Current-density pathways in figure-eight-shaped octaphyrins.

We have calculated the current density induced by an external magnetic field in a set of figure-eight-shaped expanded porphyrinoids. The studied octaphyrins can be divided into three classes (N2, N4, and N6) based on the number of the inner hydrogen atoms of the pyrrole rings. Using the Runge-Kutta method, the current density is split into diatropic and paratropic contributions that are analyzed separately. The calculations show that one common ring current consists of two rather independent pathways. Each of them follows the outer side of the molecular frame of one half of the molecule and passes to the inner side of the frame on the other half. The ring-current pathways are similar to the ones for [12]infinitene. However, the current density of the octaphyrins is more complex having many branching points and pathways. Vertical through-space current-density pathways pass in the middle of the molecules through a plane that is parallel to the figure-eight-shaped view of the molecules when the magnetic field is perpendicular to the plane. The isolectronic N2 and the N4 dication sustain a weak paratropic ring current inside the molecule, which is also observed in the 1H NMR magnetic shielding constant of the inner hydrogen atoms. The diatropic current-density contribution dominates in the studied molecules. For the N4 and N6 molecules, the global current-density pathways are only diatropic and N6 sustains the strongest global diatropic current-density flux of 13.2 nA T-1.

Current-Density Calculations on Zn-Porphyrin40 Nanorings.

Two porphyrinoid nanorings have been studied computationally. They were built by linking 40 Zn-porphyrin units with butadiyne bridges. The molecular structures belonging to the D40h point group were fully optimized with the Turbomole program at the density functional theory (DFT) level using the B3LYP functional and the def2-SVP basis sets. The aromatic character was studied at the DFT level by calculating the magnetically induced current-density (MICD) susceptibility using the GIMIC program. The neutral molecules are globally non-aromatic with aromatic Zn-porphyrin units. Charged nanorings could not be studied because almost degenerate frontier orbitals led to vanishing optical gaps for the cations. Since DFT calculations of the MICD are computationally expensive, we also calculated the MICD using three pseudo-π models. Appropriate pseudo-π models were constructed by removing the outer hydrogen atoms and replacing all carbon and nitrogen atoms with hydrogen atoms. The central Zn atom was either replaced with a beryllium atom or with two inner hydrogen atoms. Calculations with the computationally inexpensive pseudo-π models yielded qualitatively the same magnetic response as obtained in the all-electron calculations.

Nuclear export of plant pararetrovirus mRNAs involves the TREX complex, two viral proteins and the highly structured 5' leader region.

In eukaryotes, the major nuclear export pathway for mature mRNAs uses the dimeric receptor TAP/p15, which is recruited to mRNAs via the multisubunit TREX complex, comprising the THO core and different export adaptors. Viruses that replicate in the nucleus adopt different strategies to hijack cellular export factors and achieve cytoplasmic translation of their mRNAs. No export receptors are known in plants, but Arabidopsis TREX resembles the mammalian complex, with a conserved hexameric THO core associated with ALY and UIEF proteins, as well as UAP56 and MOS11. The latter protein is an orthologue of mammalian CIP29. The nuclear export mechanism for viral mRNAs has not been described in plants. To understand this process, we investigated the export of mRNAs of the pararetrovirus CaMV in Arabidopsis and demonstrated that it is inhibited in plants deficient in ALY, MOS11 and/or TEX1. Deficiency for these factors renders plants partially resistant to CaMV infection. Two CaMV proteins, the coat protein P4 and reverse transcriptase P5, are important for nuclear export. P4 and P5 interact and co-localise in the nucleus with the cellular export factor MOS11. The highly structured 5' leader region of 35S RNAs was identified as an export enhancing element that interacts with ALY1, ALY3 and MOS11 in vitro.

Transition-Metal-Stabilized Heavy Tetraphospholide Anions.

