate markers have been identified and compelling CSC theoretical models abound, actual proof for the existence of CSCs can only be had retrospectively. Hence, great store has come to be placed in isolating CSCs from cancers for in-depth analysis. On the other hand, although induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, concern exists over the inadvertent co-transplantation of partially or undifferentiated stem cells with tumorigenic capacity. Here we demonstrate that the introduction of defined reprogramming factors (OCT4, SOX2, Klf4 and c-Myc) into MCF-10A nontumorigenic mammary epithelial cells, followed by partial differentiation, transforms the bulk of cells into tumorigenic CD44(+)/CD24(low) cells with CSC properties, termed here as induced CSC-like-10A or iCSCL-10A cells. These reprogrammed cells display a malignant phenotype in culture and form tumors of multiple lineages when injected into immunocompromised mice. Compared with other transformed cell lines, cultured iCSCL-10A cells exhibit increased resistance to the chemotherapeutic compounds, Taxol and Actinomycin D, but higher susceptibility to the CSC-selective agent Salinomycin and the Pin1 inhibitor Juglone. Restored expression of the cyclin-dependent kinase inhibitor p16INK4a abrogated the CSC properties of iCSCL-10A cells, by inducing cellular senescence. This study provides some insight into the potential oncogenicity that may arise via cellular reprogramming, and could represent a valuable in vitro model for studying the phenotypic traits of CSCs per se.

Antiferromagnetic d-electron exchange via a spin-singlet pi-electron ground state in an organic conductor.

Electron spin resonance reveals the spin behavior of conduction (pi) and localized (d) electrons in beta-(BDA-TTP)2MCl4 (M=Fe, Ga). Both the Ga3+(S=0) and Fe3+(S=5/2) compounds exhibit a metal-insulator transition at 113 K with the simultaneous formation of a spin-singlet ground state in the pi electron system of the donor molecules. The behavior is consistent with charge ordering in beta-(BDA-TTP)2MCl4 at the metal-insulator transition. At 5 K, the Fe3+ compound orders antiferromagnetically, even though the pi electrons, which normally would facilitate magnetic exchange, are localized nonmagnetic singlets.

Perivascular infiltrate of memory lymphocytes and mature dendritic cells in MG thymomas.

In thymomas associated with myasthenia gravis (MG), the authors found that perivascular infiltrates of memory lymphocytes and mature dendritic cells (DCs) were more frequent in patients with early improvement after thymectomy than in patients without response to thymectomy. Although these findings may be limited to particular types of thymoma, thymectomy may interrupt the recruitment of mature DCs in thymus and export of activated T cells to extra-thymic tissues, thereby improving the disease.

Adult murine neurons: their chromatin and chromosome changes and failure to support embryonic development as revealed by nuclear transfer.

Fully differentiated neurons in adult mammalian brains do not divide; consequently, their metaphase chromosomes have never been examined. Here we report metaphase chromosome constitutions of cortical neurons in adult mice visualized by a nuclear transfer technique. We found that although some reconstructed oocytes cloned from neuronal nuclei have an apparently normal karyotype, the majority do not. Regardless of chromosome morphology, nuclei of adult neurons totally lack the ability to support embryonic development. These findings support the hypothesis that fully differentiated neurons in adult mammalian brains are genomically altered.

Chronological change of brain abscess in (1)H magnetic resonance spectroscopy.

We studied chronological magnetic resonance spectral changes in brain abscesses before and after medical and/or surgical treatment. We examined five patients with MRI imaging and (1)H magnetic resonance spectroscopy (MRS) on two or more occasions, using two volume-of-interest patterns, and saw chronological changes related to the evolution of the abscess. A spectrum specific for brain abscess was found in three of the five cases, while two showed a single lactate peak in the first study. In two cases, phenylalanine or alanine appeared in the second study. We observed the disappearance of the specific spectra and a single lactate peak following surgery. Only one patient showed different spectra in different volume of interest.

Functions and ATP-binding responses of the twelve histidine residues in the TF1-ATPase beta subunit.

