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Purely organic crystals, κ-X 3 (Cat-EDT-TTF) 2 [X = H or D, Cat-EDT-TTF = catechol-fused tetrathiafulvalene], are a new type of molecular conductor with hydrogen dynamics. In this work, hydrostatic pressure effects on these materials were investigated in terms of the electrical resistivity and crystal structure. The results indicate that the pressure induces and promotes hydrogen (deuterium) localization in the hydrogen bond, in contrast to the case of the conventional hydrogen-bonded materials (where pressure prevents hydrogen localization), and consequently leads to a significant change in the electrical conducting properties ( i . e ., the occurrence of a semiconductor-insulator transition). Therefore, we have successfully found a new type of pressure-induced phase transition where the cooperation of the hydrogen dynamics and π-electron interactions plays a crucial role., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Symmetric secondary amines were synthesized by the self-condensation of primary amines over a palladium-loaded titanium dioxide (Pd/TiO 2 ) photocatalyst. The reactions afforded a series of secondary amines in moderate to excellent isolated yields at ambient temperature (30 °C, in cyclopentyl methyl ether). Applicability for one-pot pharmaceutical synthesis was demonstrated by a photocatalytic reaction sequence of self-condensation of an amine followed by N-alkylation of the resulting secondary amine with an alcohol.

The sensitivity of shot noise to the interplay between Kondo correlations and superconductivity is investigated in a carbon nanotube quantum dot connected to superconducting electrodes. Depending on the gate voltage, the SU(2) and SU(4) Kondo unitary regimes can be clearly identified. We observe enhancement of the shot noise via the Fano factor in the superconducting state. Its divergence at low bias voltage, which is more pronounced in the SU(4) regime than in the SU(2) one, is larger than what is expected from proliferation of multiple Andreev reflections predicted by the existing theories. Our result suggests that the Kondo effect is responsible for this strong enhancement.

Objective: This study aimed to evaluate the outcomes of repeat interventions on the aorta and aortic valve after surgery for acute Stanford type A aortic dissection., Methods: The hospital records of patients who underwent repeat surgical intervention between April 2011 and March 2017 for late complications after acute type A aortic dissection repair were retrospectively reviewed., Results: We identified 17 patients with mean age of 62 ± 8 years; 13 were men. The mean interval from the initial emergency aortic repair to the repeat intervention was 5.8 ± 5.4 years (range 133 days-16.6 years). Ten patients had dilatation or rupture of the residual type B aortic dissection; six of them had retrograde type A aortic dissection at the onset and did not undergo resection of the primary entry. Five patients had a pseudoaneurysm at the anastomosis; four of them were receiving anticoagulation medication. Three patients had aortic regurgitation; two of them were associated with the gelatin-resorcinol-formaldehyde glue that was used during the initial surgery. There was no early mortality after repeat intervention and no late death after a mean follow-up period of 3.3 ± 2.0 years., Conclusions: Repeat surgical intervention on the aorta and aortic valve after repair of acute type A aortic dissection had favorable early and mid-term outcomes and was not associated with early or late death. Long-term follow-up with imaging and echocardiography was considered to be essential for early detection of residual type B dilatation, anastomotic pseudoaneurysm, and aortic regurgitation after initial aortic repair.

Purpose: Heatstroke causes systemic inflammation, followed by vascular endothelial damage. The normal vascular endothelium is coated by endothelial glycocalyx (EGCX). Dexmedetomidine (DEX) has an anti-inflammatory effect, but there has been little investigation on the influence of heatstroke on EGCX and the effect of DEX on this condition. Therefore, we examined whether EGCX was disrupted in heatstroke and if DEX improved survival and preserves EGCX., Methods: Anesthetized Wistar rats were randomly assigned to three groups: a DEX group treated with DEX (5 µg/kg/h) and 0.9% saline infused continuously at 10 ml/kg/h during heat exposure; a NSS group given 0.9% saline during heat exposure; and a SHAM group given 0.9% saline alone without heat exposure. Heatstroke was induced by exposure to an ambient temperature of 40 °C with relative humidity of 60%. The survival rate was assessed up to 2 h after the start of heat exposure. Plasma levels of syndecan-1 and the thickness of EGCX using electron microscopy were measured when the systolic blood pressure fell to less than 80 mmHg., Results: The survival rate after 2 h of heat exposure was significantly higher in the DEX group compared to the NSS group (89% vs. 22%, P = 0.004). Plasma levels of syndecan-1 were 0.6 ± 1.3, 9.7 ± 5.9, and 2.1 ± 3.4 ng/ml in the SHAM, NSS and DEX groups, respectively (P = 0.013). The thickness of EGCX was significantly higher in the DEX group compared with the NSS group (P = 0.001)., Conclusions: EGCX was disrupted in heatstroke, and DEX improved survival and preserved EGCX.