Phosphorus analogues of the ubiquitous cyclopentadienyl (Cp) are a rich and diverse family of compounds, which have found widespread use as ligands in organometallic complexes. By contrast, phospholes incorporating heavier group 14 elements (Si, Ge, Sn, and Pb) are hardly known. Here, we demonstrate the isolation of the first metal complexes featuring heavy cyclopentadienyl anions SnP42- and PbP42-. The complexes [(η4-tBu2C2P2)2Co2(µ,η5:η5-P4Tt)] [Tt = Sn (6), Pb (7)] are formed by reaction of white phosphorus (P4) with cyclooctadiene cobalt complexes [Ar'TtCo(η4-P2C2tBu2)(η4-COD)] [Tt = Sn (2), Pb (3), Ar' = C6H3-2,6{C6H3-2,6-iPr2}2, COD = cycloocta-1,5-diene] and Tt{Co(η4-P2C2tBu2)(COD)}2 [Tt = Sn (4), Pb (5)]. While the SnP42- complex 6 was isolated as a pure and stable compound, compound 7 eliminated Pb(0) below room temperature to afford [(η4-tBu2C2P2)2Co2(µ,η4:η4-P4) (8), which is a rare example of a tripledecker complex with a P42- middle deck. The electronic structures of 6-8 are analyzed using theoretical methods including an analysis of intrinsic bond orbitals and magnetic response theory. Thereby, the aromatic nature of P5- and SnP42- was confirmed, while for P42-, a specific type of symmetry-induced weak paramagnetism was found that is distinct from conventional antiaromatic species.

Five-Year Outcomes of a Randomized Trial of Treatments for Varicose Veins.

BACKGROUND: Endovenous laser ablation and ultrasound-guided foam sclerotherapy are recommended alternatives to surgery for the treatment of primary varicose veins, but their long-term comparative effectiveness remains uncertain. METHODS: In a randomized, controlled trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of laser ablation, foam sclerotherapy, and surgery. Primary outcomes at 5 years were disease-specific quality of life and generic quality of life, as well as cost-effectiveness based on models of expected costs and quality-adjusted life-years (QALYs) gained that used data on participants' treatment costs and scores on the EuroQol EQ-5D questionnaire. RESULTS: Quality-of-life questionnaires were completed by 595 (75%) of the 798 trial participants. After adjustment for baseline scores and other covariates, scores on the Aberdeen Varicose Vein Questionnaire (on which scores range from 0 to 100, with lower scores indicating a better quality of life) were lower among patients who underwent laser ablation or surgery than among those who underwent foam sclerotherapy (effect size [adjusted differences between groups] for laser ablation vs. foam sclerotherapy, -2.86; 95% confidence interval [CI], -4.49 to -1.22; P<0.001; and for surgery vs. foam sclerotherapy, -2.60; 95% CI, -3.99 to -1.22; P<0.001). Generic quality-of-life measures did not differ among treatment groups. At a threshold willingness-to-pay ratio of £20,000 ($28,433 in U.S. dollars) per QALY, 77.2% of the cost-effectiveness model iterations favored laser ablation. In a two-way comparison between foam sclerotherapy and surgery, 54.5% of the model iterations favored surgery. CONCLUSIONS: In a randomized trial of treatments for varicose veins, disease-specific quality of life 5 years after treatment was better after laser ablation or surgery than after foam sclerotherapy. The majority of the probabilistic cost-effectiveness model iterations favored laser ablation at a willingness-to-pay ratio of £20,000 ($28,433) per QALY. (Funded by the National Institute for Health Research; CLASS Current Controlled Trials number, ISRCTN51995477.).

An Anionic Amido-Substituted Seven-Vertex Siliconoid Cluster.

The silanide [Si4 {N(SiMe3 )Dipp}3 ]- (1) transforms into the anionic siliconoid cluster [Si7 {N(SiMe3 )Dipp}3 ]- (2) with four unsubstituted silicon atoms as a contact ion pair with [K([18]crown-6)] in C6 D6 at room temperature within five weeks. Anion 2 was investigated by natural population analysis and visualization of intrinsic atomic orbitals. Magnetically induced current-density calculations of 2 revealed two distinct strong diatropic vortices that sum up in one direction and create a strongly shielded apical silicon atom in 2.

A natural scheme for the quantitative analysis of the magnetically induced molecular current density using an oriented flux-weighted stagnation graph. I. A minimal example for LiH.

A new natural scheme is introduced to analyze quantitatively the magnetically induced molecular current density vector field, J. The set of zero points of J, which is called its stagnation graph (SG), has been previously used to study the topological features of the current density of various molecules. Here, the line integrals of the induced magnetic field along edges of the connected subset of the SG are calculated. The edges are oriented such that all weights, i.e., flux values become non-negative, thereby, an oriented flux-weighted (current density) stagnation graph (OFW-SG) is obtained. Since in the exact theoretical limit, J is divergence-free and due to the topological characteristics of such vector fields, the flux of all separate vortices (current density domains) and neighbouring connected vortices can be determined exactly by adding the weights of cyclic subsets of edges (i.e., closed loops) of the OFW-SG. The procedure is exemplified by the minimal example of LiH for a weak homogeneous external magnetic field, B, perpendicular to the chemical bond. The OFW-SG exhibits one closed loop (formally decomposed into two edges), and an open line extending to infinity on both of its ends. The method provides the means of accurately determining the strength of the current density even in molecules with a complicated set of distinct vortices.

