Molecular editing of aza-arene C-H bonds by distance, geometry and chirality.

Direct molecular editing of heteroarene carbon-hydrogen (C-H) bonds through consecutive selective C-H functionalization has the potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry1. In contrast to electronically biased heterocyclic C-H bonds2-9, remote benzocyclic C-H bonds on bicyclic aza-arenes are especially difficult to differentiate because of the lack of intrinsic steric/electronic biases10-12. Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C-H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C-H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different orders to suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage 'molecular editing' strategy to directly modify bicyclic aza-arenes at any given site in different orders.

Polymorphism at the nestling stage and host-specific mimicry in an Australasian cuckoo-host arms race.

Decades of research have shown that the coevolutionary arms race between avian brood parasites and their hosts can promote phenotypic diversification in hosts and brood parasites. However, relatively little is known about the role of brood parasitism in promoting phenotypic diversification of nestlings. We review field data collected over four decades in Australia, New Caledonia and New Zealand to assess potential for coevolutionary interactions between the shining bronze-cuckoo (Chalcites lucidus) and its hosts, and how diversification at the nestling stage may be generating different subspecies. The shining bronze-cuckoo is a specialist parasite of a few hosts in the family Acanthizidae. It has diversified into subspecies, of which the nestlings closely mimic the respective host nestlings in each region. Additionally, some cuckoo subspecies have polymorphic nestlings. The Acanthizidae hosts have similar breeding and nesting habits and only moderately effective frontline defences against parasitism at cuckoo egg laying or at the egg stages. However, some hosts have developed highly effective defences at the nestling stage by recognising and ejecting cuckoo nestlings from the nest. As with the cuckoo nestlings, some hosts have polymorphic nestlings. The coevolutionary interactions in each region suggest different evolutionary stages of the arms race in which either the parasite or the host is currently in the lead. The presence of moderately effective defences at the egg laying and egg stages might explain why some hosts do not have defences at the nestling stage. The south-Pacific cuckoo - host systems are excellent models to explore the evolutionary mechanisms driving the diversification at the nestling stage in the coevolutionary arms race between avian brood parasites and their hosts.

Remote site-selective C-H activation directed by a catalytic bifunctional template.

In chemical syntheses, the activation of carbon-hydrogen (C-H) bonds converts them directly into carbon-carbon or carbon-heteroatom bonds without requiring any prior functionalization. C-H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C-H bond in a substrate can be activated by using a 'directing' (usually a functional) group to obtain the desired product selectively. The applicability of such a C-H activation reaction can be severely curtailed by the distance of the C-H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C-H bonds of a substrate has been exploited to achieve meta-selective C-H activation by using a covalently attached, U-shaped template. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C-H bonds. Using this strategy, we demonstrate remote, site-selective C-H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.

Architecture of DNA elements mediating ARF transcription factor binding and auxin-responsive gene expression in Arabidopsis.

The hormone auxin controls many aspects of the plant life cycle by regulating the expression of thousands of genes. The transcriptional output of the nuclear auxin signaling pathway is determined by the activity of AUXIN RESPONSE transcription FACTORs (ARFs), through their binding to cis-regulatory elements in auxin-responsive genes. Crystal structures, in vitro, and heterologous studies have fueled a model in which ARF dimers bind with high affinity to distinctly spaced repeats of canonical AuxRE motifs. However, the relevance of this "caliper" model, and the mechanisms underlying the binding affinities in vivo, have remained elusive. Here we biochemically and functionally interrogate modes of ARF-DNA interaction. We show that a single additional hydrogen bond in Arabidopsis ARF1 confers high-affinity binding to individual DNA sites. We demonstrate the importance of AuxRE cooperativity within repeats in the Arabidopsis TMO5 and IAA11 promoters in vivo. Meta-analysis of transcriptomes further reveals strong genome-wide association of auxin response with both inverted (IR) and direct (DR) AuxRE repeats, which we experimentally validated. The association of these elements with auxin-induced up-regulation (DR and IR) or down-regulation (IR) was correlated with differential binding affinities of A-class and B-class ARFs, respectively, suggesting a mechanistic basis for the distinct activity of these repeats. Our results support the relevance of high-affinity binding of ARF transcription factors to uniquely spaced DNA elements in vivo, and suggest that differential binding affinities of ARF subfamilies underlie diversity in cis-element function.

