Safety and Applicability of Continuous Retrograde Cardioplegia in Minimally Invasive Aortic Valve Replacement: New Approaches.

PURPOSE: To discuss minimally invasive cardiac surgery aortic valve replacement (MICS-AVR) approach via anterior thoracotomy using continuous retrograde cardioplegia. Continuous retrograde cardioplegia facilitates excellent continuous homogeneous cooling of the heart during cardiac arrest. METHODS: We performed AVR using the proposed method in nine patients between June 2018 and September 2019. The median age of the patients was 73 (range: 43-84) years. The pleural space was entered via anterior thoracotomy. After opening of the right atrium, a retrograde cardioplegic cannula was inserted into the coronary sinus with a purse-string suture. Continuous cold blood retrograde cardioplegia was initiated at 700 mL/h. RESULTS: Extubation in the operating room was performed in five (56%) patients. No new decreased function of the left and right ventricles was observed in intraoperative transesophageal echography or transthoracic echocardiogram. CONCLUSION: MICA-AVR through continuous retrograde cardioplegia is a safe technique.

Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia.

Achondroplasia is caused by gain-of-function mutations in FGFR3 gene and leads to short-limb dwarfism. A stabilized analogue of C-type natriuretic peptide (CNP) is known to elongate bone by interacting with FGFR3 signals and thus is a promising drug candidate. However, it needs daily administration by percutaneous injection. FGFR inhibitor compounds are other drug candidates for achondroplasia because they directly fix the mutant protein malfunction. Although FGFR inhibitors elongate the bone of model mice, their adverse effects are not well studied. In this study, we found that a new FGFR inhibitor, ASP5878, which was originally developed as an anti-cancer drug, elongated the bone of achondroplasia model male mice at the dose of 300 µg/kg, which confers an AUC of 275 ng·h/ml in juvenile mice. Although ASP5878 was less effective in bone elongation than a CNP analogue, it is advantageous in that ASP5878 can be administered orally. The AUC at which minimal adverse effects were observed (very slight atrophy of the corneal epithelium) was 459 ng·h/ml in juvenile rats. The positive discrepancy between AUCs that brought efficacy and minimal adverse effect suggests the applicability of ASP5878 to achondroplasia in the clinical setting. We also analyzed effects of ASP5878 in a patient-specific induced pluripotent stem cell (iPSC) model for achondroplasia and found the effects on patient chondrocyte equivalents. Nevertheless, cautious consideration is needed when referring to safety data obtained from its application to adult patients with cancer in clinical tests.

Unique vapochromism of a paddlewheel-type dirhodium complex accompanied by dynamic structural and phase transitions.

The one-dimensional coordination polymer [Rh2(HA)4]n (1G; HA = hexanoate) exhibits a drastic vapochromic color change from green to red upon exposure to pyridine (py) vapor. Heating the red discrete complex [Rh2(HA)4(py)2] (1R) at 338 K affords the purple discrete tetrarhodium complex [Rh2(HA)4(py)]2 (1P), which is an intermediate species in the vapochromic transformation of 1G to 1R. The obtained complexes 1G, 1R, and 1P differ not only in their color in the solid state, but also in their temperature-dependent phase transition properties.

Photocatalytic and electrocatalytic hydrogen production using nickel complexes supported by hemilabile and non-innocent ligands.

Nickel complexes with non-innocent ligands generated by one-electron reduction of octahedral Schiff base nickel(ii) complexes with hemilabile ligands exhibited excellent catalytic activities of over 5000 TONs through a metal-ligand cooperation mechanism for hydrogen evolution from water under visible light irradiation.

Photooxidation Reactions of Cyclometalated Palladium(II) and Platinum(II) Complexes.

