The phosphatidylinositol 3 kinase (PI3K)-Akt/PKB pathway protects neurons from apoptosis caused by diverse stress stimuli. However, its protective role against the amyloid beta peptide (Ab), a major constituent of Alzheimer's disease plaques, has not been studied. We investigated the effect of the Ab-derived Ab(25±35) peptide on apoptosis and on the Akt survival pathway in PC12 cells. Cells submitted to micromolar concentrations of Ab(25±35) exhibited increased production of reactive oxygen species (ROS) and morphological alterations consistent with apoptosis. Akt1 was activated shortly after incubation with Ab(25±35) and Ab(1±40) with a kinetics different to that of nerve-derived growth factor. Akt1 activation was blocked by the PI3K inhibitor wortmannin. We tested the hypothesis that Akt1 might modify the vulnerability of neural cells to apoptosis induced by Ab(25±35). Overexpression of an active version of Akt1 attenuated the apoptotic effect of Ab(25±35) as determined by¯ow cytometry. Moreover, PC12 cells overexpressing a membrane-targeted N-myristylated fusion protein of enhanced green¯uorescence protein (EGFP) and mouse Akt1 exhibited lower levels of ROS than control EGFP-transfected cells. The present ®ndings demonstrate that Akt1 is activated in response to Ab(25±35) in a PI3K-dependent manner and that active Akt1 protects PC12 cells against the pro-apoptotic action of this peptide.

The stereoselective synthesis of ε-isomers of dimethyl esters of 1,3-diaminotruxillic acid in three steps is reported. The first step is the ortho-palladation of (Z)-2-aryl-4-aryliden-5(4H)-oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho-CH bond of the 4-arylidene ring in carboxylic acids. The second step is the [2+2]-photocycloaddition of the CC exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho-palladated cyclobutanes 3. This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the ε-1,3-diaminotruxillic acid derivatives as single isomers.

The cyclopalladation of the stabilized iminophosphoranes Ph 3 PdNC(O)C 6 H 4 R (R ) H 1a, 4-OMe 1b, 3-OMe 1c, 2-Me 1d, 3-Me 1e) results in the regioselective activation of the ortho CH bond of the benzamide ring, giving exo-[Pd(µ-Cl){C,N-C 6 H 3 (R){C(O)NdPPh 3 -2}}] 2 (R ) H 2a, 5-OMe 2b, 4-OMe 2c, 3-Me 2d, 4-Me 2e). The palladated ligand behaves as a strong C,N-chelating group and cannot be easily displaced by other chelating ligands. This is clear from the reaction of 2c with Tl(acac), py, or AgClO 4 /L∧L, which gives [Pd(acac){C,N-C 6 H 3 (MeO-4){C(O)NdPPh 3 -2}}] (3c), [PdCl{C,N-C 6 H 3 (MeO-4){C(O)NdPPh 3 -2}}(py)] (4c), or [Pd{C,N-C 6 H 3 (MeO-4){C(O)NdPPh 3 -2}}(L∧L)]ClO 4 (L∧L ) dppe 5c, bipy 6c, phen 7c). However, Pd(OAc) 2 reacts with the ylides Ph 3 PdCHC(O)C 6 H 4 R (R ) H 8a, 3-OMe 8b, 2,5-(OMe) 2 8c) to give the C,C-orthometalated complexes [Pd(µ-Cl){C,C-[C 6 H 4 (PPh 2 CHC-(O)C 6 H 4 R)-2]}] (R ) H 9a, 3-OMe 9b, 2,5-(OMe) 2 9c), which are also regioselectively obtained. The C,C-metalated chelate is very stable, as shown by the reactions of 9b with Tl(acac), PPh 3 , and AgClO 4 / L∧L. The X-ray structures of 2d and 9b have been determined. Unexpectedly, the reaction of Pd(OAc) 2 with the ylide [Ph 3 PdCHC(O)C 6 H 3 -2,4-(OMe) 2 ] (16) gives the polymer [ 17) as a result of a double palladation, giving two types of metalacycles: in one of them, the Pd atom is bonded to the ylidic CR atom and has activated an ortho C(Ph)-H bond of the PPh 3 group; in the other one, the Pd atom is bonded to the carbonyl oxygen and has activated an ortho C-H bond of the C 6 H 3 (OMe) 2 unit. This tetradentate ylide ligand is remarkably stable.

