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Sequence-controlled supramolecular polymers offer new design paradigms for generating stimuli-responsive macromolecules with enhanced functionalities. The dynamic character of supramolecular links present challenges to sequence definition in extended supramolecular macromolecules, and design principles remain nascent. Here, we demonstrate the first example of using stoichiometry-control to specify the monomer sequence in a linear supramolecular polymer by synthesizing both a homopolymer and an alternating copolymer from the same glycol-substituted cyanostar macrocycle and phenylene-linked diphosphate monomers. A 2:1 stoichiometry between macrocycle and diphosphate produces a supramolecular homopolymer of general formula ( A ) n comprised of repeating units of cyanostar-stabilized phosphate-phosphate dimers. Using a 1:1 stoichiometry, an alternating ( AB ) n structure is produced with half the phosphate dimers now stabilized by the additional counter cations that emerge hierarchically after forming the stronger cyanostar-stabilized phosphate dimers. These new polymer materials and binding motifs are sufficient to bear normal and shear stress to promote significant and tunable adhesive properties. The homopolymer ( A ) n , consisting of cyanostar-stabilized anti -electrostatic linkages, shows adhesion strength comparable to commercial superglue formulations based on polycyanoacrylate but is thermally reversible. Unexpectedly, and despite including traditional ionic linkages, the alternating copolymer ( AB ) n shows weaker adhesion strength more similar to commercial white glue based on poly(vinyl acetate). Thus, the adhesion properties can be tuned over a wide range by simply controlling the stoichiometric ratio of monomers. This study offers new insight into supramolecular polymers composed of custom-designed anion and receptor monomers and demonstrates the utility of emerging functional materials based on anion-anion linkages.

Amines are ubiquitous in the chemical industry and are present in a wide range of biological processes, motivating the development of amine-sensitive sensors. There are many turn-on amine sensors, however there are no examples of turn-on sensors that utilize the amine's ability to react by single electron transfer (SET). We investigated a new turn-on amine probe with a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophore. BODIPY fluorescence is first preprogrammed into an off state by internal photoinduced electron transfer (PET) to an electron-deficient quinolinium ring, resulting in fluorescence quenching. At low concentrations of aliphatic amine (0 to 10 mM), this PET pathway is shut down by external SET from the amine to the photoexcited charge-transfer state of the probe and the fluorescence is turned on. At high concentrations of amine (50 mM to 1 M), we observed collisional quenching of the BODIPY fluorescence. The probe is selective for aliphatic amines over aromatic amines, and aliphatic thiols or alcohols. The three molecular processes modulate the BODIPY fluorescence in a multi-mechanistic way with two of them producing a direct response to amine concentrations. The totality of the three molecular processes produced the first example of a multi-state and dose-responsive amine sensor.

The paramagnetic cyano-bridged complex PhB( t BuIm) 3 Fe-NC-Mo(N t BuAr) 3 (Ar = 3,5-Me 2 C 6 H 3 ) is readily assembled from a new four-coordinate, high-spin ( S = 2) iron(II) monocyanide complex and the three-coordinate molybdenum(III) complex Mo(N t BuAr) 3 . X-ray diffraction and IR spectroscopy reveal that delocalization of unpaired electron density into the cyanide π* orbitals leads to a reduction of the C-N bond order. Direct current (dc) magnetic susceptibility measurements, supported by electronic structure calculations, demonstrate the presence of strong antiferromagnetic exchange between spin centers, with a coupling constant of J = -122(2) cm -1 . To our knowledge, this value represents the strongest magnetic exchange coupling ever to be observed through cyanide. These results demonstrate the ability of low-coordinate metal fragments to engender extremely strong magnetic exchange coupling through cyanide by virtue of significant π-backbonding into the cyanide ligand.

Elevated intracellular levels of reactive oxygen species (ROS), e.g. resulting from exposure to xenobiotics, can cause severe damages. Antioxidant defence mechanisms, which involve regulation of enzyme activities, protect cells to a certain extent. Nevertheless, continuous or increased exposure can overwhelm this system resulting in an adverse cellular state. To simulate exposure scenarios and to investigate the transition to an adverse cellular state, a mathematical model for the dynamics of ROS in response to xenobiotic-induced oxidative stress has been developed. It is based on exposure experiments of human urothelial cells (RT4) to the nitrated polycyclic aromatic hydrocarbon 3-nitrobenzanthrone (3-NBA), a component of diesel engine exhaust, and takes into account the following metabolic pathways of the antioxidant defence system: glutathione redox cycle scavenging directly ROS, the pentose phosphate pathway and the gluconate shunt as NADPH supplier and the beginning of glycolysis. In addition, ROS generation due to the bioactivation of 3-NBA has been implemented. The regulation of enzyme activities plays an important role in the presented mathematical model. The in silico model consists of ordinary differential equations on the basis of enzyme kinetics and mass action for the metabolism of 3-NBA. Parameters are either estimated from performed in vitro experiments via least-squares fitting or obtained from the literature. The results underline the importance of the pentose phosphate pathway to cope with oxidative stress and suggest an important role of the gluconate shunt during low-dose exposure.

Exposure to xenobiotic such as benzo[a]pyrene (B[a]P) induces metabolic changes, which have a considerable impact on the cellular response. Nevertheless, we are just in the beginning to reach an understanding of these processes. In this study, a gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach was applied to distinguish the metabolic changes that bladder epithelia cells undergo upon B[a]P exposure. To closely reflect the epithelia cell conditions in vivo, freshly isolated primary porcine urinary bladder epithelial cells (PUBEC) were utilized for the current study. An untargeted metabolomics approach was used to characterize the time- (6 h, 24 h, 48 h) and dose-dependent (0.5 µM, 5 µM, 10 µM B[a]P) changes in the metabolome of PUBEC upon B[a]P exposure, which led to the profiling of more than 200 metabolites that differed significantly between control and exposed samples. Multivariate analysis of the data highlighted that in the experimental setup/model used other than the exposure concentration, it is the exposure time which seems to be most important for distinguishing between different groups and hence may have a bigger role in B[a]P-mediated toxicity but may be specific for cell model used and hence requires further investigations. Further, enrichment and pathway analysis using MetaboAnalyst highlighted that exposure to B[a]P mainly alters the cellular amino acid metabolism. Particularly, 1-pyrroline-5-carboxylic acid (P5C), an intermediate of the cycling of the amino acid proline, was identified as a differentially altered metabolite at all concentrations and exposure times used in the experiment. An increase in the activity of proline dehydrogenase/proline oxidase (PRODH/POX), which oxidizes proline to P5C, was also observed, further supporting our metabolomic data. Our findings contribute to an improved knowledge about the reprogramming of metabolism which is a fundamental element of the cellular response to B[a]P and draw attention to the role of proline in this context.