Integration of global ring currents using the Ampère-Maxwell law.

Magnetically induced ring currents are calculated from the magnetic shielding tensor by employing the Ampère-Maxwell law. The feasibility of the method is demonstrated by integrating the zz component of the shielding tensor along the symmetry axis of highly symmetric ring-shaped aromatic, antiaromatic and nonaromatic molecules. The calculated ring-current strengths agree perfectly with the ones obtained by integrating the current-density flux passing through a plane cutting half the molecular ring. The method can be used in combination with all electronic structure codes capable of calculating nuclear magnetic resonance (NMR) shielding tensors in general points in space. We also show that nucleus independent chemical shifts (NICS) along the symmetry axis are related to the spatial derivative of the strength of the global ring-current along the z axis.

Magnetically induced ring currents in metallocenothiaporphyrins.

The magnetically induced current-density susceptibility tensor (CDT) of the lowest singlet and triplet states of the metallocenothiaporphyrins, where the metal is V, Cr, Mn, Fe, Co, Ni, Mo, Tc, Ru, or Rh, have been studied with the gauge-including magnetically induced currents (GIMIC) method. The compounds containing V, Mn, Co, Tc or Rh were studied as cations because the neutral molecules have an odd number of electrons. The calculations show that the aromatic nature of most of the studied molecules follows the Hückel and Baird rules of aromaticity. CDT calculations on the high-spin states of the neutral metallocenothiaporphyrins with V, Mn, Co, Tc or Rh also shows that these molecules follow a unified extended Hückel and Baird aromaticity orbital-count rule stating that molecules with an odd number of occupied conjugated valence orbitals are aromatic, whereas molecules with an even number of occupied conjugated orbitals are antiaromatic.

Magnetically Induced Current Densities in π-Conjugated Porphyrin Nanoballs.

Magnetically induced current densities (MICDs) of Zn-porphyrinoid nanostructures have been studied at the density functional theory level using the B3LYP functional and the def2-SVP basis set. Six of the studied Zn-porphyrinoid nanostructures consist of two crossing porphyrinoid belts, and one is a porphyrinoid nanoball belonging to the octahedral (O) point group. The Zn-porphyrin units are connected to each other via butadiyne linkers as in a recently synthesized porphyrinoid structure resembling two crossed belts. The MICDs are calculated using the gauge-including magnetically induced current method. Current-density pathways and their strengths were determined by numerically integrating the MICD passing through selected planes that cross chemical bonds or molecular rings. The current-density calculations show that the studied neutral molecules are globally nonaromatic but locally aromatic sustaining ring currents only in the individual porphyrin rings or around two neighboring porphyrins. The ring-current strengths of the individual porphyrin rings are 20% weaker than in Zn-porphyrin, whereas oxidation leads to globally aromatic cations sustaining ring currents that are somewhat stronger than for Zn-porphyrin.

Magnetically Induced Current Densities in Zinc Porphyrin Nanoshells.

The molecular structures of porphyrinoid cages were obtained by constructing small polyhedral graphs whose vertices have degree-4. The initial structures were then fully optimized at the density functional theory (DFT) level using the generalized gradient approximation. Some of polyhedral vertices were replaced with Zn-porphyrin units and their edges were replaced with ethyne or butadiyne bridges or connected by fusing two neighboring Zn-porphyrin units. Molecule 1 is an ethyne-bridge porphyrinoid nanotube, whose ends are sealed with a Zn-porphyrin. Molecule 2 is the corresponding open porphyrinoid nanotube. Molecule 3 is a clam-like porphyrinoid cage, whose shells consist of fused Zn-porphyrins, and the two halves are connected via butadiyne bridges. Molecule 4 is a cross-belt of fused Zn-porphyrins, and molecule 5 is a cross-belt of Zn-porphyrins connected with butadiyne bridges. The magnetically induced current density of the optimized porphyrinoid cages was calculated for determining the aromatic character, the degree of aromaticity and the current-density pathways. The current-density calculations were performed at the DFT level with the gauge─including magnetically induced currents (GIMIC) method using the B3LYP hybrid functional and def2-SVP basis sets. Calculations of the current densities show that molecule 2 sustains a paratropic ring current around the nanotube, whereas sealing the ends as in molecule 1 leads to an almost nonaromatic nanotube. Fusing porphyrinoids as in molecules 3 and 4 results in complicated current-density pathways that differ from the ones usually appearing in porphyrinoids. The aromatic character of molecules 4 and 5 changes upon oxidation. The neutral molecule 4 is antiaromatic, whereas the dication is nonaromatic. Molecule 5 is nonaromatic, and its dication is aromatic.