Regional cerebral oximetry using near-infrared spectroscopy devices is commonly used for detecting cerebral ischemia during cardiopulmonary bypass, and aim to avoid poor cerebral perfusion which may result in perioperative neurological impairment. Today, several devices that can detect cerebral ischemia are commercially available. Although these devices operate on the same measurement principles, their algorithms for detecting and calculating cerebral ischemia are different and no criteria for directly comparing values measured by such different devices exist. From January 2017 to August 2017, 80 adult cardiovascular surgery patients were enrolled in the prospective study. In each patient, preoperative regional cerebral oxygen saturation values were measured by two different devices and their correlations with various preoperative factors were evaluated. Regional cerebral oxygen saturation levels were significantly higher for values of FORE-SIGHT ELITE (CAS Medical Systems, Branford, CT, USA) (F value) than those of the INVOS 5100C (Medtronic, Minneapolis, MN, USA) (I value). Scalp-cortex distance, hemoglobin concentration, and the presence or absence of hemodialysis showed significant correlations with ratios of measured values specific to each device (F/I). An appropriate device should be selected according to preoperative patient characteristics, and factors influencing regional cerebral oxygen saturation values should be considered to ensure the correct interpretation of measured values. This research was conducted with the approval of the ethics committee of our university (approval number: B16-96).

Case 1:An 18-year-old male underwent emergent left extracorporeal ventricular assist device(eVAD) implantation for a cardiogenic shock because of dilated cardiomyopathy (DCM). After listing for heart transplant, he underwent a HeartMate II implantation as bridge-to-bridge(BTB) therapy. The omental flap was simultaneously used to prevent device infection that could have been induced by the infected malgranulation around the cannulas of the eVAD. Eventually, he was discharged and waiting for transplantation. Case 2:A 30-year-old male with DCM underwent emergent eVAD implantation for left ventricular support, centrifugal veno-pulmonary artery extracorporeal membrane oxygenation (ECMO) for right ventricular and respiratory support, and mitral valve replacement. After weaning of ECMO, he was listed for a heart transplant and underwent a HeartMate II implantation as BTB therapy. However, liver dysfunction and malnutrition prolonged wound healing. Despite applying vacuum assist closure device to promote wound healing, part of the driveline and pump housing were exposed. Therefore, radical debridement and omentopexy were performed for infection control. He was discharged after complete wound healing.

The field-induced antipolar-polar structural transition in an organic antiferroelectric 2-trifluoromethylnaphthimidazole crystal is investigated by performing synchrotron X-ray diffraction. The polarities of all of the hydrogen-bonded chains become parallel with each other in the presence of an external electric field. The switching is accompanied by a giant electrostriction, which provides 1 order of magnitude larger strain than the piezoelectric strain of the organic ferroelectrics: croconic acid and poly(vinylidene fluoride); however, it is comparable to those of typical commercial piezoelectric ceramics. The crystal structure analysis with electric field shows that the origin of the observed giant electrostriction can be attributed to the shear strain that emerges from the polarity switching of the hydrogen-bonded chains. The antipolar-polar structural transition in antiferroelectrics could be employed for the development of high-performance electrostrictive organic materials.

Early extubation in the operating room after congenital open-heart surgery is feasible, but extubation in the intensive care unit after the operation remains common practice at many institutions. The purpose of this study was to evaluate retrospectively the adequacy of our early-extubation strategy and exclusion criteria through analysis based on the Risk Adjustment in Congenital Heart Surgery method (RACHS-1).This retrospective analysis included 359 cases requiring cardiopulmonary bypass (male, 195; female, 164; weight > 3.0 kg; aged 1 month to 18 years). Neonates and preoperatively intubated patients were excluded. Other exclusion criteria included severe preoperative pulmonary hypertension, high-dose catecholamine requirement after cardiopulmonary bypass, delayed sternal closure, laryngomalacia, serious bleeding, and delayed awakening. The early-extubation rates were compared between age groups and RACHS-1 classes.Overall, 83% of cases (298/359) were extubated in the operating room, classified by RACHS-1 categories as follows: 1, 59/59 (100%); 2, 164/200 (84%); 3, 61/78 (78%); and 4-6, 10/22 (45%). The early extubation rate in categories 1-3 (86%, 288/337) was significantly higher than for categories 4-6 (45.5%, 10/22) (P < 0.001). Because they met one of the exclusion criteria, 61 patients (17%) were not extubated in the operating room. Eight patients (2.7%) required re-intubation after early extubation in the operating room, and longer operation time was significantly associated with re-intubation (P < 0.001).Extubation in the operating room after congenital open-heart surgery was feasible based on our criteria, especially for patients in the low RACHS-1 categories, and involves a very low rate of re-intubation.