[Early Structural Valve Deterioration of Trifecta Aortic Bioprosthesis:Report of a Case].

Trifecta, an externally mounted bovine pericardial bioprosthetic aortic valve, provides excellent hemodynamic performance;however, early structural deterioration of this valve has been reported. A 60-year-old man with progressive dyspnea was admitted to the emergency unit of our institution. Seven years prior, he underwent aortic valve replacement with 23-mm Trifecta valve. Severe aortic valve regurgitation and stenosis due to structural valve deterioration was diagnosed and redo aortic valve replacement using an Inspiris valve was performed. Intraoperative findings revealed a large laceration in the left coronary cusp adjacent to the non coronary-left coronary commissure and leaflet calcification. Further, circumferential fibrous pannus ingrowth at the inflow portion was also noted. To avoid anticoagulation therapy and repeat surgery, mitral valve plasty and left atrial appendage clipping were performed simultaneously. Postoperative course was uneventful, and he was transferred to a rehabilitation facility on 36th postoperative day.

Remote C-H Olefination of Heterocyclic Biaryls Enabled by Reversibly Bound Templates.

Remote C-H functionalization of heterocyclic biaryls will be of great importance in synthesis and medicinal chemistry. Through adjusting the geometric relationship of the directing atom and target C-H bonds, two new catalytic templates have been developed to enable the functionalization of the more hindered ortho-C-H bonds of heterobiaryls bearing directing heteroatom at the meta- or para-positions, affording unprecedented site-selectivity. The use of template chaperone also overcomes product inhibition and renders the directing templates catalytic. The utility of this protocol was demonstrated by olefination of heterocyclic biaryls with various substituents, overriding conventional steric and electronic effects. These ortho-C-H olefinated heterobiaryls are sterically hindered and can often be challenging to prepare through aryl-aryl coupling reactions.

Photochemical Alkene Hydrophosphination with Bis(trichlorosilyl)phosphine.

Bis(trichlorosilyl)phosphine (HP(SiCl3)2, 1) was prepared from [TBA][P(SiCl3)2] ([TBA]2, TBA = tetra-n-butylammonium) and triflic acid in 36% yield. Phosphine 1 is an efficient reagent for hydrophosphination of unactivated terminal olefins under UV irradiation (15-60 min) and gives rise to bis(trichlorosilyl)alkylphosphines (RP(SiCl3)2, R = (CH2)5CH3, 88%; (CH2)7CH3, 98%; (CH2)2C(CH3)3, 76%; CH2Cy, 93%; (CH2)2Cy, 95%; CH2CH(CH3)(CH2)2CH3, 82%; (CH2)3O(CH2)3CH3, 95%; (CH2)3Cl, 83%; (CH2)2SiMe3, 92%; (CH2)5C(H)CH2, 44%) in excellent yields. The products require no further purification beyond filtration and removal of volatile material under reduced pressure. The P-Si bonds of prototypical products RP(SiCl3)2 (R = -(CH2)5CH3, -(CH2)7CH3) are readily functionalized to give further phosphorus-containing products: H3C(CH2)7PCl2 (56%), [H3C(CH2)5P(CH2Ph)3]Br (84%), H3C(CH2)7PH2 (61%), H3C(CH2)5P(O)(H)(OH) (81%), and H3C(CH2)5P(O)(OH)2 (55%). Experimental mechanistic investigations, accompanied by quantum chemical calculations, point toward a radical-chain mechanism. Phosphine 1 enables the fast, high-yielding, and atom-efficient preparation of compounds that contain phosphorus-carbon bonds in procedures that bypass white phosphorus (P4), a toxic and high-energy intermediate of the phosphorus industry.

Introducing N-Heterocyclic Iminophosphoranes (NHIPs): Synthesis by [3 + 2] Cycloaddition of Azophosphines with Alkynes and Reactivity Studies.