Magnetically Induced Ring-Current Strengths of Planar and Nonplanar Molecules: New Insights from the Pseudo-π Model.

The pseudo-π model yields current densities and induced magnetic fields that mimic the π-component, allowing investigations of large molecular structures, whether they are planar or not, at a low computational cost but with high accuracy. Herein the π-contribution to the magnetically induced current densities and induced magnetic fields of large planar molecules and nonplanar molecules (such as [10]cyclophenacene and chiral toroidal nanotubes C2016 and C2196) were computed using the pseudo-π model with the gauge-including magnetically induced currents method. Additionally, we provide a way to determine the π-component of the ring-current strengths, which can be used for assessing the aromatic character of large carbon molecules.

Spatial Contributions to Nuclear Magnetic Shieldings.

We develop a methodology for calculating, analyzing, and visualizing nuclear magnetic shielding densities which are calculated from the current density via the Biot-Savart relation. Atomic contributions to nuclear magnetic shielding constants can be estimated within our framework with a Becke partitioning scheme. The new features have been implemented in the GIMIC program and are applied in this work to the study of the 1H and 13C nuclear magnetic shieldings in benzene (C6H6) and cyclobutadiene (C4H4). The new methodology allows a visual inspection of the spatial origins of the positive (shielding) and negative (deshielding) contributions to the nuclear magnetic shielding constant of a single nucleus, something which has not been hitherto easily accomplished. Analysis of the shielding densities shows that diatropic and paratropic current-density fluxes yield both shielding and deshielding contributions, as the shielding or deshielding is determined by the direction of the current-density flux with respect to the studied nucleus instead of the tropicity. Becke partitioning of the magnetic shieldings shows that the magnetic shielding contributions mainly originate from the studied atom and its nearest neighbors, confirming the localized character of nuclear magnetic shieldings.

[Nuclear export of viral RNAs in metazoan]. / Export nucléaire des ARN viraux chez les métazoaires.

The nuclear export of mRNAs is a complex process, involving the participaton of numerous proteins, the recruitement of which starts during the early steps of mRNAs biosynthesis and maturation. This strategy allows the cell to export only mature and non-defective transcripts to the cytoplasm where they are directed to the translational machinery. The vast majority of mRNAs is exported by the dimeric transport receptor TAP-p15, which is mainly recruited by the large multiprotein complex TREX-1. Other mRNAs that do not display all typical features of a mature transcript use variants of the TAP-p15 export pathway or recruit the alternative export receptor CRM1. Most DNA viruses, retroviruses, and influenza viruses, the mRNAs of which are synthesized in the nucleus, also use TAP-p15 and/or CRM1 to export their mRNAs. The highjacking of the cellular export machinery by viral mRNAs usually involves the presence of constitutive structural elements that directly load cellular export factors and/or viral adaptor proteins. Associated with the host export machinery, viral mRNAs escape host surveillance, are efficiently exported in the cytoplasm in order to be translated, and thus make possible the progress toward the later events of the virus life cycles.

Aromatic and Antiaromatic Pathways in Triphyrin(2.1.1) Annelated with Benzo[b]heterocycles.

Understanding of the aromatic properties and magnetically induced current densities of highly conjugated chromophores is important when designing molecules with strongly delocalized electronic structure. Linear extension of the triphyrin(2.1.1) skeleton with an annelated benzo[b]heterocycle fragment modifies the aromatic character by extending the electron delocalization pathway. Two-electron reduction leads to an antiaromatic triphyrin(2.1.1) ring and an aromatic benzo[b]heterocycle subunit. Current-density calculations provide detailed information about the observed pathways and their strengths.

The aromatic character of [10]annulenes and dicupra[10]annulenes from current density calculations.

