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Stable carbenes deliver a carbon atom to simple amides, producing a range of cyclic compounds

Non-natural photoenzymatic reactions reported to date have depended on the excitation of electron donor-acceptor complexes formed between substrates and cofactors within protein active sites to facilitate electron transfer. While this mechanism has unlocked new reactivity, it limits the types of substrates that can be involved in this area of catalysis. Here we demonstrate that direct excitation of flavin hydroquinone within "ene"-reductase active sites enables new substrates to participate in photoenzymatic reactions. We found that by using photoexcitation these enzymes gain the ability to reduce acrylamides through a single electron transfer mechanism.

Flavin‐dependent ‘ene’‐reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic paradigms.

Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.

FROUNT is an intracellular protein that promotes pseudopodia formation by binding to the chemokine receptors CCR2 and CCR5 on macrophages. Recently, disulfiram (DSF), a drug treatment for alcoholism, was found to have FROUNT inhibitory activity. In this study, we investigated the effect of DSF eye drops in a rat corneal alkali burn model. After alkali burn, 0.5% DSF eye drops (DSF group) and vehicle eye drops (Vehicle group) were administered twice daily. Immunohistochemical observations and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed at 6 h and 1, 4, and 7 days after alkali burn. Results showed a significant decrease in macrophage accumulation in the cornea in the DSF group, but no difference in neutrophils. RT-PCR showed decreased expression of macrophage-associated cytokines in the DSF group. Corneal scarring and neovascularization were also suppressed in the DSF group. Low-vacuum scanning electron microscopy imaging showed that macrophage length was significantly shorter in the DSF group, reflecting the reduced extension of pseudopodia. These results suggest that DSF inhibited macrophage infiltration by suppressing macrophage pseudopodia formation.

Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N-heterocyclic carbene (NHC) catalyzed reactions, in which β-unsubstituted conjugate acceptors undergo homoenolate formation and C-C bond formation twice, have been developed. Specifically, the all-carbon (5+1) annulations give a range of mono- and bicyclic cyclohexanones (31 examples). In the first family of annulations, β-unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza-Stetter reaction that proceeds via imine umpolung using N-heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover-limiting addition of the NHC to the imine.

Many studies have demonstrated the therapeutic effects of hydrogen in pathological conditions such as inflammation; however, little is known about its prophylactic effects. The purpose of this study is to investigate the prophylactic effects of hydrogen-rich water instillation in a rat corneal alkali burn model. Hydrogen-rich water (hydrogen group) or physiological saline (vehicle group) was instilled continuously to the normal rat cornea for 5 min. At 6 h after instillation, the cornea was exposed to alkali. The area of corneal epithelial defect (CED) was measured every 6 h until 24 h after alkali exposure. In addition, at 6 and 24 h after injury, histological and immunohistochemical observations were made and real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to investigate superoxide dismutase enzyme (SOD)1, SOD2, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA expression. CED at 12 h and the number of inflammatory infiltrating cells at 6 h after injury were significantly smaller in the hydrogen group than the vehicle group. Furthermore, SOD1 expression was significantly higher in the hydrogen group than the vehicle group at both 6 and 24 h, and the number of PGC-1α-positive cells was significantly larger in the hydrogen group than the vehicle group at 6 h after injury. In this model, prophylactic instillation of hydrogen-rich water suppressed alkali burn-induced inflammation, likely by upregulating expression of antioxidants such as SOD1 and PGC-1α. Hydrogen has not only therapeutic potential but also prophylactic effects that may suppress corneal scarring following injury and promote wound healing.

The effects of peroxisome proliferator-activated receptor (PPAR)&beta, /&delta, ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPAR&beta, agonist) or vehicle ophthalmic solution was topically instilled onto the rat&rsquo, s cornea twice a day until day 7. Pathological findings were evaluated, and real-time reverse transcription polymerase chain reaction was performed. GW501516 strongly suppressed infiltration of neutrophils and pan-macrophages, and reduced the mRNA expression of interleukin-6, interleukin-1&beta, tumor necrosis factor alpha, and nuclear factor-kappa B. On the other hand, GW501516 promoted infiltration of M2 macrophages, infiltration of vascular endothelial cells associated with neovascularization in the wounded area, and expression of vascular endothelial growth factor A mRNA. However, 7-day administration of GW501516 did not promote neovascularization in uninjured normal corneas. Thus, the PPAR&beta, ligand suppressed inflammation and promoted neovascularization in the corneal wound healing process. These results will help to elucidate the role of PPAR&beta, in the field of ophthalmology.

