Pivotal Role of Geometry Regulation on O-O Bond Formation Mechanism of Bimetallic Water Oxidation Catalysts.

In this study, we highlight the impact of catalyst geometry on the formation of O-O bonds in Cu2 and Fe2 catalysts. A series of Cu2 complexes with diverse linkers are designed as electrocatalysts for water oxidation. Interestingly, the catalytic performance of these Cu2 complexes is enhanced as their molecular skeletons become more rigid, which contrasts with the behavior observed in our previous investigation with Fe2 analogs. Moreover, mechanistic studies reveal that the reactivity of the bridging O atom results in distinct pathways for O-O bond formation in Cu2 and Fe2 catalysts. In Cu2 systems, the coupling takes place between a terminal CuIII -OH and a bridging µ-O⋅ radical. Whereas in Fe2 systems, it involves the coupling of two terminal Fe-oxo entities. Furthermore, an in-depth structure-activity analysis uncovers the spatial geometric prerequisites for the coupling of the terminal OH with the bridging µ-O⋅ radical, ultimately leading to the O-O bond formation. Overall, this study emphasizes the critical role of precisely adjusting the spatial geometry of catalysts to align with the O-O bonding pathway.

Selective Four-Electron Reduction of Oxygen by a Nonheme Heterobimetallic CuFe Complex.

We report herein the first nonheme CuFe oxygen reduction catalyst ([CuII (bpbp)(µ-OAc)2 FeIII ]2+ , CuFe-OAc), which serves as a functional model of cytochrome c oxidase and can catalyze oxygen reduction to water with a turnover frequency of 2.4×103  s-1 and selectivity of 96.0 % in the presence of Et3 NH+ . This performance significantly outcompetes its homobimetallic analogues (2.7 s-1 of CuCu-OAc with %H2 O2 selectivity of 98.9 %, and inactive of FeFe-OAc) under the same conditions. Structure-activity relationship studies, in combination with density functional theory calculation, show that the CuFe center efficiently mediates O-O bond cleavage via a CuII (µ-η1 : η2 -O2 )FeIII peroxo intermediate in which the peroxo ligand possesses distinctive coordinating and electronic character. Our work sheds light on the nature of Cu/Fe heterobimetallic cooperation in oxygen reduction catalysis and demonstrates the potential of this synergistic effect in the design of nonheme oxygen reduction catalysts.

Heterobimetallic NiFe Cooperative Molecular Water Oxidation Catalyst.

We reported herein the development of heterobimetallic NiFe molecular platform to understand NiFe synergistic effect in water oxidation catalysis. Compared to homonuclear bimetallic compounds (NiNi and FeFe), NiFe complex possesses more remarkable catalytic water oxidation performance. Mechanistic studies suggest that this remarkable difference is attributed to the fact that NiFe synergy can effectively promote O-O bond formation. The generated NiIII (µ-O)FeIV =O is the key intermediate and O-O bond was formed via intramolecular oxyl-oxo coupling between bridged O radical and terminal FeIV =O moiety.

Proton-Coupled Electron-Transfer Reduction of Dioxygen: The Importance of Precursor Complex Formation between Electron Donor and Proton Donor.

The proton-coupled electron transfer (PCET) reaction has drawn extensive attention for its widespread occurrence in chemistry, biology, and materials science. The mechanistic studies via model systems such as tyrosine and phenol oxidation have gradually deepened the understanding of PCET reactions, which was widely accepted and applied to bond activation and transformation. However, direct PCET activation of nonpolar bonds such as the C-H bond, O2, and N2 has yet to be explored. Herein, we report that the interaction between electron donor and proton donor could overcome the barrier of direct O2 activation via a concerted electron-proton transfer mechanism. This work provides a new strategy for developing direct PCET activation of nonpolar bonds.

Identifying Metal-Oxo/Peroxo Intermediates in Catalytic Water Oxidation by In Situ Electrochemical Mass Spectrometry.