The single-molecule magnet (SMM) properties of a series of ferrocenium complexes, [Fe(η 5 -C 5 R 5 ) 2 ] + (R=Me, Bn), are reported. In the presence of an applied dc field, the slow dynamics of the magnetization in [Fe(η 5 -C 5 Me 5 ) 2 ]BAr F are revealed. Multireference quantum mechanical calculations show a large energy difference between the ground and first excited states, excluding the commonly invoked, thermally activated (Orbach-like) mechanism of relaxation. In contrast, a detailed analysis of the relaxation time highlights that both direct and Raman processes are responsible for the SMM properties. Similarly, the bulky ferrocenium complexes, [Fe(η 5 -C 5 Bn 5 ) 2 ]BF 4 and [Fe(η 5 -C 5 Bn 5 ) 2 ]PF 6 , also exhibit magnetization slow dynamics, however an additional relaxation process is clearly detected for these analogous systems., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Invited for this month's cover picture is the group of Professor Enrica Bordignon at the Ruhr University Bochum. The cover picture shows an artistic view of E. coli cells and two spin-labeled recombinantly produced proteins, which can be inserted into the cells for EPR studies. The primary sequence of the proteins is schematically shown with the one-letter amino acid code, and cysteine residues are functionalized with the two new gem diethyl nitroxide spin labels designed to better sustain the reducing cellular environment. Read the full text of their Full Paper at 10.1002/open.201900119.

Structural and spectroscopic characterization of the dimeric iron hydride complex [Ph 2 B( t BuIm) 2 FeH] 2 reveals an unusual structure in which a tetrahedral iron(II) site ( S = 2) is connected to a square planar iron(II) site ( S = 1) by two bridging hydride ligands. Magnetic susceptibility reveals strong ferromagnetic coupling between iron centers, with a coupling constant of J = +110(12) cm -1 , to give an S = 3 ground state. High-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy confirms this model. A qualitative molecular orbital analysis of the electronic structure, as supported by electronic structure calculations, reveals that the observed spin configuration results from the orthogonal alignment of two geometrically distinct four-coordinate iron fragments held together by highly covalent hydride ligands.

A suite of lanthanoenediyne complexes of the form Ln(macrocycle)X 3 (Ln = La 3+ , Ce 3+ , Eu 3+ , Gd 3+ , Tb 3+ , Lu 3+ ; X = NO 3 - , Cl - , OTf - ) was prepared by utilizing an enediyne-containing [2 + 2] hexaaza-macrocycle ( 2 ). The solid-state Bergman cyclization temperatures, measured via DSC, decrease with the denticity of X (bidentate NO 3 - , T = 267-292 °C; monodentate Cl - , T = 238-262 °C; noncoordinating OTf - , T = 170-183 °C). 13 C NMR characterization shows that the chemical shifts of the acetylenic carbon atoms also rely on the anion identity. The alkyne carbon closest to the metal binding site, C A , exhibits a Δδ > 3 ppm downfield shift, while the more distal alkyne carbon, C B , displays a concomitant Δδ ≤ 2.5 ppm upfield shift, reflecting a depolarization of the alkyne on metal inclusion. For all metals studied, the degree of perturbation follows the trend 2 < NO 3 - < Cl - < OTf - . This belies a greater degree of electronic rearrangement in the coordinated macrocycle as the denticity of X and its accompanying shielding of the metal's Lewis acidity decrease. Computationally modeled structures of LnX 3 show a systematic increase in the lanthanide- 2 coordination number (CN La-mc = 2 (NO 3 - ), 4 (Cl - ), 5 (H 2 O, model for OTf - )) and a decrease in the mean Ln-N bond length (La-N average = 2.91 Å (NO 3 - ), 2.78 Å (Cl - ), 2.68 Å (H 2 O)), further suggesting that a decrease in the anion coordination number correlates with an increase in the metal-macrocycle interaction. Taken together, these data illustrate a Bergman cyclization landscape that is influenced by the bonding of metal to an enediyne ligand but whose reaction barrier is ultimately dominated by the coordinating ability of the accompanying anion.

Conventional amide synthesis is a mainstay in discipline-spanning applications, and it is a reaction type that historically developed as a singular paradigm when considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis (UmAS) exploits the unique properties of an α-halo nitroalkane in its reaction with an amine to produce an amide. The "umpolung" moniker reflects its paradigm-breaking C-N bond formation on the basis of evidence that the nucleophilic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct observation of a HANA, its conversion thermally to an amide functionality, and quantitative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Supramolecular polymers have enabled far-reaching fundamental science and the development of diverse macromolecular technologies owing to the reversible and noncovalent chemical connectivities that define their properties. Despite the unabated development of these materials using highly tailorable recognition elements, anion-based polymers remain rare as a result of the weak interactions they mediate. Here, we use design rules inspired by cation-driven polymers to demonstrate a new noncovalent link based on receptor-stabilized anion-anion interactions that enables the efficient linear polymerization of simple difunctional phosphonates. The linear main chain connectivity and molecular topology were confirmed by single crystal X-ray diffraction, which demonstrates the rare 2:2 stoichiometry between the anionic phosphonate end groups and a pair of π-stacked cyanostar macrocycles. The stability of these links enables rapid polymerization of difunctional phosphonates employing different aliphatic linkers (C 6 H 12 , C 8 H 16 , C 10 H 20 , C 12 H 24 ). Diphosphonates with greater chain flexibility (C 12 H 24 ) enable greater polymerization with an average degree of polymerization of nine emerging at 10 mM. Viscosity measurements show a transition from oligomers to polymers at the critical polymerization concentration of 5 mM. In a rare correlation, NMR spectroscopy shows a coincident molecular signature of the polymerization at 5 mM. These polymers are highly concentration dependent, reversibly polymerize with acid and base, and respond to competitive anions. They display the design simplicity of metallo-supramolecular polymers with transfer of the strong 2:2 recognition chemistry to macromolecules. The simplicity and understanding of this new class of supramolecular polymer is anticipated to open opportunities in tailoring anion-based functional materials.