Azophosphines (Ar-N═N-PR2) were prepared from N-aryl-N'-(trimethylsilyl)diazenes (Ar-N═N-SiMe3) and R2PCl by Me3SiCl elimination or oxidation of phosphinohydrazines (Ar-NH-NH-PR2) by 2,5-dialkyl-1,4-benzoquinones. Azophosphines underwent 1,3-dipolar cycloaddition with cyclooctyne and dimethylacetylene dicarboxylate to give N-heterocyclic iminophosphoranes (NHIPs), which are structurally similar to cyclic (alkyl)(amino)carbenes. The cycloaddition reaction is compatible with various phosphorus atom substituents including phenyl (NHIP-1,4,6), isopropyl (NHIP-2), cyclohexyl (NHIP-3), and dimethylamino (NHIP-5) groups. The pKBH+ values of the NHIPs in acetonitrile range from 13.13 to 23.14. On the basis of the Huynh electronic parameter, NHIP-1 and NHIP-2 have σ-donor strengths comparable with that of 1,8-diazabicyclo[5.4.0]undec-7-ene. NHIP-1 underwent facile 1,2-addition with pentafluoropyridine to form a rare fluorophosphorane. The treatment of NHIP-1 with triphenylsilane resulted in P-N bond cleavage, accompanied by the reduction of phosphorus(V) to phosphorus(III). A homoleptic, cationic CuI-NHIP-1 complex was also prepared. The potential utility of π-donating NHIPs was demonstrated by the stabilization of a reactive iminoborane (Cl-B≡N-SiMe3). The facile scalable synthesis, tunability of steric demands, and basicity of NHIPs suggest that this new heterocycle class may find a wide range of applications in synthetic chemistry.

Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group.

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

Comparing Methods of Feature Extraction of Brain Activities for Octave Illusion Classification Using Machine Learning.

The aim of this study was to find an efficient method to determine features that characterize octave illusion data. Specifically, this study compared the efficiency of several automatic feature selection methods for automatic feature extraction of the auditory steady-state responses (ASSR) data in brain activities to distinguish auditory octave illusion and nonillusion groups by the difference in ASSR amplitudes using machine learning. We compared univariate selection, recursive feature elimination, principal component analysis, and feature importance by testifying the results of feature selection methods by using several machine learning algorithms: linear regression, random forest, and support vector machine. The univariate selection with the SVM as the classification method showed the highest accuracy result, 75%, compared to 66.6% without using feature selection. The received results will be used for future work on the explanation of the mechanism behind the octave illusion phenomenon and creating an algorithm for automatic octave illusion classification.

GH3 Auxin-Amido Synthetases Alter the Ratio of Indole-3-Acetic Acid and Phenylacetic Acid in Arabidopsis.

Auxin is the first discovered plant hormone and is essential for many aspects of plant growth and development. Indole-3-acetic acid (IAA) is the main auxin and plays pivotal roles in intercellular communication through polar auxin transport. Phenylacetic acid (PAA) is another natural auxin that does not show polar movement. Although a wide range of species have been shown to produce PAA, its biosynthesis, inactivation and physiological significance in plants are largely unknown. In this study, we demonstrate that overexpression of the CYP79A2 gene, which is involved in benzylglucosinolate synthesis, remarkably increased the levels of PAA and enhanced lateral root formation in Arabidopsis. This coincided with a significant reduction in the levels of IAA. The results from auxin metabolite quantification suggest that the PAA-dependent induction of GRETCHEN HAGEN 3 (GH3) genes, which encode auxin-amido synthetases, promote the inactivation of IAA. Similarly, an increase in IAA synthesis, via the indole-3-acetaldoxime pathway, significantly reduced the levels of PAA. The same adjustment of IAA and PAA levels was also observed by applying each auxin to wild-type plants. These results show that GH3 auxin-amido synthetases can alter the ratio of IAA and PAA in plant growth and development.

UDP-glucosyltransferase UGT84B1 regulates the levels of indole-3-acetic acid and phenylacetic acid in Arabidopsis.

