Salomonsenbjerregaard1522

The clinical translation of messengerRNA (mRNA) drugs has been slowed by a shortage of delivery vehicles that potently and safely shuttle mRNA into target cells. Here, we describe the properties of a particularly potent branched-tail lipid nanoparticle that delivers mRNA to >80% of three major liver cell types. We characterize mRNA delivery spatially, temporally, and as a function of injection type. Following intravenous delivery, our lipid nanoparticle induced greater protein expression than two benchmark lipids, C12-200 and DLin-MC3-DMA, at an mRNA dose of 0.5 mg/kg. Lipid nanoparticles were sufficiently potent to codeliver three distinct mRNAs (firefly luciferase, mCherry, and erythropoietin) and, separately, Cas9 mRNA and single guide RNA (sgRNA) for proof-of-concept nonviral gene editing in mice. Furthermore, our branched-tail lipid nanoparticle was neither immunogenic nor toxic to the liver. Together, these results demonstrate the unique potential of this lipid material to improve the management of diseases rooted in liver dysfunction.The hydrolysis of carbonyl sulfide (COS) to form H2S by carbonic anhydrase has been demonstrated to be a viable strategy to deliver H2S in a biological system. Herein, we describe N-dithiasuccinoyl amines as thiol-triggered COS/H2S donors. Notably, thiol species especially GSH and homocysteine can trigger the release of both COS and H2S directly from several specific analogues via an unexpected mechanism. Importantly, two representative analogues Dts-1 and Dts-5 show intracellular H2S release, and Dts-1 imparts potent anti-inflammatory effects in LPS-challenged microglia cells. In conclusion, N-dithiasuccinoyl amine could serve as promising COS/H2S donors for either H2S biological studies or H2S-based therapeutics development.The increased sensitivity under weighted non-uniform sampling (NUS) is demonstrated and quantified using Monte Carlo simulations of nuclear magnetic resonance (NMR) time- and frequency-domain signals. The concept of spectral knowledge is introduced and shown to be superior to the frequency-domain signal-to-noise ratio for assessing the quality of NMR data. Two methods for rigorously preserving spectral knowledge and the time-domain NUS knowledge enhancement upon transformation to the frequency domain are demonstrated, both theoretically and numerically. The first, non-uniform weighted sampling using consistent root-mean-square noise, is applicable to data sampled on the Nyquist grid, whereas the second, the block Fourier transform using consistent root-mean-square noise, can be used to transform time-domain data acquired with arbitrary, off-grid NUS.It has been only recently realized that topological vortices associated with structural distortions or ordered spins are rather common in numerous materials where long-range interactions are not dominant. Incommensurate modulations that frequently occur in charge density wave (CDW) materials are often understood in terms of discommensurations with a periodic phase shift. The accumulation of a one-dimensional (1D) phase shift can result in, for example, CDW dislocations in 2H-TaSe2 with incommensurate CDW (I-CDW). Since any atomic-scale experimental investigation of CDW dislocations in 2H-TaSe2 has been lacking, we have performed the atomic-scale observation of 2H-TaSe2 with I-CDW, stabilized with Pd intercalation or strain, with scanning probe microscopy, and unveiled the existence of topological Z6 or Z4 vortices with topologically protected 2D winding movements of atomic displacement vectors. The discovery opens the ubiquitous nature of topological vortex domains and a new avenue to explore new facets of various incommensurate modulations or discommensurations.Alkoxyl radicals play important roles in various fields of chemistry. Understanding their reactivity is essential to applying their chemistry for industrial and biological purposes. Hydrogen-atom transfer and C-C β-scission reactions have been reported from alkoxyl radicals. The ratios of these two processes were investigated using cumyloxyl (CumO•) and tert-butoxyl radicals (t-BuO•), respectively. However, the products generated from the pair of radicals have not been investigated in detail. In this study, CumO• and t-BuO• were simultaneously generated from the photolysis of tert-butyl cumyl peroxide to understand the chemical behavior of the pair of radicals by analyzing the products and their distribution. Electron paramagnetic resonance and/or transient absorption spectroscopy analyses of radicals, including CumO• and t-BuO•, provide more information about the radicals generated during the photolysis of tert-butyl cumyl peroxide. Furthermore, the photoproducts of (3-(tert-butylperoxy)pentane-3-yl)benzene demonstrated that the ether products were formed in in-cage reactions. The triplet-sensitized reaction induced by acetophenone, which is produced from CumO•, clarified that the spin state did not affect the product distribution.The direct and chemoselective conversion of the carbon-metal bond of gem-dimetallic reagents enables rapid and sequential formation of multiple carbon-carbon and carbon-heteroatom bonds, thus representing a powerful method for efficiently increasing structural complexity. Herein, we report a visible-light-induced, nickel-catalyzed, chemoselective cross-coupling reaction between gem-borazirconocene alkanes and diverse aryl halides, affording a wide range of alkyl Bpin derivatives in high yields with excellent regioselectivity. This practical method features attractively simple reaction conditions and a