Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort

STUDY FUNDING The data were collected by a Research into Ageing programme grant; research continues as part of the Age UK–funded Disconnected Mind project. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1), with funding from the BBSRC and Medical Research Council. Imaging and image analysis was performed at the Brain Research Imaging Centre (sbirc.ed.ac.uk/), Edinburgh, supported by the Scottish Funding Council SINAPSE Collaboration. Derivation of mean cortical thickness measures was funded by the Scottish Funding Council’s Postdoctoral and Early Career Researchers Exchange Fund awarded by SINAPSE to David Alexander Dickie. L.C.A.C. acknowledges funding from the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division.Peer reviewedPublisher PD

Palladium-Catalyzed Direct Arylation of 5‑Halouracils and 5‑Halouracil Nucleosides with Arenes and Heteroarenes Promoted by TBAF

The 1-<i>N</i>-benzyl-5-iodo­(or bromo)­uracil undergoes Pd-catalyzed [Pd₂(dba)₃] direct arylation with benzene and other simple arenes in the presence of TBAF in DMF without the necessity of adding any ligands or additives to give 5-arylated uracil analogues. The TBAF-promoted coupling also occurs efficiently with electron rich heteroarenes at 100 °C (1 h) even with only small excess of heteroarenes. The protocol avoids usage of the arylboronic acid or stannane precursors for the synthesis of 5-(2-furyl, or 2-thienyl, or 2-pyrrolyl)­uracil nucleosides, which are used as important RNA and DNA fluorescent probes. The fact that 1-<i>N</i>-benzyl-3-<i>N</i>-methyl-5-iodouracil did not undergo the TBAF-promoted couplings with arenes or heteroarenes suggests that the C4-alkoxide (enol form of uracil) facilitates coupling by participation in the intramolecular processes of hydrogen abstraction from arenes. TBAF-promoted arylation was extended into the other enolizable heterocyclic systems such as 3-bromo-2-pyridone. The π-excessive heteroarenes also coupled with 5-halouracils in the presence of Pd­(OAc)₂/Cs₂CO₃/PivOH combination in DMF (100 °C, 2 h) to yield 5-arylated uracils

Mechanisms and Origins of Switchable Chemoselectivity of Ni-Catalyzed C(aryl)–O and C(acyl)–O Activation of Aryl Esters with Phosphine Ligands

Many experiments have shown that nickel with monodentate phosphine ligands favors the C­(aryl)–O activation over the C­(acyl)–O activation for aryl esters. However, Itami and co-workers recently discovered that nickel with bidentate phosphine ligands can selectively activate the C­(acyl)–O bond of aryl esters of aromatic carboxylic acids. The chemoselectivity with bidentate phosphine ligands can be switched back to C­(aryl)–O activation when aryl pivalates are employed. To understand the mechanisms and origins of this switchable chemoselectivity, density functional theory (DFT) calculations have been conducted. For aryl esters, nickel with bidentate phosphine ligands cleaves C­(acyl)–O and C­(aryl)–O bonds via three-centered transition states. The C­(acyl)–O activation is more favorable due to the lower bond dissociation energy (BDE) of C­(acyl)–O bond, which translates into a lower transition-state distortion energy. However, when monodentate phosphine ligands are used, a vacant coordination site on nickel creates an extra Ni–O bond in the five-centered C­(aryl)–O cleavage transition state. The additional interaction energy between the catalyst and substrate makes C­(aryl)–O activation favorable. In the case of aryl pivalates, nickel with bidentate phosphine ligands still favors the C­(acyl)–O activation over the C­(aryl)–O activation at the cleavage step. However, the subsequent decarbonylation generates a very unstable <i>t</i>Bu-Ni­(II) intermediate, and this unfavorable step greatly increases the overall barrier for generating the C­(acyl)–O activation products. Instead, the subsequent C–H activation of azoles and C–C coupling in the C­(aryl)–O activation pathway are much easier, leading to the observed C­(aryl)–O activation products

Theoretical Elucidation of the Origins of Substituent and Strain Effects on the Rates of Diels–Alder Reactions of 1,2,4,5-Tetrazines

The Diels–Alder reactions of seven 1,2,4,5-tetrazines with unstrained and strained alkenes and alkynes were studied with quantum mechanical calculations (M06-2X density functional theory) and analyzed with the distortion/interaction model. The higher reactivities of alkenes compared to alkynes in the Diels–Alder reactions with tetrazines arise from the differences in both interaction and distortion energies. Alkenes have HOMO energies higher than those of alkynes and therefore stronger interaction energies in inverse-electron-demand Diels–Alder reactions with tetrazines. We have also found that the energies to distort alkenes into the Diels–Alder transition-state geometries are smaller than for alkynes in these reactions. The strained dienophiles, <i>trans</i>-cyclooctene and cyclooctyne, are much more reactive than unstrained <i>trans</i>-2-butene and 2-butyne, because they are predistorted toward the Diels–Alder transition structures. The reactivities of substituted tetrazines correlate with the electron-withdrawing abilities of the substituents. Electron-withdrawing groups lower the LUMO+1 of tetrazines, resulting in stronger interactions with the HOMO of dienophiles. Moreover, electron-withdrawing substituents destabilize the tetrazines, and this leads to smaller distortion energies in the Diels–Alder transition states

Real datasets used in this paper.

<p>Real datasets used in this paper.</p

Contour plots (two-dimensional) for the regularization methods.

<p>The regularization parameters are <i>λ</i> = 1 and <i>α</i> = 0.2 for the HLR method.</p

The most frequently selected 10 genes found by the five sparse logistic regression methods from the lung cancer dataset.

<p>The most frequently selected 10 genes found by the five sparse logistic regression methods from the lung cancer dataset.</p

Mean results of empirical datasets.

<p>In bold–the best performance.</p

The performance of the AUC from ROC analyzes of each method on prostate, lymphoma and lung cancer datasets.

<p>The performance of the AUC from ROC analyzes of each method on prostate, lymphoma and lung cancer datasets.</p

Hydrogermylation of 5‑Ethynyluracil Nucleosides: Formation of 5‑(2-Germylvinyl)uracil and 5‑(2-Germylacetyl)uracil Nucleosides

A stereoselective radical-mediated hydrogermylation of the protected 5-ethynyluracil nucleosides with trialkyl-, triaryl,- or tris­(trimethylsilyl)­germanes gave (<i>Z</i>)<i>-</i>5-(2-germylvinyl)­uridine, 2′-deoxyuridine, or <i>ara</i>-uridine as major products. Reaction of the β-triphenylgermyl vinyl radical intermediate with oxygen and fragmentation of the resulting peroxyradical provided also 5-[2-(triphenylgermyl)­acetyl]­pyrimidine nucleosides in low to moderate yields. Thermal isomerization of the latter in MeOH occurred via a four-centered activated complex, and subsequent hydrolysis of the resulting <i>O-</i>germyl substituted enol yielded 5-acetyluracil nucleosides in quantitative yield