Molecular catalysis of water oxidation has been intensively investigated, but its mechanism is still not yet fully understood. This study aims at capturing and identifying key short-lived intermediates directly during the water oxidation catalyzed by a cobalt-tetraamido macrocyclic ligand complex using a newly developed an in situ electrochemical mass spectrometry (EC-MS) method. Two key ligand-centered-oxidation intermediates, [(L2-)CoIIIOH] and [(L2-)CoIIIOOH], were directly observed for the first time, and further confirmed by 18O-labeling and collision-induced dissociation studies. These experimental results further confirmed the rationality of the water nucleophilic attack mechanism for the single-site water oxidation catalysis. This work also demonstrated that such an in situ EC-MS method is a promising analytical tool for redox catalytic processes, not only limited to water oxidation.

Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non-small cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for dynamically monitoring tumors. However, published data on perioperative ctDNA in patients with operable non-small cell lung cancer (NSCLC) are currently limited. METHODS: This prospective study recruited 123 patients with resectable stage I to IIIA NSCLC. Preoperative and postoperative plasma samples and tumor tissue samples were subjected to next-generation sequencing with a panel of 425 cancer-related genes. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3 to 6 months for up to 3 years. RESULTS: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 29 of 117 patients (24.8%) and was associated with inferior recurrence-free survival (RFS; hazard ratio [HR], 2.42; 95% CI, 1.11-5.27; P = .022) and inferior overall survival (OS; HR, 5.54; 95% CI, 1.01-30.35; P = .026). Similarly, ctDNA was detected in 12 of 116 first postsurgical samples (10.3%) and was associated with shorter RFS (HR, 3.04; 95% CI, 1.22-7.58; P = .012). During surveillance after surgery, longitudinal ctDNA-positive patients (37 of 119; 31.1%) had significantly shorter RFS (HR, 3.46; 95% CI, 1.59-7.55; P < .001) and significantly shorter OS (HR, 9.99; 95% CI, 1.17-85.78; P = .010) in comparison with longitudinal ctDNA-negative patients. Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 8.71 months. CONCLUSIONS: These results suggest that perioperative ctDNA analyses can predict recurrence and survival, and serial ctDNA analyses can identify disease recurrence/metastasis earlier than routine radiologic imaging in patients with resectable NSCLC. LAY SUMMARY: The utility of serial circulating tumor DNA (ctDNA) monitoring for predicting disease recurrence and survival for early-stage non-small cell lung cancer (NSCLC) has not been well characterized. The detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence and long-term patient outcomes for resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than routine radiologic imaging. ctDNA analyses can detect minimal residual disease for resectable NSCLC and thus can facilitate early intervention.

Spectra of Self-Similar Measures.

This paper is devoted to the characterization of spectrum candidates with a new tree structure to be the spectra of a spectral self-similar measure µN,D generated by the finite integer digit set D and the compression ratio N-1. The tree structure is introduced with the language of symbolic space and widens the field of spectrum candidates. The spectrum candidate considered by Laba and Wang is a set with a special tree structure. After showing a new criterion for the spectrum candidate with a tree structure to be a spectrum of µN,D, three sufficient and necessary conditions for the spectrum candidate with a tree structure to be a spectrum of µN,D were obtained. This result extends the conclusion of Laba and Wang. As an application, an example of spectrum candidate Λ(N,B) with the tree structure associated with a self-similar measure is given. By our results, we obtain that Λ(N,B) is a spectrum of the self-similar measure. However, neither the method of Laba and Wang nor that of Strichartz is applicable to the set Λ(N,B).

Bioinspired Trinuclear Copper Catalyst for Water Oxidation with a Turnover Frequency up to 20000 s-1.

Solar-powered water splitting is a dream reaction for constructing an artificial photosynthetic system for producing solar fuels. Natural photosystem II is a prototype template for research on artificial solar energy conversion by oxidizing water into molecular oxygen and supplying four electrons for fuel production. Although a range of synthetic molecular water oxidation catalysts have been developed, the understanding of O-O bond formation in this multielectron and multiproton catalytic process is limited, and thus water oxidation is still a big challenge. Herein, we report a trinuclear copper cluster that displays outstanding reactivity toward catalytic water oxidation inspired by multicopper oxidases (MCOs), which provides efficient catalytic four-electron reduction of O2 to water. This synthetic mimic exhibits a turnover frequency of 20000 s-1 in sodium bicarbonate solution, which is about 150 and 15 times higher than that of the mononuclear Cu catalyst (F-N2O2Cu, 131.6 s-1) and binuclear Cu2 complex (HappCu2, 1375 s-1), respectively. This work shows that the cooperation between multiple metals is an effective strategy to regulate the formation of O-O bond in water oxidation catalysis.