Peroxisome proliferator-activated receptor alpha (PPAR&alpha, ) and gamma (PPAR&gamma, ) agonists have anti-inflammatory and anti-neovascularization effects, but few reports have tested the combination of PPAR&alpha, and PPAR&gamma, agonists. In this study, we investigated the therapeutic effects of ophthalmic solutions of agonists of PPAR&alpha, PPAR&gamma, and the combination in a rat corneal alkali burn model. After alkali injury, an ophthalmic solution of 0.05% fenofibrate (PPAR&alpha, group), 0.1% pioglitazone (PPAR&gamma, group), 0.05% fenofibrate + 0.1% pioglitazone (PPAR&alpha, +&gamma, group), or vehicle (vehicle group) was topically instilled onto the rat&rsquo, s cornea twice a day. After instillation, upregulation was seen of PPAR mRNA corresponding to each agonist group. Administration of agonists for PPAR&alpha, and PPAR&alpha, suppressed inflammatory cells, neovascularization, and fibrotic changes. In addition, the PPAR&gamma, agonist upregulated M2 macrophages, which contributed to wound healing, whereas the PPAR&alpha, agonist suppressed immature blood vessels in the early phase. Administration of PPAR&alpha, agonists showed therapeutic effects in corneal wound healing, combining the characteristics of both PPAR&alpha, agonists. The results indicate that the combination of PPAR&alpha, and &gamma, agonists may be a new therapeutic strategy.

Capsular stabilization devices were evaluated in a zonular fiber defect model using the slit side view (SSV) system to confirm their utility for capsular stabilization during phacoemulsification. A zonular fiber defect model was made by cutting Zinn’s zonule under observation with a slit lamp microscope in a porcine eye. Phacoemulsification was performed, and the movement of the lens capsule and the depth of the anterior chamber were observed using the SSV in three groups: control group: no surgical instruments used, CE group: a capsule expander was inserted, and CTR group: a capsular tension ring was inserted. In the control group, the equator of the lens was unstable and was easily suctioned to the port of the ultrasound handpiece. The lens capsule was stable in both in the CE and CTR groups. In the CTR group, the equator responsible for the zonular rupture also returned and closed true to its original position. The utility of the capsular stabilization devices in this zonular fiber defect model was confirmed with the SSV system.

Herein we report the cycloisomerization of electron-poor 1,5-dienes via the β-azolium ylide to give enantioenriched cyclopentenes. The reaction is mediated by a chiral N-heterocyclic carbene (NHC) catalyst, exploits readily available substrates, has good generality (17 examples), and displays excellent enantioselectivity (mostly >94:6). Studies demonstrating the viability of a related dynamic kinetic resolution are reported, as are those with alternate tethers and derivatizations.

N-Heterocyclic carbene-catalyzed formation of β-anionic intermediates from enones has been employed in the enantioselective synthesis of 2-aryl propionates. The reaction was achievable using a homochiral 4-MeOC6H4 morpholinone catalyst allowing the first example of enantioselective catalysis by umpolung of α,β-unsaturated ketones. The reaction is high yielding, and shows robustness with reasonable generality. A mechanism is proposed in which the enantiodetermining protonation is achieved using either hexafluoroisopropanol or the formed naphthol product.

In 2008, Alspach [The Wonderful Walecki Construction, Bull. Inst. Combin. Appl. 52 (2008) 7–20] defined the matching sequencibility of a graph $G$ to be the largest integer $k$ such that there exists a linear ordering of its edges so that every $k$ consecutive edges in the linear ordering form a matching of $G$, which is denoted by $ms(G)$. In this paper, we show that every graph $G$ of size $q$ and maximum degree $\Delta$ satisfies $\frac{1}{2}\lfloor \frac{q}{\Delta+1} \rfloor \leq ms(G) \leq \lfloor \frac{q-1}{\Delta-1}$ by using the edge-coloring of $G$, and we also improve this lower bound for some particular graphs. We further discuss the relationship between the matching sequencibility and a conjecture of Seymour about the existence of the $k$th power of a Hamilton cycle.

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called ‘immune privilege’. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.