High spin ( S = 1) organic diradicals may offer enhanced properties with respect to several emerging technologies, but typically exhibit low singlet triplet energy gaps and possess limited thermal stability. We report triplet ground state diradical 2 with a large singlet-triplet energy gap, Δ E ST ≥ 1.7 kcal mol -1 , leading to nearly exclusive population of triplet ground state at room temperature, and good thermal stability with onset of decomposition at ∼160 °C under inert atmosphere. Magnetic properties of 2 and the previously prepared diradical 1 are characterized by SQUID magnetometry of polycrystalline powders, in polystyrene glass, and in other matrices. Polycrystalline diradical 2 forms a novel one-dimensional (1D) spin-1 ( S = 1) chain of organic radicals with intrachain antiferromagnetic coupling of J'/ k = -14 K, which is associated with the N···N and N···O intermolecular contacts. The intrachain antiferromagnetic coupling in 2 is by far strongest among all studied 1D S = 1 chains of organic radicals, which also makes 1D S = 1 chains of 2 most isotropic, and therefore an excellent system for studies of low-dimensional magnetism. In polystyrene glass and in frozen benzene or dibutyl phthalate solution, both 1 and 2 are monomeric. Diradical 2 is thermally robust and is evaporated under ultrahigh vacuum to form thin films of intact diradicals on silicon substrate, as demonstrated by X-ray photoelectron spectroscopy. Based on C-K NEXAFS spectra and AFM images of the ∼1.5 nm thick films, the diradical molecules form islands on the substrate with molecules stacked approximately along the crystallographic a-axis. The films are stable under ultrahigh vacuum for at least 60 h but show signs of decomposition when exposed to ambient conditions for 7 h.

The direct, catalytic substitution of unactivated alcohols remains an undeveloped area of organic synthesis. Moreover, catalytic activation of this difficult electrophile with predictable stereo-outcomes presents an even more formidable challenge. Described herein is a simple iron-based catalyst system which provides the mild, direct conversion of secondary and tertiary alcohols to sulfonamides. Starting from enantioenriched alcohols, the intramolecular variant proceeds with stereoinversion to produce enantioenriched 2- and 2,2-subsituted pyrrolidines and indolines, without prior derivatization of the alcohol or solvolytic conditions., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ureas of chiral diamines are prominent features of therapeutics, chiral auxiliaries, and intermediates in complex molecule synthesis. Although many methods for diamine synthesis are available, metal-free enantioselective alkene functionalizations to make protected 1,2- and 1,3-diamines from simple achiral starting materials are rare, and a single reagent that accesses a cross-section of each congener with high enantiomeric excess is not available. We describe a method to synthesize enantioenriched cyclic 5- and 6-membered ureas from allylic amines and an isocyanate using a C2-symmetric BisAmidine (BAM) catalyst that delivers N-selectivity from an ambident sulfonyl imide intermediate, overcoming electronic and steric deactivation at nitrogen. The geometry of 1,2-disubstituted alkenes is correlated to 5-exo and 6-endo cyclizations without altering alkene face selectivity, which is unexpectedly opposite that observed with O-nucleophiles. Straightforward product manipulations to diamine and imidazolidinone derivatives are underscored by the synthesis of an NK1 antagonist., Competing Interests: Notes No competing financial interests have been declared.

Here, we report the development of monodisperse Zn-doped iron oxide nanoparticles (NPs) with different amounts of Zn (Zn x Fe 3- x O 4 , 0 < x < 0.43) by thermal decomposition of a mixture of zinc and iron oleates. The as-synthesized NPs show a considerable fraction of wüstite (FeO) which is transformed to spinel upon 2 h oxidation of the NP reaction solutions. At any Zn doping amounts, we observed the enrichment of the NP surface with Zn 2+ ions, which is enhanced at higher Zn loadings. Such a distribution of Zn 2+ ions is attributed to the different thermal decomposition profiles of Zn and Fe oleates, with Fe oleate decomposing at much lower temperature than that of Zn oleate. The decomposition of Zn oleate is, in turn, catalyzed by a forming iron oxide phase. The magnetic properties were found to be strongly dependent on the Zn doping amounts, showing the saturation magnetization to decrease by 9 and 20% for x = 0.05 and 0.1, respectively. On the other hand, X-ray photoelectron spectroscopy near the Fermi level demonstrates that the Zn 0.05 Fe 2.95 O 4 sample displays a more metallic character (a higher charge carrier density) than undoped iron oxide NPs, supporting its use as a spintronic material., Competing Interests: The authors declare no competing financial interest.

This paper reports the development of robust Pd- and Ru-containing magnetically recoverable catalysts in a one-pot procedure using commercially available, branched polyethyleneimine (PEI) as capping and reducing agent. For both catalytic metals, ∼3 nm nanoparticles (NPs) are stabilized in the PEI shell of magnetite NPs, whose aggregation allows for prompt magnetic separation. The catalyst properties were studied in a model reaction of 4-nitrophenol hydrogenation to 4-aminophenol with NaBH 4 . A similar catalytic NP size allowed us to decouple the NP size impact on the catalytic performance from other parameters and to follow the influence of the catalytic metal type and amount as well as the PEI amount on the catalytic activity. The best catalytic performances, the 1.2 min -1 rate constant and the 433.2 min -1 turnover frequency, are obtained for the Ru-containing catalyst. This is discussed in terms of stability of Ru hydride facilitating the surface-hydrogen transfer and the presence of Ru 4+ species on the Ru NP surface facilitating the nitro group adsorption, both leading to an increased catalyst efficiency. High catalytic activity as well as the high stability of the catalyst performance in five consecutive catalytic cycles after magnetic separation makes this catalyst promising for nitroarene hydrogenation reactions., Competing Interests: The authors declare no competing financial interest.

Reaction of the readily reduced pincer ligand bis-tetrazinylpyridine, btzp, with the zerovalent metal source M(CO) 3 (MeCN) 3 yields M(btzp) 2 for M = Cr, Mo. These diamagnetic molecules show intrapincer bond lengths consistent with major charge transfer from metal to ligand, a result which is further supported by X-ray photoelectron spectroscopy. These molecules show up to five reversible outer-sphere electron transfers by cyclic voltammetry. The electronic structure of neutral M(btzp) 2 is analyzed by DFT and CASSCF calculations, which reveal the degree of back-donation from the metal into pincer π* orbitals and also subtle differences in metal-ligand interaction for Mo vs Cr. Near-IR absorptions exhibited by both M(btzp) 2 species originate from charge transfer among differently reduced tetrazine rings, which thus further support pincer reduction in these species.