New C,N,S-cyclometalated palladium(II) and platinum(II) complexes have been synthesized and their structural, electrochemical, and photochemical properties examined. The blue color of these complexes in solution changed to yellow under visible-light irradiation. By measurement of the absorption spectra for quantifying changes in color, isosbestic points for each complex clearly indicated the presence of only two species responsible for the change of color. X-ray analysis revealed that the visible-light-induced yellow species were S-oxygenated sulfinato complexes. Photosensitized generation of singlet oxygen (1O2) was confirmed by the direct detection of singlet oxygen luminescence at 1275 nm. The present cyclometalated palladium(II) and platinum(II) complexes are efficient photosensitizers of singlet oxygen, which rapidly reacts with coordinating sulfur atoms.

Author Correction: Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers.

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Mid-term outcomes of simultaneous mitral valve repair in patients with miral regurgitation and concomitant annulo-aortic ectasia.

OBJECTIVE: This study investigated the mid-term outcomes of simultaneous mitral valve repair in patients with mitral regurgitation (MR) and concomitant annulo-aortic ectasia. METHODS: The study included 26 patients with MR and annulo-aortic ectasia [mean age 46.0 ± 19.9 (10-86) years] who underwent simultaneous mitral valve repair between January 2007 and March 2018. Of these 26 patients, 11 (42.3%) were diagnosed with Marfan syndrome and 10 (38.5%) with Barlow's disease. All patients underwent complete ring annuloplasty; a semi-rigid ring was used in 14 (53.8%) and a semi-flexible ring (anterior-flexible) in 12 patients (46.2%). All patients underwent valve-sparing root replacement using the reimplantation technique. RESULTS: The overall 3-year survival rate was 95.7 ± 4.3%. The 3-year freedom from > moderate MR rate was 94.7 ± 5.1%, and the 3-year freedom from > moderate aortic regurgitation (AR) rate was 86.7 ± 7.3%. The 3-year freedom from reoperation rate was 100%. The 3-year freedom from > moderate MR rate was 100% in the semi-rigid ring group and 85.7 ± 13.2% in the semi-flexible ring group (log-rank test, p = 0.5371). The 3-year freedom from > moderate AR rate was 100% in the semi-rigid ring group and 72.9 ± 16.5% in the semi-flexible ring group (log-rank test, p = 0.0815). CONCLUSIONS: Simultaneous mitral valve repair in patients with MR and concomitant annulo-aortic ectasia showed favorable mid-term outcomes.

Intrinsic hydrogen evolution capability and a theoretically supported reaction mechanism of a paddlewheel-type dirhodium complex.

The intrinsic capability of the paddlewheel-type dirhodium tetraacetate complex, [Rh2(O2CCH3)4(H2O)2] ([1(H2O)2]), as a hydrogen evolution catalyst (HEC) for photochemical hydrogen evolution from aqueous solution was illustrated. This was achieved by using an optimized artificial photosynthesis (AP) system with a cyclometalated iridium complex [Ir(ppy)2(bpy)](PF6) ([Ir-PS-1]) and triethylamine (TEA) serving as a photosensitizer (PS) and a sacrificial donor, respectively. The total amount of hydrogen evolution and the turnover number (TON) of catalysis using this AP system were 385.7 µmol and 3857 (per Rh ion), respectively; these values are higher than those of [Rh(dtBubpy)3](PF6)3, which is the most efficient HEC among the mononuclear rhodium complexes, and RhCl3. Moreover, the catalytic performance of [1(H2O)2] was further accelerated by using [Ir(ppy)2(dtBubpy)](PF6) [Ir-PS-3] as a PS; 9886 TON (H2 per Rh ion) was verified after 12 h of irradiation. In addition, the detailed mechanism of hydrogen evolution catalyzed by [1(H2O)2] was clarified by combining electro- and photochemical analyses and DFT calculations. The optimized geometries of [1(H2O)2], [1], hydride intermediates [H-Rh2(O2CCH3)4] ([H-1]), and their reduced species were theoretically verified by DFT calculations. Moreover, their redox potentials were theoretically estimated and compared with the observed potentials. Their combination analyses indicated that (i) the formation of [1], which has an open-metal site for hydrogen evolution and can be reduced by the one-electron reduced species of [Ir-PS-1], is a trigger for hydrogen evolution; (ii) [H-1] and its reduced species, which are verified by CV analyses, are key intermediate species in this reaction; and (iii) photochemical hydrogen evolution catalyzed by [1(H2O)2] occurred by two-electron reduction processes.