We have investigated the aromatic properties of seven low-lying isomers of [10]annulene and of the recently synthesized dicupra[10]annulene compounds that were crystallised with two or four lithium counterions (Wei et al., J. Am. Chem. Soc., 2016, 138, 60-63). The molecular structures of the [10]annulene conformers and the dicupra[10]annulenes with bulky trimethylsilyl (TMS) and phenyl groups, as well as the corresponding unsubstituted dicupra[10]annulenes were optimised using density functional theory, employing a semi-empirical dispersion correction to consider van der Waals interactions. The structures of the hydrocarbon annulenes were subsequently optimised at the SCS-MP2/def2-QZVPD level. Single-point coupled-cluster calculations with explicit treatment of the electron correlation CCSD(F12)(T) were performed to obtain the relative energies of the hydrocarbon annulenes. Four of the conformations lie close in energy relative to each other. Three substituted and three unsubstituted dicupra[10]annulene structures with either four, two or no Li+ counterions were investigated. Magnetically induced current densities calculated using the GIMIC program were used for the assessment of the aromatic properties of the studied molecules. The conformations of [10]annulene with lowest energies are non-aromatic. The calculations revealed that the electron donation of the lithium atoms to the dicupra[10]annulene core significantly affects the electronic and molecular structures of the dicupra[10]annulenes. The annulene ring is non-planar for all studied dicupra[10]annulenes except for the unsubstituted one with four Li+ counterions, which was also found to be the only molecule that sustains a strong diatropic ring current around the dicupra[10]annulene ring. The other five dicupra[10]annulenes sustain very weak net ring currents and can be considered non-aromatic.

TOR and S6K1 promote translation reinitiation of uORF-containing mRNAs via phosphorylation of eIF3h.

Mammalian target-of-rapamycin (mTOR) triggers S6 kinase (S6K) activation to phosphorylate targets linked to translation in response to energy, nutrients, and hormones. Pathways of TOR activation in plants remain unknown. Here, we uncover the role of the phytohormone auxin in TOR signalling activation and reinitiation after upstream open reading frame (uORF) translation, which in plants is dependent on translation initiation factor eIF3h. We show that auxin triggers TOR activation followed by S6K1 phosphorylation at T449 and efficient loading of uORF-mRNAs onto polysomes in a manner sensitive to the TOR inhibitor Torin-1. Torin-1 mediates recruitment of inactive S6K1 to polysomes, while auxin triggers S6K1 dissociation and recruitment of activated TOR instead. A putative target of TOR/S6K1-eIF3h-is phosphorylated and detected in polysomes in response to auxin. In TOR-deficient plants, polysomes were prebound by inactive S6K1, and loading of uORF-mRNAs and eIF3h was impaired. Transient expression of eIF3h-S178D in plant protoplasts specifically upregulates uORF-mRNA translation. We propose that TOR functions in polysomes to maintain the active S6K1 (and thus eIF3h) phosphorylation status that is critical for translation reinitiation.

The influence of heteroatoms on the aromatic character and the current pathways of B2N2-dibenzo[a,e]pentalenes.

Four polycyclic molecules have been investigated at the DFT B3LYP/def2-TZVP level of theory using calculated magnetically induced current densities as an indicator of their (anti)aromaticity. Complicated current pathways were found in dibenzo[a,e]pentalene and its three heterocyclic analogues each containing two boron and two nitrogen atoms. The antiaromatic character of the pentalene moiety is weaker in the hydrocarbon molecule and in 5,11-dihydrobenzo[d]benzo[4,5][1,2,3]azadiborolo[3,2-b][1,2,3]azadiborole as compared to the pentalene molecule. The antiaromatic character of the pentalene moiety is completely absent in the other two heterocyclic structures. In 6,12-dihydrobenzo[d]benzo[4,5][1,2,3]diazaborolo[2,1-a][1,2,3]diazaborole all four molecular rings are aromatic according to the ring-current criterion, and in 6,12-dihydrobenzo[d]benzo[3,4][1,2,5]azadiborolo[1,2-a][1,3,2]diazaborole, the diazaborole ring is aromatic, while the azadiborole ring is antiaromatic. In all four molecules the six-membered rings are aromatic sustaining a weaker ring current than benzene does.

Le virus de la mosaïque du chou-fleur (CaMV), encore et toujours.

As a pararetrovirus and because of the non-canonical translation of its polycistronic pregenomic 35S RNA, Cauliflower mosaic virus (CaMV) is an original model system that has been extensively studied. Recent advances have improved our understanding of CaMV aphid transmission, cell-to-cell movement, protein expression and virus counter-defense strategy against host plant defense. Since P6/TAV is involved in many aspects of viral pathogenesis as well as in some replication steps, it is considered as the key player of CaMV infectious cycle. This paper reviews our current knowledge on CaMV multiplication and pathogenesis, with special emphasis on steps in which P6/TAV has a major role.