Duvelisib is an orally active dual inhibitor of PI3K-δ and PI3K-γ in clinical development in hematologic malignancies (HM). To identify novel pairings for duvelisib in HM, it was evaluated alone and in combination with 35 compounds comprising a diverse panel of standard-of-care agents and emerging drugs in development for HM. These compounds were tested in 20 cell lines including diffuse large B-cell, follicular, T-cell, and mantle cell lymphomas, and multiple myeloma. Single agent activity was seen in fourteen cell lines, with a median GI50 of 0.59 μM. A scalar measure of the strength of synergistic drug interactions revealed a synergy hit rate of 19.3% across the matrix of drug combinations and cell lines. Synergy with duvelisib was prominent in lymphoma lines with approved and emerging drugs used to treat HM, including dexamethasone, ibrutinib, and the BCL-2 inhibitor venetoclax. Western blotting revealed that certain duvelisib-treated cell lines showed inhibition of phosphorylated (p) AKT at serine 473 only out to 12 hours, with mTORC2 dependent re-phosphorylation of pAKT evident at 24 hours. Combination with dexamethasone or ibrutinib, however, prevented this reactivation leading to durable inhibition of pAKT. The combination treatments also inhibited downstream signaling effectors pPRAS40 and pS6. The combination of duvelisib with dexamethasone also significantly reduced p-4EBP1, which controls cap dependent translation initiation, leading to decreased levels of c-MYC 6 hours after treatment. In support of the in vitro studies, in vivo xenograft studies revealed that duvelisib in combination with the mTOR inhibitor everolimus led to greater tumor growth inhibition compared to single agent administration. These data provide a rationale for exploring multiple combinations in the clinic and suggest that suppression of mTOR-driven survival signaling may be one important mechanism for combination synergy., Competing Interests: All authors were employees and shareholders of Infinity Pharmaceuticals at the time this work was performed. Kerrie Faia is currently employed by Blueprint Medicines. Blueprint Medicines was not involved in any aspect of the study or this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Hierarchical assembly provides a route to complex architectures when using building blocks with strong and structurally well-defined recognition elements. These rules are traditionally expressed using cationic templates with reliable metal-ligand bonding but use of anions is rare on account of weak anion-host contacts. We investigate an approach that relies on host-host interactions to fortify assemblies formed between bisulfate anion dimers, [HSO4⋅⋅⋅HSO4] 2- , and shape-persistent macrocycles called tricarbazole triazolophanes. These macrocycles have significant self-association. In chloroform, they form high fidelity, triple-decker stacks with bisulfate dimers. The strength of host-host interactions allows for preferential formation of the 3:2 tricarb:bisulfate architecture over an ion-paired architecture seen with analogous macrocycles with much weaker self-association. Solvent was expected and found to tune host-host contacts enabling formation of a 2:2 complex and solvent-driven switching between triple- and double-stacked structures. Crystallography of the 2:2:2 complex supports the idea that significant host-host interactions with tricarb arises from dipole-stabilized π-stacking. Computational studies were also conducted further highlighting the importance of host-host interactions in stacked complexes of tricarb. These findings unambiguously verify the importance of host-host interactions in the assembly and stability of discrete, responsive anion-templated architectures., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Here, we report transfer hydrogenation of nitroarenes to aminoarenes using 2-propanol as a hydrogen source and Ag-containing magnetically recoverable catalysts based on partially reduced graphene oxide (pRGO) sheets. X-ray diffraction and X-ray photoelectron spectroscopy data demonstrated that, during the one-pot catalyst synthesis, formation of magnetite nanoparticles (NPs) is accompanied by the reduction of graphene oxide (GO) to pRGO. The formation of Ag 0 NPs on top of magnetite nanoparticles does not change the pRGO structure. At the same time, the catalyst structure is further modified during the transfer hydrogenation, leading to a noticeable increase of sp 2 carbons. These carbons are responsible for the adsorption of substrate and intermediates, facilitating a hydrogen transfer from Ag NPs and creating synergy between the components of the catalyst. The nitroarenes with electron withdrawing and electron donating substituents allow for excellent yields of aniline derivatives with high regio and chemoselectivity, indicating that the reaction is not disfavored by these functionalities. The versatility of the catalyst synthetic protocol was demonstrated by a synthesis of an Ru-containing graphene derivative based catalyst, also allowing for efficient transfer hydrogenation. Easy magnetic separation and stable catalyst performance in the transfer hydrogenation make this catalyst promising for future applications.

A new rotamer-based strategy for negative allostery has been used to control host-host interactions and product yield upon anion complexation. Coassembly of anion dimers as guests inside two cyanostar macrocycles drives selection of one rotamer in which all ten steric groups get directed outward to destabilize triply stacked macrocycles. A large entropy penalty (Δ S) is quantified upon anion binding when the multiple dynamic rotamers collapse down to one.

The bis-pyrazolato pyridine complex LCo(PEt 3 ) 2 serves as a masked form of three-coordinate Co II and shows diverse reactivity in its reaction with several potential outer sphere oxidants and oxygen atom transfer reagents. N-Methylmorpholine N-oxide (NMO) oxidizes coordinated PEt 3 from LCo(PEt 3 ) 2 , but the final cobalt product is still divalent cobalt, in LCo(NMO) 2 . The thermodynamics of a variety of oxygen atom transfer reagents, including NMO, are calculated by density functional theory, to rank their oxidizing power. Oxidation of LCo(PEt 3 ) 2 with AgOTf in the presence of LiCl as a trapping nucleophile forms the unusual aggregate [LCo(PEt 3 ) 2 Cl(LiOTf) 2 ] 2 held together by Li + binding to very nucleophilic chloride on Co(III) and triflate binding to those Li + . In contrast, Cp 2 Fe + effects oxidation to trivalent cobalt, to form (HL)Co(PEt 3 ) 2 Cl + ; proton and the chloride originate from solvent in a rare example of CH 2 Cl 2 dehydrochlorination. An unexpected noncomplementary redox reaction is reported involving attack by 2e reductant PEt 3 nucleophile on carbon of the 1e oxidant radical Cp 2 Fe + , forming a P-C bond and H + ; this reaction competes in the reaction of LCo(PEt 3 ) 2 with Cp 2 Fe + .

The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform., (Copyright © 2018 Intellia Therapeutics, Inc. Published by Elsevier Inc. All rights reserved.)