Synthesis, Characterization, Absorption Properties, and Electronic Structures of Paddlewheel-Type Dirhodium(II) Tetra-µ-(n-naphthoate) Complexes: An Experimental and Theoretical Study.

The reactions of [Rh2(O2CCH3)4(OH2)2] with n-naphthalenecarboxylic acids (n = 1: 1-HNC, n = 2: 2-HNC) afford the dirhodium tetra-µ-(n-naphthoate) complexes [Rh2(1-NC)4] (1) and [Rh2(2-NC)4] (2), respectively. Single crystal X-ray diffraction analyses of [1(OCMe2)2] and [2(OCMe2)2], which were obtained by recrystallization from acetone (OCMe2) solutions of 1 and 2, reveal that the dirhodium cores are coordinated by four equatorially bridging naphthoate ligands and two axial OCMe2 ligands. Density functional theory (DFT) calculation confirmed that (i) the single Rh⁻Rh bond is formed between the two Rh ions and (ii) the electronic structures between two Rh ions in [1(OCMe2)2] and [2(OCMe2)2] are best described as π4δ²σ²Î´*²π*4 and δ²π4σ²Î´*²π*4, respectively. Time-dependent DFT (TDDFT) calculations clarify the absorption band characters of [1(OCMe2)2] and [2(OCMe2)2]; the former shows the bands due to d⁻d and metal⁻to⁻metal-ligand charge transfer (MMLCT) excitations in the visible light region, whereas the latter shows the bands due to only d⁻d excitations in the same region. The electrochemical properties and thermal stabilities of [1(OCMe2)2] and [2(OCMe2)2] were also investigated in this study.

Experimental and theoretical study of dimer-of-dimers-type tetrarhodium(ii) complexes bridged by 1,4-benzenedicarboxylate linkers.

Two dimer-of-dimers-type tetrarhodium complexes, [Rh4(piv)6(BDC)] ([1]; piv = pivalate) and [Rh4(piv)6(F4BDC)] ([2]), in which two paddlewheel-type dirhodium units are linked by 1,4-benzenedicarboxylate (BDC) and 1,4-tetrafluorobenzenedicarboxylate (F4BDC), respectively, have been synthesized and characterized via single-crystal X-ray diffraction analyses, ESI-MS, 1H NMR, infrared spectroscopy, Raman spectroscopy, and elemental analyses. Crystal structure analyses of [1(THF)4] and [2(THF)4], which are crystallized from THF solutions of [1] and [2], respectively, revealed that dihedral angles (φ) between two -CO2 units and phenyl rings of the BDC linker in [1(THF)4] are almost co-planar (φ = 2.8°), whereas those of the F4BDC linker in [2(THF)4] are largely inclined (φ = 78.3°). Density functional theory calculations clarified that (i) their dihedral angles of optimized geometries of [1(THF)4] and [2(THF)4] are almost the same as their experimental geometries, and (ii) the rotation energy barriers of phenyl moieties in [1(THF)4] and [2(THF)4] estimated by potential energy surface analyses are 12.0 and 8.4 kcal mol-1, respectively, indicating that hydrogen bondings are formed between two -CO2 units and four hydrogen atoms of phenyl rings of the BDC linker in [1(THF)4], whereas two -CO2 units and four fluorine groups on the phenyl ring of the F4BDC linker in [2(THF)4] are electrostatically and sterically repulsed. Electrochemical properties and electronic structures of [1(THF)4] and [2(THF)4] are strongly influenced by the electronic states of dicarboxylate linkers, whereas absorption spectra are strongly influenced by the dihedral angles between two -CO2 units and phenyl rings of dicarboxylate linkers.

Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers.

Cell therapy using renal progenitors differentiated from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) has the potential to significantly reduce the number of patients receiving dialysis therapy. However, the differentiation cultures may contain undifferentiated or undesired cell types that cause unwanted side effects, such as neoplastic formation, when transplanted into a body. Moreover, the hESCs/iPSCs are often genetically modified in order to isolate the derived renal progenitors, hampering clinical applications. To establish an isolation method for renal progenitors induced from hESCs/iPSCs without genetic modifications, we screened antibodies against cell surface markers. We identified the combination of four markers, CD9-CD140a+CD140b+CD271+, which could enrich OSR1+SIX2+ renal progenitors. Furthermore, these isolated cells ameliorated renal injury in an acute kidney injury (AKI) mouse model when used for cell therapy. These cells could contribute to the development of hiPSC-based cell therapy and disease modeling against kidney diseases.

Photo- and Electrocatalytic Hydrogen Production Using Valence Isomers of N2S2-Type Nickel Complexes.

Three Schiff-base-type nickel(II) complexes (1a-3a) and the corresponding noninnocent-type complexes (1b-3b) were synthesized, and the equilibria between these valence isomers were observed in tetrahydrofuran (THF) at room temperature. The electronic state of the noninnocent-type nickel complex was also confirmed by isolation of the one-electron-reduced species. The catalytic ability for the photogeneration of hydrogen from water was examined about 1a-3a and 1b-3b in the presence of a photosensitizer and a sacrificial electron donor. Then, a Schiff-base-type complex with chlorine atoms (2a) and a noninnocent-type complex with methyl groups (3b) on the pendant phenyl rings being present as the minor species in THF exhibited high activity of over 400 turnover numbers. The dynamic light scattering and transmission electron microscopy measurements suggested the formation of NiSx-like aggregate species under photocatalytic conditions. The electrocatalytic activities of the nickel complexes for hydrogen production were also investigated, and a plausible reaction mechanism was proposed on the basis of a combined electrochemical and density functional theory study.

Dinuclear Ruthenium(III)-Ruthenium(IV) Complexes, Having a Doubly Oxido-Bridged and Acetato- or Nitrato-Capped Framework.

Dinuclear ruthenium complexes in a mixed-valence state of Ru(III)-Ru(IV), having a doubly oxido-bridged and acetato- or nitrato-capped framework, [{Ru(III,IV)(ebpma)}2(µ-O)2(µ-L)](PF6)2 [ebpma = ethylbis(2-pyridylmethyl)amine; L = CH3COO(-) (1), NO3(-) (2)], were synthesized. In aqueous solutions, the diruthenium complex 1 showed multiple redox processes accompanied by proton transfers depending on the pH. The protonated complex of 1, which is described as 1H+, was obtained.

Transition-Metal-Mediated Cleavage of Fluoro-Silanes under Mild Conditions.

Si-F bond cleavage of fluoro-silanes was achieved by transition-metal complexes under mild and neutral conditions. The Iridium-hydride complex [Ir(H)(CO)(PPh3 )3 ] was found to readily break the Si-F bond of the diphosphine- difluorosilane {(o-Ph2 P)C6 H4 }2 Si(F)2 to afford a silyl complex [{[o-(iPh2 P)C6 H4 ]2 (F)Si}Ir(CO)(PPh3 )] and HF. Density functional theory calculations disclose a reaction mechanism in which a hypervalent silicon species with a dative Ir→Si interaction plays a crucial role. The Ir→Si interaction changes the character of the H on the Ir from hydridic to protic, and makes the F on Si more anionic, leading to the formation of H(δ+) ⋅⋅⋅F(δ-) interaction. Then the Si-F and Ir-H bonds are readily broken to afford the silyl complex and HF through σ-bond metathesis. Furthermore, the analogous rhodium complex [Rh(H)(CO)(PPh3 )3 ] was found to promote the cleavage of the Si-F bond of the triphosphine-monofluorosilane {(o-Ph2 P)C6 H4 }3 Si(F) even at ambient temperature.

Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice.

UNLABELLED: Acute kidney injury (AKI) is defined as a rapid loss of renal function resulting from various etiologies, with a mortality rate exceeding 60% among intensive care patients. Because conventional treatments have failed to alleviate this condition, the development of regenerative therapies using human induced pluripotent stem cells (hiPSCs) presents a promising new therapeutic option for AKI. We describe our methodology for generating renal progenitors from hiPSCs that show potential in ameliorating AKI. We established a multistep differentiation protocol for inducing hiPSCs into OSR1+SIX2+ renal progenitors capable of reconstituting three-dimensional proximal renal tubule-like structures in vitro and in vivo. Moreover, we found that renal subcapsular transplantation of hiPSC-derived renal progenitors ameliorated the AKI in mice induced by ischemia/reperfusion injury, significantly suppressing the elevation of blood urea nitrogen and serum creatinine levels and attenuating histopathological changes, such as tubular necrosis, tubule dilatation with casts, and interstitial fibrosis. To our knowledge, few reports demonstrating the therapeutic efficacy of cell therapy with renal lineage cells generated from hiPSCs have been published. Our results suggest that regenerative medicine strategies for kidney diseases could be developed using hiPSC-derived renal cells. SIGNIFICANCE: This report is the first to demonstrate that the transplantation of renal progenitor cells differentiated from human induced pluripotent stem (iPS) cells has therapeutic effectiveness in mouse models of acute kidney injury induced by ischemia/reperfusion injury. In addition, this report clearly demonstrates that the therapeutic benefits come from trophic effects by the renal progenitor cells, and it identifies the renoprotective factors secreted by the progenitors. The results of this study indicate the feasibility of developing regenerative medicine strategy using iPS cells against renal diseases.

Generation of robust vascular networks from cardiovascular blast populations derived from human induced pluripotent stem cells in vivo and ex vivo organ culture system.

Vascular network formation is a key therapeutic event in regenerative medicine because it is essential for mitigating or ameliorating ischemic conditions implicated in various diseases and repair of tissues and organs. In this study, we induced human induced pluripotent stem cells (hiPSCs) to differentiate into heterogeneous cell populations which have abilities to form vascular vessel-like structures by recapitulating the embryonic process of vasculogenesis in vitro. These cell populations, named cardiovascular blast populations (CBPs) in this report, primarily consisted of CD31(+) and CD90(+) cells. By using cell-sheet technology, we observed that CBP with CD31(+) cells to CD90(+) cells in the ratio of 1:1.5 could reproducibly form robust vascular networks in vivo and ex vivo organ culture system. To our knowledge, this is the first report demonstrating the generation of vascular network from hiPSCs in ex vivo organ culture system that correlates closely with in vivo results. Our results suggest that CBP provides a promising approach for studying vasculogenesis and subsequently can be used in regenerative medicine.

Chirality transfer based on reversible C-C bond formation/breaking in nickel(II) complexes.

The reaction of (1R)-(-)-myrtenal-derived benzothiazoline with nickel(II) acetate in ethanol exclusively gave a Schiff base-type nickel(II) complex having M helical configurational myrtenyl arms, which is reversibly converted to a non-innocent-type complex having additional S,S configurational asymmetric carbon centres.

Autoxidation of thiol-containing amino acid to its disulfide derivative that links two copper(II) centers: the important role of auxiliary ligand.

Treatment of Cu(AcO)(2) with D-penicillamine or L-cysteine in the presence of 2,2'-bipyridine afforded dicopper(II) complexes with a bis(bidentate-N,O) disulfide ligand, the formation mechanism of which was discussed on the basis of Cu(II)-thiolate interaction affected by an auxiliary ligand.