Emeryyde1295

Here, we introduce Golem, an algorithm that is agnostic to the choice of experiment planning strategy and that enables robust experiment and process optimization. Golem identifies optimal solutions that are robust to input uncertainty, thus ensuring the reproducible performance of optimized experimental protocols and processes. It can be used to analyze the robustness of past experiments, or to guide experiment planning algorithms toward robust solutions on the fly. We assess the performance and domain of applicability of Golem through extensive benchmark studies and demonstrate its practical relevance by optimizing an analytical chemistry protocol under the presence of significant noise in its experimental conditions.An octanuclear M8L12 coordination cage catalyses the Kemp elimination reaction of 5-nitro-1,2-benzisoxazole (NBI) with hydroxide to give 2-cyano-4-nitrophenolate (CNP) as the product. In contrast to the previously-reported very efficient catalysis of the Kemp elimination reaction of unsubstituted benzisoxazole, which involves the substrate binding inside the cage cavity, the catalysed reaction of NBI with hydroxide is slower and occurs at the external surface of the cage, even though NBI can bind inside the cage cavity. The rate of the catalysed reaction is sensitive to the presence of added anions, which bind to the 16+ cage surface, displacing the hydroxide ions from around the cage which are essential reaction partners in the Kemp elimination. Thus we can observe different binding affinities of anions to the surface of the cationic cage in aqueous solution by the extent to which they displace hydroxide and thereby inhibit the catalysed Kemp elimination and slow down the appearance of CNP. For anions with a -1 charge the observed affinity order for binding to the cage surface is consistent with their ease of desolvation and their ordering in the Hofmeister series. With anions that are significantly basic (fluoride, hydrogen carbonate, carboxylates) the accumulation of the anion around the cage surface accelerates the Kemp elimination compared to the background reaction with hydroxide, which we ascribe to the ability of these anions to participate directly in the Kemp elimination. This work provides valuable mechanistic insights into the role of the cage in co-locating the substrate and the anionic reaction partners in a cage-catalysed reaction.Photodynamic immunotherapy has emerged as a promising strategy to treat cancer. However, the hypoxic nature of most solid tumors and notoriously immunosuppressive tumor microenvironment could greatly compromise the efficacy of photodynamic immunotherapy. To address this challenge, we rationally synthesized a type I photosensitizer of TPA-DCR nanoparticles (NPs) with aggregation-enhanced reactive oxygen species generation via an oxygen-independent pathway. We demonstrated that the free radicals produced by TPA-DCR NPs could reprogram M0 and M2 macrophages into an anti-tumor state, which is not restricted by the hypoxic conditions. The activated M1 macrophages could further induce the immunogenic cell death of cancer cells by secreting pro-inflammatory cytokines and phagocytosis. In addition, in vivo anti-tumor experiments revealed that the TPA-DCR NPs could further trigger tumor immune response by re-educating tumor-associated macrophages toward M1 phenotype and promoting T cell infiltration. Climbazole nmr Overall, this work demonstrates the design of type I organic photosensitizers and mechanistic investigation of their superior anti-tumor efficacy. The results will benefit the exploration of advanced strategies to regulate the tumor microenvironment for effective photodynamic immunotherapy against hypoxic tumors.Biocatalysis is increasingly used for synthetic purposes in the chemical and especially the pharmaceutical industry. Enzyme discovery and optimization which is frequently needed to improve biocatalytic performance rely on high-throughput methods for activity determination. These methods should ideally be generic and applicable to entire enzyme families. Hydrogen peroxide (H2O2) is a product of several biocatalytic oxidations and its formation can serve as a proxy for oxidative activity. We designed a genetically encoded sensor for activity measurement of oxidative biocatalysts via the amount of intracellularly-formed H2O2. A key component of the sensor is an H2O2-sensitive transcriptional regulator, OxyR, which is used to control the expression levels of fluorescent proteins. We employed the OxyR sensor to monitor the oxidation of glycerol to glyceraldehyde and of toluene to o-cresol catalysed by recombinant E. coli expressing an alcohol oxidase and a P450 monooxygenase, respectively. In case of the P450 BM3-catalysed reaction, we additionally monitored o-cresol formation via a second genetically encoded sensor based on the phenol-sensitive transcriptional activator, DmpR, and an orthogonal fluorescent reporter protein. Single round screens of mutant libraries by flow cytometry or by visual inspection of colonies on agar plates yielded significantly improved oxidase and oxygenase variants thus exemplifying the suitability of the sensor system to accurately assess whole-cell oxidations in a high-throughput manner.Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein-ligand-bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.Conductive nanopipettes have been extensively used as powerful multifunctional probes for electrochemical and ion transport measurements, while the involved charge transfer processes have not been fully explored. In this paper, we use both experimental and simulation methods to de-convolute and quantify the respective electron transfer (ET) and ion transport (IT) contributions to the resulting current signals in carbon nanopipettes (CNPs). The results present that the current signals in CNPs are determined by ET in the case of low solution depth and long timescales, while IT becomes dominant at short timescales or high solution depth. In addition, the electrochemically and chemically irreversible ET processes in CNPs were also quantified. The elucidated and quantified charge transport processes inside CNPs will help control and optimize the IT and ET processes at the nanoscale, promoting better and broad usage of conductive nanopipettes in single-entity sensing and imaging applications.Despite the extensive employment of binary/ternary mixed-carbonate electrolytes (MCEs) for Li-ion batteries, the role of each ingredient with regards to the solvation structure, transport properties, and reduction behavior is not fully understood. Herein, we report the atomistic modeling and transport property measurements of the Gen2 (1.2 M LiPF6 in ethylene carbonate (EC) and ethyl methyl carbonate (EMC)) and EC-base (1.2 M LiPF6 in EC) electrolytes, as well as their mixtures with 10 mol% fluoroethylene carbonate (FEC). Due to the mixing of cyclic and linear carbonates, the Gen2 electrolyte is found to have a 60% lower ion dissociation rate and a 44% faster Li+ self-diffusion rate than the EC-base electrolyte, while the total ionic conductivities are similar. Moreover, we propose for the first time the anion-solvent exchange mechanism in MCEs with identified energetic and electrostatic origins. For electrolytes with additive, up to 25% FEC coordinates with Li+, which exhibits a preferential reduction that helps passivate the anode and facilitates an improved solid electrolyte interphase. The work provides a coherent computational framework for evaluating mixed electrolyte systems.The ortho-alkynylation of nitro-(hetero)arenes takes place in the presence of a Rh(iii) catalyst to deliver a wide variety of alkynylated nitroarenes regioselectively. These interesting products could be further derivatized by selective reduction of the nitro group or palladium-catalysed couplings. Experimental and computational mechanistic studies demonstrate that the reaction proceeds via a turnover-limiting electrophilic C-H metalation ortho to the strongly electron-withdrawing nitro group.An innovative method of synthesis is reported for the large and diverse (RE)6(TM) x (Tt)2S14 (RE = rare-earth, TM = transition metals, Tt = Si, Ge, and Sn) family of compounds (∼1000 members, ∼325 contain Si), crystallizing in the noncentrosymmetric, chiral, and polar P63 space group. Traditional synthesis of such phases involves the annealing of elements or binary sulfides at elevated temperatures. The atomic mixing of refractory components technique, presented here, allows the synthesis of known members and vastly expands the family to nearly the entire transition metal block, including 3d, 4d, and 5d TMs with oxidation states ranging from 1+ to 4+. Arc-melting of the RE, TM, and tetrel elements of choice forms an atomically-mixed precursor, which readily reacts with sulfur providing bulk powders and large single crystals of the target quaternary sulfides. Detailed in situ and ex situ experiments show the mechanism of formation, which involves multiphase binary sulfide intermediates. Crystal structures and metal oxidation states were corroborated by a combination of single crystal X-ray diffraction, elemental analysis, EPR, NMR, and SQUID magnetometry. The potential of La6(TM) x (Tt)2S14 compounds for non-linear optical applications was also demonstrated.Developing single-component materials with bright-white emission is required for energy-saving applications. Self-trapped exciton (STE) emission is regarded as a robust way to generate intrinsic white light in halide perovskites. However, STE emission usually occurs in low-dimensional perovskites whereby a lower level of structural connectivity reduces the conductivity. Enabling conventional three-dimensional (3D) perovskites to produce STEs to elicit competitive white emission is challenging. Here, we first achieved STEs-related emission of white light with outstanding chromaticity coordinates of (0.330, 0.325) in typical 3D perovskites, Mn-doped CsPbBr3 nanocrystals (NCs), through pressure processing. Remarkable piezochromism from red to blue was also realized in compressed Mn-doped CsPbBr3 NCs. Doping engineering by size-mismatched Mn dopants could give rise to the formation of localized carriers. Hence, high pressure could further induce octahedra distortion to accommodate the STEs, which has never occurred in pure 3D perovskites.