The importance of phosphate in biology and chemistry has long motivated investigation of its recognition. Despite this interest, phosphate's facile oligomerization is only now being examined following the discovery of complexes of anion-anion dimers of hydroxyanions. Here we address how oligomerization dictates phosphate's recognition properties when engaged with planar cyanostar macrocycles that can also oligomerize by stacking. The crystal structure of cyanostar with phosphate shows an unprecedented tetrameric stack of cyanostar macrocycles threaded by a phosphate trimer, [H 2 PO 4 ···H 2 PO 4 ···H 2 PO 4 ] 3- . The solution behaviour, studied as a function of solvent quality, highlights how dimers and trimers of phosphate drive formation of higher order stacks of cyanostar into dimer, trimer and tetramer co-assemblies. Solution behaviors differ significantly from simpler complexes of bisulfate hydroxyanion dimers. Phosphate oligomerization is: (1) preferred over ion pairing with tetrabutylammonium cations, (2) inhibits disassembly of the complexes upon dilution, and (3) resists interference from competitive anion solvation. The phosphate oligomers also appear critical for stability; complexation of just one phosphate with cyanostars is unfavored. The cyanostar's ability to self-assemble is found to create a tubular, highly electropositive cavity that complements the size and shape of the phosphate oligomers as well as their higher charge. When given the opportunity, phosphate will cooperate with the receptor to form co-assembled architectures.

The enantioselective desymmetrization of carboxylic acids by chiral Brønsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Brønsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter and can be derivatized to functionalized cyclopentanes.

The behavior of the complex (H 2 L)CoCl 2 , where H 2 L is a bis-(pyrazol-3-yl)pyridine, towards Brønsted bases is studied, to evaluate peripheral NH deprotonation as a route to a dianionic pincer ligand on a d 7 center. Deprotonation is found to also remove chloride from cobalt, and the decreased metal coordination number is then satisfied by bimolecular reaction of the newly formed peripheral deprotonated pyrazolate nitrogen, leading to Co 2 units bridged by some of the pyrazolates, in the analogous species [Co 2 (L)(LH)] 2 (L) and [Co 2 (L)(HL)] 2 [Co(L) 2 ], but also occasionally by chloride retention, in LiCo 2 L 2 Cl. Reacting LiCo 2 L 2 Cl with tBuNC, yields monomeric LCo(tBuNC) 2 , shown to be a 17 valence electron species. Use of excess LiN(SiMe 3 ) 2 in deprotonation of (H 2 L)CoCl 2 leads to a product containing a Co[N(SiMe 3 ) 2 ] 2 substructure, which illustrates opening of the Co 2 L 2 dimer in response to an attacking nucleophile.

Here, we present a controlled synthesis of Mn-doped ZnO nanoparticles (NPs) with predominantly nail-like shapes, whose formation occurs via tip-to-base-oriented attachment of initially formed nanopyramids, followed by leveling of sharp edges that lead to smooth single-crystalline "nails". This shape is prevalent in noncoordinating solvents such as octadecene and octadecane. Yet, the double bond in the former promotes oriented attachment. By contrast, Mn-doped ZnO NP synthesis in a weakly coordinating solvent, benzyl ether, results in dendritic structures because of random attachment of initial NPs. Mn-doped ZnO NPs possess a hexagonal wurtzite structure, and in the majority of cases, the NP surface is enriched with Mn, indicating a migration of Mn 2+ ions to the NP surface during the NP formation. When the NP formation is carried out without the addition of octadecyl alcohol, which serves as a surfactant and a reaction initiator, large, concave pyramid dimers are formed whose attachment takes place via basal planes. UV-vis and photoluminescence spectra of these NPs confirm the utility of controlling the NP shape to tune electro-optical properties.

A series of Mn(II) complexes of differently substituted pyridinophane ligands, (Py 2 NR 2 )MnCl 2 (R = i Pr, Cy) and [(Py 2 NR 2 )MnF 2 ](PF 6 ) (R = i Pr, Cy, t Bu) are synthesized and characterized. The electrochemical properties of these complexes are investigated by cyclic voltammetry, along with those of previously reported (Py 2 NMe 2 )MnCl 2 and the Mn(III) complex [(Py 2 NMe 2 )MnF 2 ](PF 6 ). The electronic structure of this and other Mn(III) complexes is probed experimentally and theoretically, via high-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy ab initio quantum chemical theory (QCT), respectively. These studies show that the complexes contain relatively typical six-coordinate Mn(III). The catalytic activity of these complexes toward both H 2 O 2 disproportionation and H 2 O oxidation has also been investigated. The rate of H 2 O 2 disproportionation decreases with increasing substituent size. Some of these complexes are active for electrocatalytic H 2 O oxidation; however this activity cannot be rationalized in terms of simple electronic or steric effects.

A product of incomplete combustion of diesel fuel, 3-nitrobenzanthrone (3-NBA), has been classified as a cancer-causing substance. It first gained attention as a potential urinary bladder carcinogen due to the presence of its metabolite in urine and formation of DNA adducts. The aim of the present study was to characterize the dose-response relationship of 3-NBA in human urothelial cancer cell line (RT4) exposed to concentrations ranging from 0.0003 μM (environmentally relevant) to 80 μM by utilizing toxicological and metabolomic approaches. We observed that the RT4 cells were capable of bioactivation of 3-NBA within 30 min of exposure. Activity measurements of various enzymes involved in the conversion of 3-NBA in RT4 cells demonstrated NAD(P)H:quinone oxidoreductase (NQO1) as the main contributor for its bioactivation. Moreover, cytotoxicity assessment exhibited an initiation of adaptive mechanisms at low dosages, which diminished at higher doses, indicating that the capacity of these mechanisms no longer suffices, resulting in increased levels of intracellular reactive oxygen species, reduced proliferation, and hyperpolarisation of the mitochondrial membrane. To characterize the underlying mechanisms of this cellular response, the metabolism of 3-NBA and metabolomic changes in the cells were analyzed. The metabolomic analysis of the cells (0.0003, 0.01, 0.08, 10, and 80 μM 3-NBA) showed elevated levels of various antioxidants at low concentrations of 3-NBA. However, at higher exposure concentrations, it appeared that the cells reprogrammed their metabolism to maintain the cell homeostasis via activation of pentose phosphate pathway (PPP).