The C2 proton signals of all (twelve) histidine residues of the TF1 beta subunit in the 1H-NMR spectrum have been identified and assigned by means of pH change experiments and site-directed substitution of histidines by glutamines. pH and ligand titration experiments were carried out for these signals. Furthermore, the ATPase activity of the reconstituted alpha3beta3gamma complex was examined for the twelve mutant beta subunits. Two of three conserved histidines, namely, His-119 and 324, were found to be important for expression of the ATPase activity. The former fixes the N-terminal domain to the central domain. His-324 is involved in the formation of the interface essential for the alpha3beta3gamma complex assembly. The other conserved residue, His-363, showed a very low pK(a), suggesting that it is involved in the tertiary structure formation. On the binding of a nucleotide, only the signals of His-173, 179, 200, and 324 shifted. These histidines are located in the hinge region, and its proximity, of the beta subunit. This observation provided further support for the conformational change of the beta monomer from the open to the closed form on the binding of a nucleotide proposed by us [Yagi et al. (1999) Biophys. J. 77, 2175-2183]. This conformational change should be one of the essential driving forces in the rotation of the alpha3beta3gamma complex.

Increased attentional blink after focal cerebral lesions.

BACKGROUND: Once a person identifies a visual object, the ability to detect a second object is impaired for the next few hundred milliseconds. This attentional blink is reported to increase in subjects with neglect due to acute right hemisphere lesions. METHOD: To examine neural substrates of the attentional blink, the authors examined the performance of 13 subjects with chronic focal brain lesions visualized by MRI and nine control subjects without neurologic impairments on a rapid serial visual presentation task that used letters as targets. RESULTS: Attentional blink length in the lesion group was more than twice that of controls (p < 0.05). The magnitude of the attentional blink deficit was greatest when the second target appeared 200 ms after the first target, recovering close to baseline by 1,200 ms. Abnormal attentional blink occurred (even in the absence of neglect) with lesions in the occipitotemporal areas (associated with "object" vision) and the prefrontal cortices (thought to mediate visual working memory). CONCLUSIONS: Attentional blink length and attentional blink magnitude measure different components of the attentional blink process. Abnormal attentional blink can occur with different chronic focal brain lesions in a network of structures for vision and attention, and it has no special status in hemispatial neglect. Abnormal attentional blink may help explain difficulties on rapid, visually demanding cognitive tasks such as reading and automobile driving and may explain performance deficits in brain damaged patients with nonspatial disorders of visual processing.

Epigenetic instability in ES cells and cloned mice.

Cloning by nuclear transfer (NT) is an inefficient process in which most clones die before birth and survivors often display growth abnormalities. In an effort to correlate gene expression with survival and fetal overgrowth, we have examined imprinted gene expression in both mice cloned by nuclear transfer and in the embryonic stem (ES) cell donor populations from which they were derived. The epigenetic state of the ES cell genome was found to be extremely unstable. Similarly, variation in imprinted gene expression was observed in most cloned mice, even in those derived from ES cells of the same subclone. Many of the animals survived to adulthood despite widespread gene dysregulation, indicating that mammalian development may be rather tolerant to epigenetic aberrations of the genome. These data imply that even apparently normal cloned animals may have subtle abnormalities in gene expression.

New organic superconductors beta-(BDA-TTP)2X [BDA-TTP + 2,5-bis(1,3-dithian-2ylidene)-1,3,4,6-tetrathiapentalene; X(-) = SbF6(-), AsF6(-), and PF6(-)].

The synthesis, electrochemical properties, and molecular structure of a new pi-electron donor, 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), is described. In contrast to the hitherto-known tetrachalcogenafulvalene pi-donors providing organic superconductors, this donor contains only the bis-fused 1,3-dithiole-2-ylidene unit as a pi-electron system, yet produces a series of ambient-pressure superconductors beta-(BDA-TTP)2X [X = SbF6 (magnetic T(c) = 6.9 K, resistive T(c) = 7.5 K), AsF6 (magnetic T(c) = 5.9 K, resistive T(c) = 5.8 K), and PF6 (magnetic T(c) = 5.9 K)], which are isostructural. The values of the intermolecular overlap integrals calculated on the donor layers of these superconductors suggest a two-dimensional (2D) electronic structure with loose donor packing. Tight-binding band calculations also indicate that these superconductors have the 2D band dispersion relations and closed Fermi surfaces.