Regional cerebral oximetry using near-infrared spectroscopy device, an INVOS 5100 C (Medtronic, Minneapolis, MN, USA), during cardiac surgery aims to avoid perioperative neurological impairment, especially during cardiopulmonary bypass. However, it is not uncommon to encounter critically low initial cerebral regional oxygen saturation or a low value unresponsive to intervention. Therefore, it is important to identify factors associated with low saturation value other than true cerebral hypoxia. We investigated the relationship between preoperative regional cerebral oxygen saturation and clinical variables during cardiac surgery. From January 2013 to May 2016, 462 patients underwent elective cardiac surgery. Patient's ≤12 years of age, with acute cerebral infarction, with previous intracranial hemorrhage or neurosurgery, with concomitant aortic surgery, and having off-pump coronary artery bypass surgery were excluded. The remaining 223 patients were monitored by intraoperative regional cerebral oximetry. Univariate analysis found that scalp-cortex distance, cerebrospinal fluid thickness, left ventricular ejection fraction, hemoglobin concentration, estimated glomerular filtration rate, and hemodialysis were significantly correlated with the initial regional oxygen saturation value. Multiple regression analysis revealed that scalp-cortex distance, left ventricular ejection fraction, hemoglobin, and hemodialysis remained as significant variables. A receiver operating characteristic analysis found that for a low initial regional oxygen saturation value of 40%, the thresholds of scalp-cortex distance, left ventricular ejection fraction, and hemoglobin concentration were 17.6 mm, 45.2%, and 7.5 g/dl, respectively. In conclusion, brain atrophy, poor left ventricular function, anemia, and hemodialysis were associated with low initial cerebral regional oxygen saturation values in adult cardiac surgery patients.

Universal properties of entangled many-body states are controlled by their symmetry and quantum fluctuations. By the magnetic-field tuning of the spin-orbital degeneracy in a Kondo-correlated quantum dot, we have modified quantum fluctuations to directly measure their influence on the many-body properties along the crossover from SU(4) to SU(2) symmetry of the ground state. High-sensitive current noise measurements combined with the nonequilibrium Fermi liquid theory clarify that the Kondo resonance and electron correlations are enhanced as the fluctuations, measured by the Wilson ratio, increase along the symmetry crossover. Our achievement demonstrates that nonlinear noise constitutes a measure of quantum fluctuations that can be used to tackle quantum phase transitions.

Minimally invasive atrial septal defect closure and tricuspid annuloplasty in female patients are normally performed through a right submammary anterior minithoracotomy approach. However, when the aortic root is located higher, the direction of aortic cannulation becomes not ideal through the submammary incision. In such cases, transareolar approach is useful. Through this approach, aortic cannulation and tricuspid operation can be performed with endoscopic assistance, and ASD closure can be performed under direct vision.

A tracheal tube can be safely replaced by using a tube exchanger (TE). However, only a thin TE can be used to replace a double-lumen tracheal tube (DLT) with a standard single-lumen tracheal tube (SLT). We successfully replaced a DLT to a SLT by inserting an Aintree Intubation Catheter® (AIC) over a TE in two cases. The AIC (diameter : 19 Fr, overall length : 56 cm) is mainly used for the replacement of various supra- glottic apparatuses using a SLT. In our cases, an AIC with an internal diameter of 4.7 mm was placed over a thin TE with an external diameter of 3.7 mm (11 Fr) to increase the support, and the difference between the SLT with an internal diameter of 7.5 mm and an AIC with an external diameter of 6.3 mm (19 Fr) was decreased, resulting in smooth replacement of the tubes. Even for those cases in which tube replacement might be difficult, acute administration of oxygen could be provided using an AIC with a larger internal lumenthan TE. In conclusion, replacement of a DLT with a SLT i safe and useful through the concomitant use of an AI( and a TE.