The new iron(IV) nitride complex PhB( i Pr 2 Im) 3 Fe≡N reacts with 2 equiv of bis(diisopropylamino)cyclopropenylidene (BAC) to provide PhB( i Pr 2 Im) 3 Fe(CN)(N 2 )(BAC). This unusual example of a four-electron reaction involves carbon atom transfer from BAC to create a cyanide ligand along with the alkyne i Pr 2 N-C≡C-N i Pr 2 . The iron complex is in equilibrium with an N 2 -free species. Further reaction with CO leads to formation of a CO analogue, which can be independently prepared using NaCN as the cyanide source, while reaction with B(C 6 F 5 ) 3 provides the cyanoborane derivative.

Here, we report on the development of novel Zn-, Zn-Cr-, and Zn-Cu-containing catalysts using magnetic silica (Fe 3 O 4 -SiO 2 ) as the support. Transmission electron microscopy, powder X-ray diffraction, and X-ray photoelectron spectroscopy (XPS) showed that the iron oxide nanoparticles are located in mesoporous silica pores and the magnetite (spinel) structure remains virtually unchanged despite the incorporation of Zn and Cr. According to XPS data, the Zn and Cr species are intermixed within the magnetite structure. In the case of the Zn-Cu-containing catalysts, a separate Cu 2 O phase was also observed along with the spinel structure. The catalytic activity of these catalysts was tested in methanol synthesis from syngas (CO + H 2 ). The catalytic experiments showed an improved catalytic performance of Zn- and Zn-Cr-containing magnetic silicas compared to that of the ZnO-SiO 2 catalyst. The best catalytic activity was obtained for the Zn-Cr-containing magnetic catalyst prepared with 1 wt % Zn and Cr each. X-ray absorption spectroscopy demonstrated the presence of oxygen vacancies near Fe and Zn in Zn-containing, and even more in Zn-Cr-containing, magnetic silica (including oxygen vacancies near Cr ions), revealing a correlation between the catalytic properties and oxygen vacancies. The easy magnetic recovery, robust synthetic procedure, and high catalytic activity make these catalysts promising for practical applications.

The heat-induced food contaminant 3-monochloropropane-1,2-diol (3-MCPD) and its fatty acid esters exert nephrotoxicity in rodents. Previous studies including a non-targeted toxicoproteomics approach using samples from a 28-day oral toxicity study in rats with 10 mg/kg body weight (b.w.) of 3-MCPD, an equimolar dose of 53 mg/kg b.w. 3-MCPD dipalmitate and a lower dose of 13.3 mg/kg b.w. of 3-MCPD dipalmitate, revealed substance-induced alterations in metabolic pathways, especially for glycolysis and energy metabolism. In order to obtain deeper insight into mechanisms of 3-MCPD toxicity, samples from the above-mentioned study were reanalyzed using a lanthanum chloride precipitation-based toxicoproteomics approach in order to increase the yield of phosphorylated proteins, crucial players in cellular signaling. A comparison of standard 2D-gel-based proteomics and lanthanum chloride precipitation was performed, thus providing a comprehensive case study on these two methods using in vivo effects of an important food toxicant in a primary target organ. While resulting in similar 2D-gel electrophoresis pherograms and spot counts, data analysis demonstrated that lanthanum precipitation yielded more significantly deregulated proteins thus considerably improving our knowledge on 3-MCPD-dependent proteomic alterations in the kidney. 3-MCPD-induced deregulation of the phosphorylated, active version of extracellular signal-regulated kinase 2 (ERK2) in rat kidney was demonstrated using mass spectrometry and immunohistochemistry. In summary, this paper for the first time links 3-MCPD effects to deregulation of the ERK/mitogen-activated protein kinase signaling pathway in rat kidney and demonstrates that lanthanum chloride precipitation is suited to support the gain of mechanistic knowledge on organ toxicity using 2D-gel-based proteomics.

The complex (PNP)Ti═CH t Bu(CH 2 t Bu) (PNP = N[2-P i Pr 2 -4-methylphenyl] 2 - ) dehydrogenates cyclohexane to cyclohexene by forming a transient low-valent titanium-alkyl species, [(PNP)Ti(CH 2 t Bu)], which reacts with 2 equiv of quinoline (Q) at room temperature to form H 3 C t Bu and a Ti(IV) species where the less hindered C 2 ═N 1 bond of Q is ruptured and coupled to another equivalent of Q. The product isolated from this reaction is an imide with a tethered cycloamide group, (PNP)Ti═N[C 18 H 13 N] (1). Under photolytic conditions, intramolecular C-H bond activation across the imide moiety in 1 occurs to form 2, and thermolysis reverses this process. The reaction of 2 equiv of isoquinoline (Iq) with intermediate [(PNP)Ti(CH 2 t Bu)] results in regioselective cleavage of the C 1 ═N 2 and C 1 -H bonds, which eventually couple to form complex 3, a constitutional isomer of 1. Akin to 1, the transient [(PNP)Ti(CH 2 t Bu)] complex can ring-open and couple two pyridine molecules, to produce a close analogue of 1, complex (PNP)Ti═N[C 10 H 9 N] (4). Multinuclear and multidimensional NMR spectra confirm structures for complexes 1-4, whereas solid-state structural analysis reveals the structures of 2, 3, and 4. DFT calculations suggest an unprecedented mechanism for ring-opening of Q where the reactive intermediate in the low-spin manifold crosses over to the high-spin surface to access a low-energy transition state but returns to the low-spin surface immediately. This double spin-crossover constitutes a rare example of a two-state reactivity, which is key for enabling the reaction at room temperature. The regioselective behavior of Iq ring-opening is found to be due to electronic effects, where the aromatic resonance of the bicycle is maintained during the key C-C coupling event.

Benzo[a]pyrene (B[a]P), a well-known polyaromatic hydrocarbon, is known for its lung carcinogenicity, however, its role in bladder cancer development is still discussed. Comparative two-dimensional blue native SDS-PAGE analysis of protein complexes isolated from subcellular fractions of 0.5 µM B[a]P-exposed cells indicated a differential regulation of proteins involved in carbohydrate, fatty acid, and nucleotide metabolism, suggesting a possible metabolic flux redistribution. It appeared that B[a]P exposure led to a repression of enzymes (fructose-bisphosphate aldolase A, glucose-6-phosphate isomerase, lactate dehydrogenase) involved in glycolysis, and an up-regulation of proteins (glucose-6-phosphate 1-dehydrogenase, 6-phosphogluconolactonase) catalyzing the pentose phosphate pathway and one carbon metabolism (10-formyltetrahydrofolate dehydrogenase, bifunctional purine biosynthesis protein). Untargeted metabolomics further supported the proteomic data, a lower concentration of glycolytic metabolite was observed as compared to glutamine, xylulose and fatty acids. The analysis of the glutathione and NADPH/NADP + content of the cells revealed a significant increase of these cofactors. Concomitantly, we did not observe any detectable increase in the production of ROS. With the present work, we shed light on an early phase of the metabolic stress response in which the urothelial cells are capable of counteracting oxidative stress by redirecting the metabolic flux from glycolysis to pentose phosphate pathway.