Activation of the G Protein-Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell.

G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.

LncRNA LOC102176306 plays important roles in goat testicular development.

Long ncRNAs regulate a complex array of fundamental biological processes, while its molecular regulatory mechanism in Leydig cells (LCs) remains unclear. In the present study, we established the lncRNA LOC102176306/miR-1197-3p/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) regulatory network by bioinformatic prediction, and investigated its roles in goat LCs. We found that lncRNA LOC102176306 could efficiently bind to miR-1197-3p and regulate PPARGC1A expression in goat LCs. Downregulation of lncRNA LOC102176306 significantly supressed testosterone (T) synthesis and ATP production, decreased the activities of antioxidant enzymes and mitochondrial complex I and complex III, caused the loss of mitochondrial membrane potential, and inhibited the proliferation of goat LCs by decreasing PPARGC1A expression, while these effects could be restored by miR-1197-3p inhibitor treatment. In addition, miR-1197-3p mimics treatment significantly alleviated the positive effects of lncRNA LOC102176306 overexpression on T and ATP production, antioxidant capacity and proliferation of goat LCs. Taken together, lncRNA LOC102176306 functioned as a sponge for miR-1197-3p to maintain PPARGC1A expression, thereby affecting the steroidogenesis, cell proliferation and oxidative stress of goat LCs. These findings extend our understanding of the molecular mechanisms of T synthesis, cell proliferation and oxidative stress of LCs.

Iron-Catalyzed Water Oxidation: O-O Bond Formation via Intramolecular Oxo-Oxo Interaction.

Herein, we report the importance of structure regulation on the O-O bond formation process in binuclear iron catalysts. Three complexes, [Fe2 (µ-O)(OH2 )2 (TPA)2 ]4+ (1), [Fe2 (µ-O)(OH2 )2 (6-HPA)]4+ (2) and [Fe2 (µ-O)(OH2 )2 (BPMAN)]4+ (3), have been designed as electrocatalysts for water oxidation in 0.1 M NaHCO3 solution (pH 8.4). We found that 1 and 2 are molecular catalysts and that O-O bond formation proceeds via oxo-oxo coupling rather than by the water nucleophilic attack (WNA) pathway. In contrast, complex 3 displays negligible catalytic activity. DFT calculations suggested that the anti to syn isomerization of the two high-valent Fe=O moieties in these catalysts takes place via the axial rotation of one Fe=O unit around the Fe-O-Fe center. This is followed by the O-O bond formation via an oxo-oxo coupling pathway at the FeIV FeIV state or via oxo-oxyl coupling pathway at the FeIV FeV state. Importantly, the rigid BPMAN ligand in complex 3 limits the anti to syn isomerization and axial rotation of the Fe=O moiety, which accounts for the negligible catalytic activity.

Redox-Active Ligand Assisted Catalytic Water Oxidation by a RuIV =O Intermediate.

Water splitting is one of the most promising solutions for storing solar energy in a chemical bond. Water oxidation is still the bottleneck step because of its inherent difficulty and the limited understanding of the O-O bond formation mechanism. Molecular catalysts provide a platform for understanding this process in depth and have received wide attention since the first Ru-based catalyst was reported in 1982. RuV =O is considered a key intermediate to initiate the O-O bond formation through either a water nucleophilic attack (WNA) pathway or a bimolecular coupling (I2M) pathway. Herein, we report a Ru-based catalyst that displays water oxidation reactivity with RuIV =(O) with the help of a redox-active ligand at pH 7.0. The results of electrochemical studies and DFT calculations disclose that ligand oxidation could significantly improve the reactivity of RuIV =O toward water oxidation. Under these conditions, sustained water oxidation catalysis occurs at reasonable rates with low overpotential (ca. 183 mV).