Ferroelectrics based on proton tautomerism are promising in low-field and above-room-temperature operations. Here seven organic ferroelectric crystals are examined to search for efficient switching of strong spontaneous polarization on proton tautomerism. Solution-grown crystals exhibit strong pinning of ferroelectric domain walls, but excellent switching performance is awakened by depinning domain walls under thermal annealing and/or repetitive bipolar pulses with a high voltage. Compared with ferroelectric polymers such as polyvinylidefluoride, the optimized polarizations are comparable or stronger in magnitude whereas the coercive fields are two orders of magnitude weaker. The polarization of croconic acid, in particular, breaks its own record for organic systems in increasing from 21 to 30 μC cm -2 and now exceeds those of some commercial ferroelectric materials such as SrBi 2 Ta 2 O 9 and BaTiO 3 . Optimization reduces the discrepancy of the spontaneous polarization with the results of the first-principles calculations to less than 15%. The cooperative roles of proton transfer and π-bond switching are discussed by employing the point-charge model and hydrogen-bond geometry.

We report a case of pericardial fenestration in a patient with myocardial metastasis and cardiac tamponade after surgery for esophageal cancer. A 66-year-old man had been suffering from orthopnea, hypotension and general malaise due to cardiac tamponade and heart failure. Esophagectomy was performed with substernal gastric tube reconstruction for advanced esophageal carcinoma. Nine months after the operation, heart failure developed, and myocardial and pericardial metastasis was subsequently detected. Subxiphoidal pericardiocentesis was abandoned due to the substernal gastric tube, and pericardial fenestration was performed through a small left anterior thoracotomy at the 5th intercostal space. His symptoms were ameliorated immediately and the procedure contributed greatly to maintain his quality of life. Preoperative computed tomography was useful for revealing the anatomical positions of the gastric tube and important vessels.

Quaking (QKI), which belongs to the STAR family of KH domain-containing RNA-binding proteins, functions in pre-mRNA splicing, microRNA regulation, and formation of circular RNA. QKI plays critical roles in myelinogenesis in the central and peripheral nervous systems and has been implicated neuron-glia fate decision in the brain; however, neither the expression nor function of QKI in the neural retina is known. Here we report the expression of QKI RNA-binding protein in the developing and mature mouse retina. QKI was strongly expressed by Müller glial cells in both the developing and adult retina. Intriguingly, during development, QKI was expressed in early differentiating neurons, such as the horizontal and amacrine cells, and subsequently in later differentiating bipolar cells, but not in photoreceptors. Neuronal expression was uniformly weak in the adult. Among QKI isoforms (5, 6, and 7), QKI-5 was the predominantly expressed isoform in the adult retina. To study the function of QKI in the mouse retina, we examined quakingviable(qkv) mice, which have a dysmyelination phenotype that results from deficiency of QKI expression and reduced numbers of mature oligodendrocytes. In homozygous qkv mutant mice (qkv/qkv), the optic nerve expression levels of QKI-6 and 7, but not QKI-5 were reduced. In the retina of the mutant homozygote, QKI-5 levels were unchanged, and QKI-6 and 7 levels, already low, were also unaffected. We conclude that QKI is expressed in developing and adult Müller glia. QKI is additionally expressed in progenitors and in differentiating neurons during retinal development, but expression weakened or diminished during maturation. Among QKI isoforms, we found that QKI-5 predominated in the adult mouse retina. Since Müller glial cells are thought to share properties with retinal progenitor cells, our data suggest that QKI may contribute to maintaining retinal progenitors prior to differentiation into neurons. On the other hand, the expression of QKI in different retinal neurons may suggest a role in neuronal cell type specific fate determination and maturation. The data raises the possibility that QKI may function in retinal cell fate determination and maturation in both glia and neurons.

We performed noise measurements for a Corbino disk in the quantum Hall effect breakdown regime. We investigated two Corbino-disk-type devices with different sizes and observed that the Fano factor increases when the length between the contacts doubles. This observation is consistent with the avalanche picture suggested by the bootstrap electron heating model. The temperature dependence of the Fano factor indicates that the avalanche effect becomes more prominent as temperature decreases. Moreover, in the highly nonlinear regime, negative differential resistance and temporal oscillation due to bistability are found. A possible interpretation of this result is that Zener tunneling of electrons between Landau levels occurs.