The hierarchical assembly of colored cationic molecules with receptor-modified counteranions can be used to control optical properties in materials. However, our knowledge of when the optical properties emerge in the hierarchical organization and the variety of cation-anion salts that are available to create these materials is limited. In this work, we extend the salts from small halides to large inorganic anions and determine how the structure coevolves with the emission properties using solution assemblies. We study the chromogenic trioxatriangulenium (TOTA + ) cation and its coassembly with cyanostar (CS) macrocycles selected to modify tetrafluoroborate (BF 4 - ) counteranions through formation of 2:1 sandwich complexes. In the solid state, the TOTA + cation stacks in an alternating manner with the sandwich complexes producing new red-shifted emission and absorption bands. Critical to assigning the structural origin of the new optical features across the four levels of organization (1° → 4°) is the selection of specific solvents to produce and characterize different assemblies present in the hierarchical structure. A key species is the electrostatically stabilized ion pair between the TOTA + cation and sandwich complex. The red-shifted features only emerge when the ion pairs oligomerize together into larger (TOTA·[CS 2 BF 4 ]) n assemblies. New electronic states emerge as a result of multiple copies of the TOTA + making π-contact with cyanostar-anion complexes. Our findings and the ease with which the materials can be prepared as crystals and films by mixing the salt with a receptor provide a strong platform for the de novo design of new optical materials.

We report the design, synthesis, and electron spin relaxation properties of hydrophilic tetracarboxylate ester pyrroline nitroxides 1 and 2, which serve as models in the search for new spin labels for DEER distance measurement at room temperature. The nitroxides are designed to have the methyl groups further away from the N-O spin site to decrease the inequivalent couplings of the unpaired electron to the methyl protons that shorten T m at T > 70 K in currently used labels. The key step in the synthesis of 1 and 2 is the reaction of the dianion of pyrrole-1,2,5-tricarboxylic acid tert-butyl ester dimethyl ester with electrophiles such as methyl chloroformate and methyl bromoacetate. Structures of 1 and 2 are confirmed by X-ray crystallography. Studies of electron spin relaxation rates in rigid trehalose/sucrose matrices reveal approximately temperature independent values of 1/T m for 1 and 2 up to about 160 K and modest temperature dependence up to 295 K, demonstrating that increasing the distance between the nitroxide moiety and methyl groups is effective in lengthening T m at T > 70 K.

A new family of Ni-, Co-, and Cr-doped Zn-containing magnetic oxide nanoparticles (NPs) stabilized by polyphenylquinoxaline (PPQ) and hyperbranched pyridylphenylene polymer (PPP) has been developed. These NPs have been synthesized by thermal decomposition of Zn and doping metal acetylacetonates in the reaction solution of preformed magnetite NPs, resulting in single-crystal NPs with spinel structure. For the PPQ-capped NPs, it was demonstrated that all three types of metal species (Fe, Zn, and a doping metal) reside within the same NPs, the surface of which is enriched with Zn and a doping metal, while the deeper layers are enriched with Fe. The Cr-doped NPs at the high Cr loading are an exception due to favored deposition of Cr on magnetite located in the NP depth. The PPP-capped NPs exhibit similar morphology and crystallinity; however, the detailed study of the NP composition was barred due to the high PPP amount retained on the NP surface. The catalyst testing in syngas conversion to methanol demonstrated outstanding catalytic properties of doped Zn-containing magnetic oxides, whose activities are dependent on the doping metal content and on the stabilizing polymer. The PPP stabilization allows for better access to the catalytic species due to the open and rigid polymer architecture and most likely optimized distribution of doping species. Repeat experiments carried out after magnetic separation of catalysts from the reaction mixture showed excellent catalyst stability even after five consecutive catalytic runs.

Bulky tris(carbene)borate ligands provide access to high spin iron(ii) phosphido complexes. The complex PhB(MesIm) 3 FeP(H)Ph is thermally unstable, and [PPh] group insertion into a C-H bond of the supporting ligand is observed. An arrested α-hydride migration mechanism suggests increased nucleophilicity of the phosphorus atom facilitates [PPh] group transfer reactivity.

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8 + T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.

Anion-templated rotaxanes are a rare class of functional organic molecules capable of novel switching and mechanical behaviors. Yet, investigations of these properties are limited by existing synthetic strategies. We show a high-yielding synthesis (80%) of [3]rotaxanes using shape-persistent macrocycles, cyanostars, and anionic organo-phosphate templates catalyzed by low steric-demand click chemistry. The reaction yields correlate with the template's binding affinities. Use of longer linkers relieves steric congestion to enable a reversible acid-base response, opening the way to molecular switching.

Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.

Encapsulation of unstable guests is a powerful way to enhance their stability. The lifetimes of organic anions and their radicals produced by reduction are typically short on account of reactivity with oxygen while their larger sizes preclude use of traditional anion receptors. Here we demonstrate the encapsulation and noncovalent stabilization of organic radical anions by C-H hydrogen bonding in π-stacked pairs of cyanostar macrocycles having large cavities. Using electrogenerated tetrazine radical anions, we observe significant extension of their lifetimes, facile molecular switching, and extremely large stabilization energies. The guests form threaded pseudorotaxanes. Complexation extends the radical lifetimes from 2 h to over 20 days without altering its electronic structure. Electrochemical studies show tetrazines thread inside a pair of cyanostar macrocycles following voltage-driven reduction (+e - ) of the tetrazine at -1.00 V and that the complex disassembles after reoxidation (-e - ) at -0.05 V. This reoxidation is shifted 830 mV relative to the free tetrazine radical indicating it is stabilized by an unexpectedly large -80 kJ mol -1 . The stabilization is general as shown using a dithiadiazolyl anion. This finding opens up a new approach to capturing and studying unstable anions and a radical anions when encapsulated by size-complementary anion receptors.