Auxin is a key plant growth regulator for diverse developmental processes in plants. Indole-3-acetic acid (IAA) is a primary plant auxin that regulates the formation of various organs. Plants also produce phenylacetic acid (PAA), another natural auxin, which occurs more abundantly than IAA in various plant species. Although it has been demonstrated that the two auxins have distinct transport characteristics, the metabolic pathways and physiological roles of PAA in plants remain unsolved. In this study, we investigated the role of Arabidopsis UDP-glucosyltransferase UGT84B1 in IAA and PAA metabolism. We demonstrated that UGT84B1, which converts IAA to IAA-glucoside (IAA-Glc), can also catalyze the conversion of PAA to PAA-glucoside (PAA-Glc), with a higher catalytic activity in vitro. Furthermore, we showed a significant increase in both the IAA and PAA levels in the ugt84b1 null mutants. However, no obvious developmental phenotypes were observed in the ugt84b1 mutants under laboratory growth conditions. Moreover, the overexpression of UGT84B1 resulted in auxin-deficient root phenotypes and changes in the IAA and PAA levels. Our results indicate that UGT84B1 plays an important role in IAA and PAA homeostasis in Arabidopsis.

[Hybrid Two-stage Repair of Syphilitic Aortic Aneurysm, Total Arch Replacement and Thoracic Endovascular Aortic Repair;Report of a Case].

Syphilitic aortic aneurysm is seldom seen in the antibiotic era. Statistically the number of patients is increasing today and 10% of them seem to develop syphilitic aortitis. A 59-year-old male visited the emergency room due to chest discomfort and general fatigue. Treponema pallidum latex agglutination (TPLA) and rapid plasma reagin (RPR) were both strongly positive on blood tests. White blood cell counts and C-reactive protein elevation were also found. He couldn't figure out how or when he was suffering from syphilis. He needed to undergo a hybrid 2-stage surgery urgently, Total arch replacement and thoracic endovascular aortic repair (TEVAR), because his thoracic aortic aneurysm was growing more rapidly. No complication has occurred during or after surgery. Computed tomography after surgery showed successful exclusion of the thoracic aneurysm. It is important not to forget that syphilis is one of the causes of aortic aneurysm.

[Bentall Procedure for Annuloaortic Ectasia in a Patient with Systemic Lupus Erythematosus;Report of a Case].

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, rarely complicated with cardiac valvular abnormality or aortic aneurysm. An asymptomatic 40-year-old woman with a 15-year history of SLE developed annuloaortic ectasia and aortic valve regurgitation. She had long been maintained on steroid therapy for the treatment of SLE. Her serum anti-phospholipid antibodies were positive. An enhanced computed tomography revealed a dilated aortic root and ascending aorta (57 mm in diameter). Cardiac ultrasonography demonstrated severe aortic regurgitation. We performed the Bentall procedure using a composite graft with the Carrel patch technique. Histopathological examination of the aortic wall showed cystic medial necrosis without any evidence of vascu-litis. Careful long-term follow-up is mandatory for assessing the risk of later anastomotic dehiscence and pseudoaneurysm formation.

Hemilabile Benzyl Ether Enables γ-C(sp3)-H Carbonylation and Olefination of Alcohols.

Pd-catalyzed C(sp3)-H activation of alcohol typically shows ß-selectivity due to the required distance between the chelating atom in the attached directing group and the targeted C-H bonds. Herein we report the design of a hemilabile directing group which exploits the chelation of a readily removable benzyl ether moiety to direct γ- or δ-C-H carbonylation and olefination of alcohols. The utility of this approach is also demonstrated in the late-stage C-H functionalization of ß-estradiol to rapidly prepare desired analogues that required multi-step syntheses with classical methods.

Surgical Treatment of Coronary to Pulmonary Artery Fistulas in Adults.