broad substrate scope. Additionally, we systematically investigated a Bpin-directed chain walking process underlying the regioselectivity of alkylzirconocenes, thus uncovering the mechanism of the remote functionalization of internal olefins achieved with our method. Finally, DFT calculations indicate that the high regioselectivity of this reaction originates from the directing effect of the Bpin group.A new organic-inorganic hybrid heteropolyoxoniobate, [Cu(en)(H2O)4Cu(en)2(H2O)Cu(en)2(H2O)2]1.5[H8SiTe8Nb15O64]·6H2O (1; en = ethanediamine), has been successfully synthesized by a conventional method. The compound was directed by pairs of [TeO3]2-/[SiO3]2- ions, generating two novel TeNb9 and SiTeNb6 subunits in situ owing to the mixed heteroanion. In addition, the solution behavior of compound 1 was investigated.In this work, two iron(II) coordination compounds with a N2O2 coordinating Schiff base-like ligand bearing a redox active tetrathiafulvalene (TTF) unit and pyridine or trans-1,2-bis(4-pyridylethylene) as an axial ligand are synthesized. Crystals suitable for single X-ray structure analysis were obtained for the new ligand. The complexes were characterized by magnetic susceptibility measurements, T-dependent UV-vis spectroscopy, and cyclic voltammetry. Both complexes display spin transition behavior below room temperature with T1/2 values of 146 and 156 K. The mononuclear iron(II) complex [FeTTFL(py)2] is relatively stable up to 400 K compared to similar complexes, showing no loss of axial ligands upon heating. Temperature dependent Mössbauer spectroscopy was conducted for the coordination polymer [FeTTFL(bpee)]n to get more information regarding the origin of the stepwise spin crossover (SCO) behavior observed in the magnetic measurements. The change of the spin state is accompanied by a change of the optical properties, which can be monitored by VT-UV-vis spectroscopy for the mononuclear complex and has been analyzed in theoretical studies. The redox behavior of the iron(II) complexes reveals three reversible redox steps which are located at the iron center and at the TTF unit of the ligand. Oxidation of the TTF unit induces characteristic changes in the UV-vis spectrum that can be followed by spectroelectrochemical UV-vis spectroscopy. Addressing the potential of the iron-centered redox process results in similar changes in the UV-vis spectrum, which indicates an electronic coupling of the redox active unit with the metal center under certain circumstances.Previously, Lin et al. reported the isolation and structural determination of two triterpenoids, garcinielliptin oxide (GO) and garcinielliptone E (GE). Their unusual structural features, which remained unparalleled in subsequent decades despite the intervening discovery of hundreds of other polycyclic polyprenylated acylphloroglucinols (PPAPs), caused us to question the originally assigned structures, so GO was reisolated from Garcinia subelliptica, and its NMR spectra were reacquired. In this Note, we revise the structures of GO and the related GE via NMR analysis, biosynthetic considerations, and chemical conversion. Garcinielliptone T, a new PPAP, was also isolated and characterized. GO exhibited weak inhibitory activity against acetylcholinesterase with an IC50 value of 20.7 μM.To study the Chinese human milk N-glycome over lactation, N-glycans were released and separated from serum proteins, purified by solid-phase extraction, and analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). In total, 66 different putative N-glycans were found in the colostrum (week 1) and mature milk (week 4) of seven Chinese mothers. A clear difference was observed between milk of five secretor and two nonsecretor mothers, based on the type and relative amounts of the individual N-glycans. AZ191 The relative levels of the total neutral nonfucosylated and the fucosylated N-glycans in milk of five secretor mothers increased and decreased over lactation, respectively. This pattern could not be observed for the milk from the two nonsecretor mothers. Overall, this was the first study that provided detailed information on individual N-glycans in milk among mothers and over time as well as that fucosylation of N-glycans in milk was associated with the mother's secretor status.The need for effective candidates as cytotoxic drugs that at the same time challenge cancer multidrug resistance encouraged a search for these in plants of central Argentina. Bioassay-guided fractionation of the cytotoxic extract from Dimerostemma aspilioides led to the isolation of the germacranolide tomenphantin A (1), along with three new analogues (2-4). These efficiently inhibited the proliferation of the leukemia cell lines K562 and CCRF-CEM and their resistant variants, Lucena 1 and CEM/ADR5000, respectively, with IC50 values ranging from 0.40 to 7.7 μM. The structures and relative configurations of compounds 1-4 were elucidated by analysis of the spectroscopic data, in particular NMR spectroscopy. The most active among these was compound 1 (IC50 = 0.40-5.1 μM), and, therefore, this was selected as a model for a mechanistic study, which revealed that its antiproliferative effect was mediated by cell cycle arrest in the G2/M phase followed by apoptosis. The activity of compound 1 was selective, given the absence of cytotoxicity toward peripheral blood mononuclear cells. The results show the potential of these compounds, and in particular of compound 1, as leads for the development of drug candidates to fight sensitive and resistant leukemia cells.Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.