Effect of PPARGC1A on the development and metabolism of early rabbit embryos in vitro.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) is a central regulator of mitochondrial biogenesis and metabolism, and its expression is closely related to embryo development. To gain insights into the possible mechanisms of PPARGC1A during early embryogenesis, the development potential, mitochondrial biogenesis, and the culture medium metabolomics of embryos were evaluated when PPARGC1A overexpressed or suppressed in rabbit zygotes. Results showed that different PPARGC1A levels in rabbit zygotes could affect blastocyst percentage, and the expressions of mitochondrial biogenesis and metabolic-related genes, as well as the glutathione and adenosine triphosphate levels during early embryo development. In addition, compared with the controls, 12 and 10 different metabolites involved in carbohydrate, amino acid, and fatty acid metabolism were screened in the 5 day's spent culture medium of PPARGC1A overexpressed and suppressed embryos by gas chromatography-mass spectrometer, respectively. Consistent with these metabolite changes, the transcriptions of genes encoding glucose transporters and fatty acid biosynthetic proteins in the embryos from different groups were regulated by PPARGC1A during rabbit embryo development. Taken together, these data provide evidence that PPARGC1A may regulate early rabbit embryo development through mitochondrial biogenesis and metabolism.

Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation.

The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein-coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.

A Supramolecular Radical Dimer: High-Efficiency NIR-II Photothermal Conversion and Therapy.

Photothermal therapy at the NIR-II biowindow (1000-1350 nm) is drawing increasing interest because of its large penetration depth and maximum permissible exposure. Now, the supramolecular radical dimer, fabricated by N,N'-dimethylated dipyridinium thiazolo[5,4-d]thiazole radical cation (MPT.+ ) and cucurbit[8]uril (CB[8]), achieves strong absorption at NIR-II biowindow. The supramolecular radical dimer (2MPT.+ -CB[8]) showed highly efficient photothermal conversion and improved stability, thus contributing to the strong inhibition on HegG2 cancer cell under 1064 nm irradiation even penetrating through chicken breast tissue. This work provides a novel approach to construct NIR-II chromophore by tailor-made assembly of organic radicals. It is anticipated that this study provides a new strategy to achieve NIR-II photothermal therapy and holds promises in luminescence materials, optoelectronic materials, and also biosensing.

Redox-Active Ligand Assisted Multielectron Catalysis: A Case of CoIII Complex as Water Oxidation Catalyst.

Water oxidation is the key step in both natural and artificial photosynthesis to capture solar energy for fuel production. The design of highly efficient and stable molecular catalysts for water oxidation based on nonprecious metals is still a great challenge. In this article, the electrocatalytic oxidation of water by Na[(L4-)CoIII], where L is a substituted tetraamido macrocyclic ligand, was investigated in aqueous solution (pH 7.0). We found that Na[(L4-)CoIII] is a stable and efficient homogeneous catalyst for electrocatalytic water oxidation with 380 mV onset overpotential in 0.1 M phosphate buffer (pH 7.0). Both ligand- and metal-centered redox features are involved in the catalytic cycle. In this cycle, Na[(L4-)CoIII] was first oxidized to [(L2-)CoIIIOH] via a ligand-centered proton-coupled electron transfer process in the presence of water. After further losing an electron and a proton, the resting state, [(L2-)CoIIIOH], was converted to [(L2-)CoIV═O]. Density functional theory (DFT) calculations at the B3LYP-D3(BJ)/6-311++G(2df,2p)//B3LYP/6-31+G(d,p) level of theory confirmed the proposed catalytic cycle. According to both experimental and DFT results, phosphate-assisted water nucleophilic attack to [(L2-)CoIV═O] played a key role in O-O bond formation.

Electrocatalytic Water Oxidation by an Unsymmetrical Di-Copper Complex.

An unsymmetrical di-copper complex, ([Cu2(TPMAN)(µ-OH)(H2O)]3+, was prepared and used for electrocatalytic water oxidation in neutral conditions. This complex is a stable and efficient homogeneous catalyst during the electrocatalytic oxygen evolution process ( kcat = 0.78 s-1) with 780 mV onset overpotential in 0.1 M phosphate buffer (pH 7.0). The water oxidation mechanism of the unsymmetrical catalyst [Cu2(TPMAN)(µ-OH)]3+ exhibits different behaviors than that of [Cu2(BPMAN)(µ-OH)]3+, such as two redox steps with different pH dependences, a significant kinetic isotope effect, and buffer concentration dependence. All these changes were ascribed to the open site on the Cu center that is formed by removal of the hemilabile pyridyl site, which acts as an intramolecular proton acceptor to assist the O-O bond formation step.

Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells.

During goat follicular development, abnormal expression of nuclear respiratory factor 1 (NRF1) in granulosa cells may drive follicular atresia with unknown regulatory mechanisms. In this study, we investigated the effects of NRF1 on steroidogenesis and cell apoptosis by overexpressing or silencing it in goat luteinized granulosa cells (LGCs). Results showed that knockdown of NRF1 expression significantly inhibited the expression of STAR and CYP19A1, which are involved in sex steroid hormones synthesis, and led to lower estrogen levels. Knockdown of NRF1 resulted in an increased percentage of apoptosis, probably due to the release of cytochrome c from mitochondria, accompanied by upregulating mRNA and protein levels of apoptosis-related markers BAX, caspase 3 and caspase 9. These data indicate that NRF1 might be related with steroidogenesis and cell apoptosis. Furthermore, NRF1 silence reduced mitochondrial transcription factor A (TFAM) transcription activity, mtDNA copy number and ATP level. Simultaneously, knockdown of NRF1 suppressed the transcription and translation levels of SOD, GPx and CAT, decreased glutathione level and increased 8-OHdG level. However, the overexpression of NRF1 in LGCs or gain of TFAM in NRF1 silenced LGCs increased the expression of genes involved in mitochondrial function and biogenesis, and elevated the antioxidant stress system and steroids synthesis. Taken together, aberrant expression of NRF1 could induce mitochondrial dysfunction and disturb the cellular redox balance, which lead to disturbance of steroid hormone synthesis, and trigger LGC apoptosis through the mitochondria-dependent pathway. These findings will be helpful for understanding the role of NRF1 in goat ovarian follicular development and atresia.

Hand-assisted laparoscopic right hemicolectomy with complete mesocolic excision and central vascular ligation: a novel technique for right colon cancer.

BACKGROUND: It can be difficult to locate the superior mesenteric vein and dissect around middle colic vessels during laparoscopic right hemicolectomy with complete mesocolon excision due to a high rate of vascular variations in the superior mesenteric vessels. Therefore, we report a modified technique for hand-assisted laparoscopic right hemicolectomy with complete mesocolic excision and central vascular ligation, which addresses these two problems. METHODS: Thirty-one consecutive patients with right colon cancer underwent this procedure from March 2014 to August 2015. Extracorporeally, the transverse colon and distal ileum were excised with a transumbilical hand-port incision, and the distal part of the superior mesenteric vein was identified. Intracorporeally, with the assistance of the surgeon's left hand inserted through the incision, D3-lymphadenectomy with central vascular ligation was performed, and the colon with the tumor, which had no blood supply, was removed. Patients' demographic data and intraoperative, postoperative and pathological characteristics were examined. RESULTS: The median operative time was 130.0 (range 115-180) minutes. The median blood loss was 45.0 (range 20-300) milliliters. The median length of the hand-port incision was 7.3 (range 6.0-8.2) centimeters. The median numbers of lymph nodes and central lymph nodes was 34.0 (range 18-91) and 13.0 (range 3-28), respectively. Five (16.1%) of 31 patients had positive central lymph nodes. Specimen morphometric quantitation was as follows: the median distances from the tumor and nearest bowel wall to the high tie were 10.5 (range 5.0-15.0) and 8.0 (range 6.0-12.0) centimeters, respectively; the median resected area of the mesentery was 200.0 (range 96.0-300.0) square centimeters; the median width of the chain of lymph-adipose tissue at the central lymph nodes area was 2.0 (range 0.8-8.0) centimeters; and the median length of the central lymph-adipose chain was 19.0 (range 3.0-26.0) centimeters. CONCLUSIONS: Our procedure confers technical advantages and is feasible for treatment of right colon cancer.

Erratum to: Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients.

Erratum to: Breast Cancer Res Treat (2012),134:549­560,DOI 10.1007/s10549-012-2080-y. In the original publication of the article, Fig. 5c was published incorrectly. The authors apologize for this error and the correct Fig. 5c is given below.