Mesoscopic systems - small electric circuits working in quantum regime - offer us a unique experimental stage to explorer quantum transport in a tunable and precise way. The purpose of this Review is to show how they can contribute to statistical physics. We introduce the significance of fluctuation, or equivalently noise, as noise measurement enables us to address the fundamental aspects of a physical system. The significance of the fluctuation theorem (FT) in statistical physics is noted. We explain what information can be deduced from the current noise measurement in mesoscopic systems. As an important application of the noise measurement to statistical physics, we describe our experimental work on the current and current noise in an electron interferometer, which is the first experimental test of FT in quantum regime. Our attempt will shed new light in the research field of mesoscopic quantum statistical physics.

The fabrication of single-crystalline thin-film arrays for an organic ferroelectric small molecule is achieved by a simple solution process without additional thermal annealing. Based on a cooperative proton tautomerism through a hydrogen-bonding network, films show the polarity switching with an operating voltage of less than 5 V at room temperature. This approach provides a low-cost and eco-friendly fabrication of ferroelectric devices., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Massless Dirac electron systems such as graphene exhibit a distinct half-integer quantum Hall effect, and in the bipolar transport regime co-propagating edge states along the p-n junction are realized. Additionally, these edge states are uniformly mixed at the junction, which makes it a unique structure to partition electrons in these edge states. Although many experimental works have addressed this issue, the microscopic dynamics of electron partition in this peculiar structure remains unclear. Here we performed shot-noise measurements on the junction in the quantum Hall regime as well as at zero magnetic field. We found that, in sharp contrast with the zero-field case, the shot noise in the quantum Hall regime is finite in the bipolar regime, but is strongly suppressed in the unipolar regime. Our observation is consistent with the theoretical prediction and gives microscopic evidence that the edge states are uniquely mixed along the p-n junction.

When an electric current passes across a potential barrier, the partition process of electrons at the barrier gives rise to the shot noise, reflecting the discrete nature of the electric charge. Here we report the observation of excess shot noise connected with a spin current which is induced by a nonequilibrium spin accumulation in an all-semiconductor lateral spin-valve device. We find that this excess shot noise is proportional to the spin current. Additionally, we determine quantitatively the spin-injection-induced electron temperature by measuring the current noise. Our experiments show that spin accumulation driven shot noise provides a novel means of investigating nonequilibrium spin transport.

Three polymorphic forms of 6,6'-dimethyl-2,2'-bipyridinium chloranilate crystals were characterized to understand the origin of polarization properties and the thermal stability of ferroelectricity. According to the temperature-dependent permittivity, differential scanning calorimetry, and X-ray diffraction, structural phase transitions were found in all polymorphs. Notably, the ferroelectric α-form crystal, which has the longest hydrogen bond (2.95 Å) among the organic acid/base-type supramolecular ferroelectrics, transformed from a polar structure (space group, P21) into an anti-polar structure (space group, P21/c) at 378 K. The non-ferroelectric β- and γ-form crystals also exhibited structural rearrangements around hydrogen bonds. The hydrogen-bonded geometry and ferroelectric properties were compared with other supramolecular ferroelectrics. A positive relationship between the phase-transition temperature (TC ) and hydrogen-bond length () was observed, and was attributed to the potential barrier height for proton off-centering or order/disorder phenomena. The optimized spontaneous polarization (Ps ) agreed well with the results of the first-principles calculations, and could be amplified by separating the two equilibrium positions of protons with increasing . These data consistently demonstrated that stretching is a promising way to enhance the polarization performance and thermal stability of hydrogen-bonded organic ferroelectrics., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a case of aortic valve replacement( AVR) for recurrent aortic stenosis(AS) after percutaneous transluminal balloon aortic valvuloplasty( PTAV) in a patient with left renal pelvis carcinoma. A 65-year-old female had been suffering from shortness of breath and syncope due to severe AS. She was considered to be a candidate for AVR. Preoperative examination revealed advanced left renal pelvis carcinoma that was a critical comorbidity for AVR. Ureteronephrectomy was also considered to be a contraindication. Despite conservative treatment, her condition was deteriorated. Emergency PTAV was performed when she was transferred to our hospital with circulatory shock. Her symptoms were ameliorated and left ureteronephrectomy was conducted 8 month after the PTAV. She was readmitted to our hospital 16 month after the PTAV and AVR was performed successfully.Antegrade transseptal PTAV is a very useful palliative therapy for AS with severe comorbidities as a bridge to surgery.