Orthopalladated complexes derived from (Z)-2-aryl-4-arylidene-5(4H)-oxazolones have been prepared by reaction of the oxazolone with palladium acetate in acidic medium. The reaction is regioselective, only the ortho C-H bond of the arylidene ring being activated, producing a six-membered ring. The scope and reaction conditions of the orthopalladation are dependent on the acidity of the solvent. In CF(3)CO(2)H a large number of oxazolones can be metalated under mild conditions. As acidity decreases a lesser number of oxazolones can be efficiently palladated and harsher conditions must be used to achieve similar yields. The C-H bond activation in acidic medium agrees with an ambiphilic mechanism, as determined from kinetic measurements at variable temperature and pressure for different oxazolones substituted at the arylidene ring. The mechanism has been confirmed by density functional theory (DFT) calculations, where the formation of the six-membered ring is shown to be favored from both a kinetic and a thermodynamic perspective. In addition, the dependence of the reaction rate on the acidity of the medium has also been accounted for via a fine-tuning between the C-H agostic precoordination and the proton abstraction reaction in the overall process occurring on coordinatively saturated [Pd(κ(N)-oxazolone)(RCO(2)H)(3)](2+).

Significant advances are realized in perovskite-converted hybrid light-emitting diodes (pc-HLEDs). However, long-living devices at high efficiencies still represent a major milestone with average stabilities of <200 h at ≈50 lm W −1 under low applied currents (<15 mA). Herein, a dual metal oxide-coated CsPbBr 3 @SiO 2 /ZrO 2 composite is prepared in a one-pot synthesis through the kinetic control of the sol-gel reaction, followed by a gentle drying process in air. These hybrid nanoparticles show photoluminescence quantum yields of ≈65% that are stable under temperature, ambient, and irradiation stress scenarios. This is translated to pc-HLEDs with a near-unity conversion efficiency at any applied current, high efficiencies around 75 lm W −1 , and one of the most remarkable stabilities of ≈200 and 700 h at 100 and 10 mA, respectively. In addition, the device degradation mechanism is thoughtfully rationalized comparing devices operating under ambient/inert conditions. As such, this work provides three milestones: i) a new room temperature one-pot protocol to realize the first SiO 2 /ZrO 2 metal oxide coating that effectively protects the emitting perovskite nanoparticle core, ii) one of the most stable and efficient pc-HLEDs operating under ambient condition at any applied current, and iii) new insights for the degradation of pc-HLEDs.

Norovirus was a frequent cause of acute severe sporadic gastroenteritis in children representing the second etiologic agent after rotavirus.

No drug therapy has shown to limit abdominal aortic aneurysm (AAA) growth or rupture, and the understanding of the disease biology is incomplete; whereby, one challenge of vascular medicine is the development of good animal models and therapies for this life-threatening condition. The nuclear receptor NOR-1 (neuron-derived orphan receptor 1) controls biological processes involved in AAA; however, whether it plays a role in this pathology is unknown. Through a gain-of-function approach we assessed the impact of NOR-1 expression on the vascular response to Ang II (angiotensin II). We used 2 mouse models that overexpress human NOR-1 in the vasculature, one of them specifically in vascular smooth muscle cells. NOR-1 transgenesis amplifies the response to Ang II enhancing vascular inflammation (production of proinflammatory cytokines, chemokines, and reactive oxygen species), increasing MMP (matrix metalloproteinase) activity and disturbing elastin integrity, thereby broking the resistance of C57BL/6 mice to Ang II-induced AAA. Genes encoding for proteins critically involved in AAA formation ( Il [interleukin]-6 , Il-1β , Cxcl2 , [C-X-C motif chemokine ligand 2], Mcp-1 [monocyte chemoattractant protein 1] , and Mmp2 ) were upregulated in aneurysmal tissues. Both animal models show a similar incidence and severity of AAA, suggesting that high expression of NOR-1 in vascular smooth muscle cell is a sufficient condition to strengthen the response to Ang II. These alterations, including AAA formation, were prevented by the MMP inhibitor doxycycline. Microarray analysis identified gene sets that could explain the susceptibility of transgenic animals to Ang II-induced aneurysms, including those related with extracellular matrix remodeling, inflammatory/immune response, sympathetic activity, and vascular smooth muscle cell differentiation. These results involve NOR-1 in AAA and validate mice overexpressing this receptor as useful experimental models.

The ortho functionalization of methyl R-phenylglycinate has been easily achieved using the known orthopalladated complex [Pd(mu-Cl){R-C(6)H(4)(CH(CO(2)Me)NH(2))-2}](2) (1) as synthetic tool. Different functional groups have been introduced at the ortho position of the aryl ring. The reaction of (R)-1 with X(2) or PhI(OAc)(2) gives XC(6)H(4)(CH(CO(2)Me)NH(2))-2 (X = I, Br, OMe, OEt) through oxidative coupling, while the reaction with CO gives an isoindolone. (R)-1 also reacts with one, two, or three alkyne molecules to give different metal-containing or metal-free heterocycles. The resulting functionalized amino esters or heterocycles retain the chirality of (R)-1, according with the values of the optical rotation and the obtained ee values ranging from 22%-87%. The X-ray structures of six representative compounds have also been determined.