[Impact of high remnant-like lipoproteins on the function of peripheral arterial endothelium in patients with hyperlipidemia and normolipidemia: estimation using Doppler flow analysis].

OBJECTIVES: Cholesterol levels of remnant-like lipoprotein (RLP-cholesterol: RLP-C), which reflect remnant lipoproteins, are associated with coronary arterial endothelial functions and cardiovascular events. The influence of RLP-C on peripheral vascular endothelial functions in patients with hyperlipidemia and normolipidemia was evaluated based on the reactivity of the antecubital artery to acetylcholine (Ach) and isosorbide dinitrate (ISDN) using a Doppler guidewire. METHODS: Protocol 1: Five patients were selected, and the dose-response of the antecubital artery was evaluated by administering Ach (0.5, 5, and 50 micrograms/30 sec) or ISDN (0.025, 0.25, and 2.5 mg/30 sec). An index of vascular reactivity (brachial artery response: BR) was determined by dividing the maximal blood flow velocity after the administration of Ach or ISDN by resting blood flow velocity. Protocol 2: BR was evaluated in 48 patients after administering Ach 50 micrograms or ISDN 2.5 mg. Subsequently, these patients were divided into the following three groups based on early morning RLP-C levels: Group L (n = 11), RLP-C < 2.0 mg/dl (minimal detectable level); Group M (n = 21), 2.0 mg/dl < or = RLP-C < 5.0 mg/dl; and Group H (n = 16), 5.0 mg/dl < or = RLP-C. The factors that regulate BR-Ach 50 micrograms were also evaluated in 34 normolipidemic patients. RESULTS: Protocol 1: BR dose-dependently increased after the administration of Ach and ISDN. Protocol 2: BR-Ach 50 micrograms was significantly less in Group H (3.1 +/- 0.8) than in Groups M (3.8 +/- 0.9, p < 0.03) and L (4.2 +/- 0.9, p < 0.01). However, there were no significant differences in BR-ISDN 2.5 mg between the three groups. Univariate analysis in normolipidemic patients revealed that BR-Ach 50 micrograms was correlated with age (r = -0.355, p < 0.05), RLP-C (r = -0.488, p < 0.01), low-density lipoprotein cholesterol (r = -0.382, p < 0.03), systolic blood pressure (r = -0.354, p < 0.05), and diastolic blood pressure (r = -0.406, p < 0.02). Multivariate analysis using these five factors as independent variables revealed that age, RLP-C, and low-density lipoprotein cholesterol regulated BR-Ach 50 micrograms. CONCLUSIONS: Peripheral vascular endothelial dysfunction may occur in patients with high levels of RLP-C. RLP-C is an independent lipid factor that regulates peripheral vascular endothelial functions even in normolipidemic patients.

Beneficial effect of troglitazone, an insulin-sensitizing antidiabetic agent, on coronary circulation in patients with non-insulin-dependent diabetes mellitus.

Evidence is increasing for small vessel remodeling and disturbance of endothelium-dependent vasodilation in diabetic patients. Insulin increases vascular wall thickening and produces endothelial dysfunction. Troglitazone, a new insulin-sensitizer antidiabetic agent, is considered to reduce plasma insulin level and the present study assessed its effect on the coronary circulation of the patients with non-insulin-dependent diabetes mellitus (NIDDM). Analysis of the myocardial washout rate with adenosine triphosphate-stress thallium-201 scintigraphy was used to estimate coronary circulation, and for estimation of insulin sensitivity, the homeostasis model insulin resistance index (HOMA-R) was calculated. Patients were treated with monotherapy of either troglitazone (200 mg bid, n=12) or glibenclamide (2.5 mg daily, n=12) for 3 months. Age-, sex- and risk factors-matched subjects without NIDDM were employed as a control. Fasting plasma glucose and hemoglobin A1c were similarly decreased by troglitazone or glibenclamide. Plasma insulin level (pmol/L) decreased from 66.6+/-10.8 to 39.0+/-7.2 with troglitazone, but was unchanged by glibenclamide (58.8+/-7.2 to 66.0+/-10.8). The diabetic groups had a significantly lower washout rate than controls, which was improved by troglitazone, but not by glibenclamide. In addition, the increase in washout rate correlated significantly with the decrease in HOMA-R in the troglitazone group. In conclusion, troglitazone can restore coronary circulation by improving insulin resistance in patients with NIDDM.