Coronary to pulmonary artery fistulas (CPAFs) are abnormal communications between the coronary and pulmonary arteries. They are an uncommon congenital heart disease and usually remain asymptomatic until later in life. However, there is no consensus on their management. We present four adult patients who required surgery for coronary to pulmonary artery fistulas to illuminate this issue. The clinical presentations were variable depending on the anatomical features of coronary to pulmonary artery fistulas and the presence or absence of other cardiac diseases. We successfully performed surgical closure of the coronary to pulmonary artery fistulas in each of the cases. In this report, we describe our experience with these cases and outline the available therapeutic strategies and treatment options for coronary to pulmonary artery fistulas.

[Coronary-pulmonary Artery Fistula in a Hemodialysis Patient].

We report a case of coronary-pulmonary artery fistula in a hemodialysis patient treated surgically. A 47-year-old man was admitted with chest pain and exertional dyspnea that progressively worsened over the previous 2 months. He had a history of end-stage renal disease and has been on hemodialysis for 5 years. Coronary angiography and computed tomography revealed coronary-pulmonary artery fistula that originated from both the left anterior descending coronary artery and the right coronary artery. Under cardiopulmonary bypass, we opened the pulmonary artery and closed the fistula. The symptoms of the patient improved after the surgery, and he was discharged without major complications. Coronary-pulmonary artery fistulas in hemodialysis patients are rare. The presence of additional arteriovenous fistula used for dialysis in these patients increases the left-to-right shunt flow and might cause progression of heart failure. Even if the left-to-right shunt volume is small, surgical treatment is highly recommended at an early stage of the coronary-pulmonary artery fistula in hemodialysis patients.

[A Case of Locally Far-Advanced Colon Cancer Resected by Laparoscopic Surgery after Colonic Stent Insertion and Neoadjuvant Chemotherapy].

We report a case of locally far-advanced colon cancer resected by laparoscopic surgery after colonic stent insertion and neoadjuvant chemotherapy. A 71-year-old man with obstructive symptoms was admitted to our hospital in July 2015. CT revealed a sigmoid colon tumor infiltrating the retroperitoneum and small intestine. Lower gastrointestinal endoscopy showed a sigmoid colon cancer. Self-expandable metallic stent insertion for obstructive colon cancer alleviated the patient's symptoms quickly. Four courses of neoadjuvant chemotherapy(XELOX)reduced the primary tumor in size, allowing for laparoscopic surgical resection. Combination therapy with colonic stenting and neoadjuvant chemotherapy can be an effective treatment for obstructive colon cancer. However, further studies and additional cases are needed to assess the safety and efficacy of this combination therapy.

Ligand-Enabled Stereoselective ß-C(sp(3))-H Fluorination: Synthesis of Unnatural Enantiopure anti-ß-Fluoro-α-amino Acids.

A quinoline-based ligand was shown to promote palladium-catalyzed ß-C(sp(3))-H fluorination for the first time. A range of unnatural enantiopure fluorinated α-amino acids were obtained through sequential ß-C(sp(3))-H arylation and subsequent stereoselective fluorination from readily available L-alanine.

Distinct Characteristics of Indole-3-Acetic Acid and Phenylacetic Acid, Two Common Auxins in Plants.

The phytohormone auxin plays a central role in many aspects of plant growth and development. IAA is the most studied natural auxin that possesses the property of polar transport in plants. Phenylacetic acid (PAA) has also been recognized as a natural auxin for >40 years, but its role in plant growth and development remains unclear. In this study, we show that IAA and PAA have overlapping regulatory roles but distinct transport characteristics as auxins in plants. PAA is widely distributed in vascular and non-vascular plants. Although the biological activities of PAA are lower than those of IAA, the endogenous levels of PAA are much higher than those of IAA in various plant tissues in Arabidopsis. PAA and IAA can regulate the same set of auxin-responsive genes through the TIR1/AFB pathway in Arabidopsis. IAA actively forms concentration gradients in maize coleoptiles in response to gravitropic stimulation, whereas PAA does not, indicating that PAA is not actively transported in a polar manner. The induction of the YUCCA (YUC) genes increases PAA metabolite levels in Arabidopsis, indicating that YUC flavin-containing monooxygenases may play a role in PAA biosynthesis. Our results provide new insights into the regulation of plant growth and development by different types of auxins.