Contrary to the simple expectations from Coulomb's law, Weinhold proposed that anions can stabilize each other as metastable dimers, yet experimental evidence for these species and their mutual stabilization is missing. We show that two bisulfate anions can form such dimers, which stabilize each other with self-complementary hydrogen bonds, by encapsulation inside a pair of cyanostar macrocycles. The resulting 2:2 complex of the bisulfate homodimer persists across all states of matter, including in solution. The bisulfate dimer's OH⋅⋅⋅O hydrogen bonding is seen in a 1 H NMR peak at 13.75 ppm, which is consistent with borderline-strong hydrogen bonds., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

E- and P-selectin ligands (E- and P-ligs) guide effector memory T cells into skin and inflamed regions, mediate the inflammatory recruitment of leukocytes, and contribute to the localization of hematopoietic precursor cells. A better understanding of their molecular regulation is therefore of significant interest with regard to therapeutic approaches targeting these pathways. In this study, we examined the transcriptional regulation of fucosyltransferase 7 (FUT7), an enzyme crucial for generation of the glycosylated E- and P-ligs. We found that high expression of the coding gene fut7 in murine CD4 + T cells correlates with DNA demethylation within a minimal promoter in skin/inflammation-seeking effector memory T cells. Retinoic acid, a known inducer of the gut-homing phenotype, abrogated the activation-induced demethylation of this region, which contains a cAMP responsive element. Methylation of the promoter or mutation of the cAMP responsive element abolished promoter activity and the binding of CREB, confirming the importance of this region and of its demethylation for fut7 transcription in T cells. Furthermore, studies on human CD4 + effector memory T cells confirmed demethylation within FUT7 corresponding to high FUT7 expression. Monocytes showed an even more extensive demethylation of the FUT7 gene whereas hepatocytes, which lack selectin ligand expression, exhibited extensive methylation. In conclusion, we show that DNA demethylation within the fut7 gene controls selectin ligand expression in mice and humans, including the inducible topographic commitment of T cells for skin and inflamed sites., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Reaction of 3,6-disubstituted-1,2,4,5-tetrazines with water and PEt 3 forms the corresponding 1,4-dihydrotetrazine and OPEt 3 . Thus PEt 3 , as a stoichiometric reductant, reduces water, and the resulting two reducing equivalents serve to doubly hydrogenate the tetrazine. A variety of possible initial interactions between electron-deficient tetrazine and electron-rich PR 3 , including a charge transfer complex, were evaluated by density functional calculations which revealed that the energy of all these make them spectroscopically undetectable at equilibrium, but one of these is nevertheless suggested as the intermediate in the observed redox reaction. The relationship of this to the Mitsunobu reaction, which absorbs the components of water evolved in the conversion of alcohol and carboxylic acid to ester, with desirable inversion at the alcohol carbon, is discussed. This enables a modified Mitsunobu reaction, with tetrazine replacing EtO 2 CN=NCO 2 Et (DEAD), which has the advantage that dihydrotetrazine can be recycled to tetrazine by oxidation with O 2 , something impossible with the hydrogenated DEAD. For this tetrazine version, a betaine-like intermediate is undetectable, but its protonated form is characterized, including by X-ray structure and NMR spectroscopy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

P-selectin ligands (P-ligs) support the recruitment of lymphocytes into inflamed tissues. Binding to P-selectin is mediated by oligosaccharide groups synthesized by means of several glycosyltransferases including core 2 ß1,6-N-acetylglucosaminyltransferase-I (C2GlcNAcT-I), encoded by the gene Gcnt1. Using Gcnt1(-/-) Th1 cells, we show that C2GlcNAcT-I is crucial for inflammatory T cell homing in vivo. To understand the molecular regulation of Gcnt1 in CD4(+) T helper cells, we performed ChIP-on-chip experiments across the Gcnt1 locus assessing the chromatin structure in P-lig-expressing versus non-expressing CD4(+) T cells. This identified a distal region about 20kb upstream of the promoter where the presence of a H3K27me3 mark correlated with Gcnt1 repression. This region possessed IL-12-dependent enhancer activity in reporter assays, in accordance with preferential IL-12-dependent induction of Gcnt1 in vitro. STAT4 and T-bet cooperated in control of the enhancer activity. Deficiency in either one resulted in drastically reduced Gcnt1 mRNA expression in differentiated Th1 cells. While both STAT4 and T-bet were bound to the enhancer early after activation only T-bet binding persisted throughout the expansion phase after TCR signal cessation. This suggests sequential action of STAT4 and T-bet at the enhancer. In summary, we show that Gcnt1 transcription and subsequent P-lig induction in Th1 cells is governed by binding of STAT4 and T-bet to a distal enhancer and further regulated by epigenetic marks such as H3K27me3., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Structural, spectroscopic and magnetic methods have been used to characterize the tris(carbene)borate compound PhB(MesIm) 3 Mn≡N as a four-coordinate manganese(IV) complex with a low spin ( S = 1/2) configuration. The slow relaxation of the magnetization in this complex, i.e. its single-molecule magnet (SMM) properties, is revealed under an applied dc field. Multireference quantum mechanical calculations indicate that this SMM behavior originates from an anisotropic ground doublet stabilized by spin-orbit coupling. Consistent theoretical and experiment data show that the resulting magnetization dynamics in this system is dominated by ground state quantum tunneling, while its temperature dependence is influenced by Raman relaxation.

Biomass processing to value-added chemicals and biofuels received considerable attention due to the renewable nature of the precursors. Here, we report the development of Ru-containing magnetically recoverable catalysts for cellulose hydrogenolysis to low alcohols, ethylene glycol (EG) and propylene glycol (PG). The catalysts are synthesized by incorporation of magnetite nanoparticles (NPs) in mesoporous silica pores followed by formation of 2 nm Ru NPs. The latter are obtained by thermal decomposition of ruthenium acetylacetonate in the pores. The catalysts showed excellent activities and selectivities at 100% cellulose conversion, exceeding those for the commercial Ru/C. High selectivities as well as activities are attributed to the influence of Fe3O4 on the Ru(0)/Ru(4+) NPs. A facile synthetic protocol, easy magnetic separation, and stability of the catalyst performance after magnetic recovery make these catalysts promising for industrial applications.

Triplet ground-state organic molecules are interesting with respect to several emerging technologies but typically exhibit limited stability. We report two organic diradicals, one of which possesses a triplet ground state (2J/kB = 234 ± 36 K) and robust stability at elevated temperatures. We are able to sublime this high-spin diradical under high vacuum at 140 °C with no significant decomposition.