A unique N(+)-H···N hydrogen-bonded (H-bonded) dimer motif based on partially oxidized pyridyl-substituted TTF was constructed in the charge-transfer complex. The charge ordering in the TTF column by the charge disproportionation in the dimer regulates the arrangement of the H-bonded proton, evidencing the proton-electron coupled state.

Ferroelectric polarization of 6.3  μC cm(-2) is induced by the neutral-to-ionic transition, upon which nonpolar molecules of electron donor tetrathiafulvalene (TTF) and acceptor p-chloranil (CA) are incompletely ionized to ±0.60e and dimerized along the molecular stacking chain. We find that the ferroelectric properties are governed by intermolecular charge transfer rather than simple displacement of static point charge on molecules. The observed polarization and poling effect on the absolute structural configuration can be interpreted in terms of electronic ferroelectricity, which not only exhibits antiparallel polarity to the ionic displacement but also enhances the polarization more than 20 times that of the point-charge model.

The demonstration of quantized spin splitting by Stern and Gerlach is one of the most important experiments in modern physics. Their discovery was the precursor of recent developments in spin-based technologies. Although electrical spin separation of charged particles is fundamental in spintronics, in non-uniform magnetic fields it has been difficult to separate the spin states of charged particles due to the Lorentz force, as well as to the insufficient and uncontrollable field gradients. Here we demonstrate electronic spin separation in a semiconductor nanostructure. To avoid the Lorentz force, which is inevitably induced when an external magnetic field is applied, we utilized the effective non-uniform magnetic field which originates from the Rashba spin-orbit interaction in an InGaAs-based heterostructure. Using a Stern-Gerlach-inspired mechanism, together with a quantum point contact, we obtained field gradients of 10(8) T m(-1) resulting in a highly polarized spin current.

We measure the current and shot noise in a quantum dot in the Kondo regime to address the nonequilibrium properties of the Kondo effect. By systematically tuning the temperature and gate voltages to define the level positions in the quantum dot, we observe an enhancement of the shot noise as temperature decreases below the Kondo temperature, which indicates that the two-particle scattering process grows as the Kondo state evolves. Below the Kondo temperature, the Fano factor defined at finite temperature is found to exceed the expected value of unity from the noninteracting model, reaching 1.8±0.2.

We experimentally demonstrate the validity of nonequilibrium fluctuation relations by using a quantum coherent conductor. In equilibrium the fluctuation-dissipation relation leads to the correlation between current and current noise at the conductor, namely, the Johnson-Nyquist relation. When the conductor is voltage biased so that the nonlinear regime is entered, the fluctuation theorem has predicted similar nonequilibrium fluctuation relations, which hold true even when the Onsager-Casmir relations are broken in magnetic fields. Our experiments qualitatively validate the predictions as the first evidence of this theorem in the nonequilibrium quantum regime.

Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.

Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure-activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.

The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.

The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.

The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.

A structure-activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over binding affinity for hERG and other opioid receptors.

Time-resolved soft x-ray transmission microscopy is applied to image the current-induced resonant dynamics of the magnetic vortex core realized in a micron sized Permalloy disk. The high spatial resolution better than 25 nm enables us to observe the resonant motion of the vortex core. The result also provides the spin polarization of the current to be 0.67+/-0.16 for Permalloy by fitting the experimental results with an analytical model in the framework of the spin-transfer torque.

A rhombic shaped pulmonary autograft patch was applied to enlarge an ostial stenosis of the left main coronary artery (LMCA) in a 25-year-old woman diagnosed with vasculitis syndrome. The patch increased the width of the ostial stenosis and made a funnel-shaped connection. At eighteen months of follow-up, a coronary angiogram by computed tomography showed no restenosis at the LMCA. The rhombic-shaped pulmonary autograft patch might be an ideal shape and material for angioplasty of the ostial stenosis of the LMCA.

Structure-activity studies on benzimidazole lead 1 obtained from library screening led to the discovery of potent and selective ORL1 antagonist 28, 5-chloro-2-[(1-ethyl-1-methylpropyl)thio]-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-benzimidazole, which is structurally distinct from conventional non-peptide antagonists known to date.

Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described.

We describe a new technique of mitral valve repair based on two reconstructive techniques: (1) the folding leaflet method, and (2) the classic annular plication. This combination appears to be useful in cases with a large prolapsing posterior mitral leaflet with excessive leaflet height or in cases with commissural prolapse involving both the anterior and posterior leaflets.