Identification of a small tetraheme cytochrome c and a flavocytochrome c as two of the principal soluble cytochromes c in Shewanella oneidensis strain MR1.

Two abundant, low-redox-potential cytochromes c were purified from the facultative anaerobe Shewanella oneidensis strain MR1 grown anaerobically with fumarate. The small cytochrome was completely sequenced, and the genes coding for both proteins were cloned and sequenced. The small cytochrome c contains 91 residues and four heme binding sites. It is most similar to the cytochromes c from Shewanella frigidimarina (formerly Shewanella putrefaciens) NCIMB400 and the unclassified bacterial strain H1R (64 and 55% identity, respectively). The amount of the small tetraheme cytochrome is regulated by anaerobiosis, but not by fumarate. The larger of the two low-potential cytochromes contains tetraheme and flavin domains and is regulated by anaerobiosis and by fumarate and thus most nearly corresponds to the flavocytochrome c-fumarate reductase previously characterized from S. frigidimarina to which it is 59% identical. However, the genetic context of the cytochrome genes is not the same for the two Shewanella species, and they are not located in multicistronic operons. The small cytochrome c and the cytochrome domain of the flavocytochrome c are also homologous, showing 34% identity. Structural comparison shows that the Shewanella tetraheme cytochromes are not related to the Desulfovibrio cytochromes c(3) but define a new folding motif for small multiheme cytochromes c.

Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation.

To assess whether heterozygosity of the donor cell genome was a general parameter crucial for long-term survival of cloned animals, we tested the ability of embryonic stem (ES) cells with either an inbred or F(1) genetic background to generate cloned mice by nuclear transfer. Most clones derived from five F(1) ES cell lines survived to adulthood. In contrast, clones from three inbred ES cell lines invariably died shortly after birth due to respiratory failure. Comparison of mice derived from nuclear cloning, in which a complete blastocyst is derived from a single ES cell, and tetraploid blastocyst complementation, in which only the inner cell mass is formed from a few injected ES cells, allows us to determine which phenotypes depend on the technique or on the characteristics of the ES cell line. Neonatal lethality also has been reported in mice entirely derived from inbred ES cells that had been injected into tetraploid blastocysts (ES cell-tetraploids). Like inbred clones, ES cell-tetraploid pups derived from inbred ES cell lines died shortly after delivery with signs of respiratory distress. In contrast, most ES cell-tetraploid neonates, derived from six F(1) ES cell lines, developed into fertile adults. Cloned pups obtained from both inbred and F(1) ES cell nuclei frequently displayed increased placental and birth weights whereas ES cell-tetraploid pups were of normal weight. The potency of F(1) ES cells to generate live, fertile adults was not lost after either long-term in vitro culture or serial gene targeting events. We conclude that genetic heterozygosity is a crucial parameter for postnatal survival of mice that are entirely derived from ES cells by either nuclear cloning or tetraploid embryo complementation. In addition, our results demonstrate that tetraploid embryo complementation using F(1) ES cells represents a simple, efficient procedure for deriving animals with complex genetic alterations without the need for a chimeric intermediate.

A simple, rapid, and highly efficient gene expression system for multiheme cytochromes c.

The genes of tetraheme cytochrome c3 and hexadecaheme high-molecular-weight cytochrome c from Desulfovibrio vulgaris could be overexpressed as holoproteins in Shewanella oneidensis TSP-C using pUC-type vectors of E. coli. Surprisingly, S. oneidensis was transformed directly by pUC-type vectors through electroporation. The yields of the recombinant proteins in this expression system were much higher than the previously reported ones.