Polarity inversion is the hallmark of N-heterocyclic carbene (NHC) organocatalysis, with the generation and reaction of acyl anion equivalents known for more than 70 years. In contrast, polarity inversion through 1,4-addition of NHCs to conjugate acceptors was first applied in a catalytic reaction in 2006. This sub-field of NHC-organocatalysis has developed steadily over the subsequent years, enabling novel coupling reactions, enantioselective cycloisomerizations, polymerizations, and other reactions. In this review, this emerging area of NHC-organocatalysis is discussed with comprehensive coverage. In addition, notes regarding the use of other Lewis base catalysts for related reactions, and comments regarding NHC selection for this type of catalysis, are provided.

Initiating and terminating free-radical reactionis via hydrogen atom transfer (HAT) is an attractive means of avoiding substrate prefunctionalization. Small molecule catalysts and reagents, however, struggle to execute this fundamental step with useful levels of diastereoselectivity and enantioselectivity. In contrast, nature often carries out HAT with exquisite levels of selectivity for even electronically unactivated carbon–hydrogen bonds. By understanding how enzymes exploit and control this fundamental step, new strategies can be developed to address several long-standing challenges in free-radical reactions. This review will cover recent discoveries in biocatalysis that exploit a HAT mechanism to either initiate or terminate novel one-electron reactions.

Lewis base catalysis by lone pair donation into anti-bonding π orbitals (n–π*) is a growing field with a range of Lewis bases capable of this type of catalysis. In this review, catalysis of the Morita–Baylis–Hillman reaction, the Steglich rearrangement, and the annulation of α,β-unsaturated acyl Lewis adducts are discussed, using N-heterocyclic carbene (NHC), isothiourea, bicyclic tertiary amine and electron-rich pyridyl catalysts. In many cases, each of these popular Lewis base catalysts is viable for the given reaction, with the degree of utility defined by the catalyst’s nucleophilicity and Lewis basicity. 1 Introduction to Lewis Base Catalysis 2 Enolates from 1,4-Addition: Morita–Baylis–Hillman Reaction 3 O→C Carboxyl Transfer: Steglich Rearrangement 4 Annulations of α,β-Unsaturated Acyl Lewis Base Adducts 5 Summary and Outlook

Using a chiral morpholine-fused triazolium salt as NHC precatalyst, the first examples for the enantioselective synthesis of 2-aryl propionates by umpolung of α,β-unsaturated ketones are presented.

The extended velocities of money given by the ratio of NGDP and M2+CD in Japan’s lost decade are analyzed through the non-linear time series analysis based upon the theory of KM2O-Langevin equations. The time series of logarithmic returns of some extended velocities of money are judged to have a determinacy property in a specified time domain whose final time coincides with the time 1999q1 when the Bank of Japan took the zero interest rate policy. This implies that there exists a stochastic process with the time series stated above its realization and it satisfies certain functional relation. This gives a meaning from a viewpoint of time series analysis that the velocity of money can be regarded as an equilibrium solution of the demand and the supply between the goods market and the money market.

Since the actual and microscopic structure of hard-sphere-type colloidal crystals has not been fully understood, we performed detailed microscopic structural characterization of the sedimentation-grown opal-type colloidal crystals by conventional optical microscopy, laser conforcal microscopy, and secondary electron microscopy. It is directly proved for the first time, to the best of our knowledge, that iridescent striations originate from the repetition of twin structures and stacking faults in crystal structures. We propose "subdomain" as an intrinsic constitutional unit of a monocolored iridescent "domain" and the subdomain boundary is defined as the envelope of the edges of stacking faults. Every domain forming the bulk crystal contains a high concentration of slanted stacking faults at various tilt angles inherent to the domain. These observations show that the bulk colloidal crystals can be described in terms of five stages of hierarchical structure units, bulk crystal, domains, sub-domains, pristine single-crystal lamellae, and silica particles.

生物多様性国家戦略の策定ならび外来生物法の施行などにより法面緑化に対しても生物多様性に配慮した自然回復緑化を行うことが要求され，埋土種子を用いる森林表土利用工，自然侵入を待ち受ける自然侵入促進工，あるいはこれに類するものと考えられる四省庁による緑化植物取扱方針において示された緑化植物の当面の望ましい取扱方向(案)の草高の低い品種・種を少量播種し粗な植生を造成するという方向，および点・島(縞)状緑化に対する生育判定の有り様を探るため，緑化工学会誌に掲載された関連論文・技術報告を整理・分析を試みた。結果，資料が少なくばらつきが多いものの，土工指針に代表される現行の植生の量的な側面に留意する成績判定基準を適用することが困難であることが判明した。このため，自然回復緑化を行うに際の生育判定に関しては，植物生育基盤の安定性，侵入定着した木本類の被圧に着目し，植生の質的な側面より判断する方向について提案した。

