Geislerboel2319

An asymmetric domino reaction combining vinylogous Michael reaction, hydration of aldehyde, and oxy-Michael reaction proceeds with α,β-unsaturated aldehydes and α-acyl α,β-unsaturated cyclic ketones in the presence of diphenylprolinol silyl ether to afford tetrahydrochromane derivatives with excellent enantioselectivity. After the domino reaction, addition of Wittig reagent and acid in the same reaction vessel promoted a second domino reaction incorporating retro oxy-Michael reaction, isomerization, and Wittig reaction to afford chiral functionalized cyclic 1,3-diene derivatives with excellent enantioselectivity. Overall, six reaction steps proceed in a one-pot procedure.A unique chiral amine organocatalyst with a bispidine structure was found to be efficient for the diastereo- and enantioselective Mannich reaction of isatin ketimines with ketones. A series of 3-substituted 3-amino-2-oxindoles bearing vicinal tertiary and quaternary chiral stereogenic centers were obtained in excellent yields with excellent dr and ee values. The gram-scale synthesis and transformation of the product showed the practicability of this methodology. In addition, a possible transition state model was proposed to explain the origin of the stereoselectivity.We present a new approach to femtosecond direct laser writing lithography to pattern nanocavities in ferromagnetic thin films. To demonstrate the concept, we irradiated 300 nm thin nickel films by single intense femtosecond laser pulses through glass substrate. Using a fluence above the ablation threshold, the process is destructive, leading to the formation of an ablation crater. By progressively lowering the laser fluence, the formation of closed spallation cavities below the ablation threshold is achieved. Systematic studies by the electron and optical interferometric microscopies, supported by molecular dynamics simulations, enabled us to gain an understanding of the thermo-mechanical spallation mechanism at the solid-molten interface. We achieved the fabrication of periodic arrangements of closed spallation nanocavities. Due to their topology, closed magnetic nanocavities can support unique couplings of multiple excitations (magnetic, optical, acoustic, spintronic). Thereby, they offer a unique physics playground for emerging fields in magnetism, magneto-photonic, and magneto-acoustic applications.Oxidation of monometallic Pd and bimetallic Pd3Au alloy surfaces are observed by in situ ambient-pressure X-ray photoelectron spectroscopy (AP-XPS) at an elevated pressure (100 mTorr O2 ambient). It is directly evidenced that the alloying with Au hinders the surface oxidation of Pd3Au surfaces compared with monometallic Pd surfaces. Remarkably, the oxidation behavior is clearly different between Pd3Au(111) and (100) surfaces. The (100) surface has a relatively Pd-rich surface composition, and the surface oxide layer is formed, whereas the (111) surface has a Au-rich composition, and the surface oxidation is quite limited. A combined approach of experimental and theoretical techniques reveals that Pd/Au surface composition and atomic arrangement are key factors determining the oxidation behavior.Nonreactive force fields are defined by perturbations of electron density that are relatively small, whereas chemical reactivity involves wholesale electronic rearrangements that make and break bonds. Thus, reactive force fields are incredibly difficult to develop compared to nonreactive force fields, yet at the same time, they fill a critical need when ab initio molecular dynamics methods are not affordable. We introduce a new reactive force field model for water that combines modified nonbonded terms of the ReaxFF model and its embedding in the electrostatic interactions described by our recently introduced coarse-grained electron model (C-GeM). The ReaxFF/C-GeM force field is characterized for many energetic and dissociative water properties for water clusters, structure, and dynamical properties under ambient conditions in the condensed phase, as well as the temperature dependence of density and water diffusion, with very good agreement with experiment. The ReaxFF/C-GeM force field should be more transferable and more broadly applicable to a range of reactive systems involving both proton and electron transfer in the condensed phase.Immune checkpoint inhibitors, including PD-L1/PD-1, are key regulators of the immune response and promising targets in cancer immunotherapy. N-glycosylation of PD-L1 affects its interaction with PD-1, but little is known about the distribution of glycoforms at its four NXS/T sequons. We optimized LC-MS/MS methods using collision energy modulation for the site-specific resolution of specific glycan motifs. We demonstrate that PD-L1 on the surface of breast cancer cell line carries mostly complex glycans with a high proportion of polyLacNAc structures at the N219 sequon. Contrary to the full-length protein, the secreted form of PD-L1 expressed in breast MDA-MB-231 or HEK293 cells demonstrated minimum N219 occupancy and low contribution of the polyLacNAc structures. Molecular modeling of PD-L1/PD-1 interaction with N-glycans suggests that glycans at the N219 site of PD-L1 and N74 and N116 of PD-1 may be involved in glycan-glycan interactions, but the impact of this potential interaction on the protein function remains at this point unknown. selleck chemical The interaction of PD-L1 with clinical antibodies is also affected by glycosylation. In conclusion, PD-L1 expressed in the MDA-MB-231 breast cancer cell line carries polyLacNAc glycans mostly at the N219 sequon, which displays the highest variability in occupancy and is most likely to influence the interaction with PD-1.Gene therapy directly targets mutations causing disease, allowing for a specific treatment at a molecular level. Adeno-associated virus (AAV) has been of increasing interest as a gene delivery vehicle, as AAV vectors are safe, effective, and capable of eliciting a relatively contained immune response. With the recent FDA approval of two AAV drugs for treating rare genetic diseases, AAV vectors are now on the market and are being further explored for other therapies. While showing promise in immune privileged tissue, the use of AAV for systemic delivery is still limited due to the high prevalence of neutralizing antibodies (nAbs). To avoid nAb-mediated inactivation, engineered AAV vectors with modified protein capsids, materials tethered to the capsid surface, or fully encapsulated in a second, larger carrier have been explored. Many of these engineered AAVs have added benefits, including avoided immune response, overcoming the genome size limit, targeted and stimuli-responsive delivery, and multimodal therapy of two or more therapeutic modalities in one platform.