The strong plantar joint capsule consisting of the deep transverse metatarsal ligament and plantar plate, long and short flexor tendons, and lumbrical muscles are considered to be obstructions that interfere with the reduction of irreducible dorsal dislocation, independently or in combination with each other [2,3,5–7]. However, dorsal approaches were used previously in surgically treated cases of dorsal dislocation, and the excised deep transverse metatarsal ligament and plantar plate remained unsutured [3,5–7]. In our patient, the deep transverse metatarsal ligament in the plantar region independently interfered with the reduction of the dorsal MTP joint dislocation. Therefore, the use of a plantar approach during surgery was considered to be appropriate from the anatomical and physiological perspectives.

Lewis base catalysis by lone pair donation into anti-bonding π orbitals (n–π*) is a growing field with a range of Lewis bases capable of this type of catalysis. In this review, catalysis of the Morita–Baylis–Hillman reaction, the Steglich rearrangement, and the annulation of α,β-unsaturated acyl Lewis adducts are discussed, using N-heterocyclic carbene (NHC), isothiourea, bicyclic tertiary amine and electron-rich pyridyl catalysts. In many cases, each of these popular Lewis base catalysts is viable for the given reaction, with the degree of utility defined by the catalyst’s nucleophilicity and Lewis basicity. 1 Introduction to Lewis Base Catalysis 2 Enolates from 1,4-Addition: Morita–Baylis–Hillman Reaction 3 O→C Carboxyl Transfer: Steglich Rearrangement 4 Annulations of α,β-Unsaturated Acyl Lewis Base Adducts 5 Summary and Outlook

Additionally to the first total syntheses of the target compounds several novel syntheses of monoterpene fragments are described.

A concise method to oxabicyclo[3.2.1]octanes and [4.2.1]nonanes is developed via 1,2-olefin functionalization cascade using two distinct nucleophiles.

A full account of our oxidative radical cyclization approach to the synthesis of garcibracteatone and doitunggarcinone A is presented. This includes the first enantioselective synthesis of garcibracteatone, which allowed the absolute configuration of the natural compound to be determined. The first synthesis of doitunggarcinone A is also described, which confirms our reassignment of the relative configuration of this molecule. Novel syntheses of monoterpene fragments used to construct the target molecules are also reported.

As part of a collaborative project to determine the minimum administration period to detect compound effects on male reproductive organs in Sprague-Dawley (Crj:CD(SD)) male rats, 6- and 8- week-old rats were administered ethylene glycol monomethyl ether (EGME) daily at 100 and 200 mg/kg/day for 2 weeks or 100 mg/kg/day for 4 weeks, and histopathological changes in the testes and epididymides were examined. Testis and epididymis weights in the 2-week 200 mg/kg and 4-week 100 mg/kg groups were obviously decreased. On histopathological examination, severe degenerative changes in the testis such as atrophy of the seminiferous tubules and multinucleated giant cell formation were observed in all 2-week 200 mg/kg group rats. Degeneration of pachytene spermatocytes in Stages X IV-II, III and a decrease in the number of germ cells was observed with both 2 and 4 weeks treatments at 100 mg/kg/day. In the epididymides, the number of sperm in the caput decreased with 100 mg/kg/day groups after both 2 and 4 weeks. In addition, degeneration of pachytene spermatocytes induced by EGME was found to be exclusively due to apoptotic death. Similar testicular and epididymal changes were observed with 2 and 4 weeks treatments at 100 mg/kg/day of EGME. Therefore, we conclude that a 2 weeks administration period is sufficient for detection of EGME effects on male reproductive organs.

A case of a 64-year-old male with low-grade chondrosarcoma of the left posterolateral lamina of the cricoid cartilage is reported, in which a total cricoidectomy and partial resection of the left thyroid cartilage were performed. The rest of the thyroid cartilage and the arytenoid mucosa were approximated with sutures to the first tracheal ring, and a silastic T-tube was placed through the tracheostoma as a stent. The postoperative course has been successful except for the existence of a tracheal stoma and slight hoarseness. There has been no evidence of laryngeal stenosis nor recurrence at about 9 years postoperatively.

Iodobenzene-catalyzed 1,2-olefin functionalization via C-C and C-O bond formation has been achieved with electron rich aromatic groups and vinylogous esters acting as independent nucleophiles. The reaction provides oxabicyclo[3.2.1]octanes and [4.2.1]nonanes from commercially available 3-alkoxy cycohexen-2-ones in three steps.