Godfreywiggins4512

Acyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals. However, development of highly efficient asymmetric catalytic methods for the construction of these privileged motifs represents a longstanding challenge in organic synthesis. Herein, an efficient chiral phosphoric acid catalyzed direct asymmetric addition of α-alkynyl acyclic ketones with allenamides has been developed, furnishing the acyclic all-carbon quaternary stereocenters with excellent regioselectivities and high enantioselectivities. Extensive and detailed experimental mechanistic studies were performed to investigate the mechanism of this reaction. Despite a novel covalent allyl phosphate intermediate was found in these reactions, further studies indicated that a SN2-type mechanism with the ketone nucleophiles is not very possible. Instead, a more plausible mechanism involving the elimination of the allyl phosphate to give the α,β-unsaturated iminium intermediate, which underwent the asymmetric conjugate addition with the enol form of ketone nucleophiles under chiral anion catalysis, was proposed. In virtue of the fruitful functional groups bearing in the chiral products, the diverse derivatizations of the chiral products provided access to a wide array of chiral scaffolds with quaternary stereocenters.Rhizobium etli, a nitrogen-fixing bacterial symbiont of legume plants, encodes an essential L-asparaginase (ReAV) with no sequence homology to known enzymes with this activity. High-resolution crystal structures of ReAV show indeed a structurally distinct, dimeric enzyme, with some resemblance to glutaminases and β-lactamases. However, ReAV has no glutaminase or lactamase activity, and at pH 9 its allosteric asparaginase activity is relatively high, with Km for L-Asn at 4.2 mM and kcat of 438 s-1. The active site of ReAV, deduced from structural comparisons and confirmed by mutagenesis experiments, contains a highly specific Zn2+ binding site without a catalytic role. The extensive active site includes residues with unusual chemical properties. There are two Ser-Lys tandems, all connected through a network of H-bonds to the Zn center, and three tightly bound water molecules near Ser48, which clearly indicate the catalytic nucleophile.Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington's disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain.Sand spikes, pin-shaped, carbonate-cemented sandstone bodies of variable size widely interpreted as sedimentary concretions, have been enigmatic for nearly two centuries. We here present a high-energy mechanism for their formation. Two classic sand spike occurrences are found in the North Alpine Foreland Basin of Central Europe and at Mount Signal in southern California, USA. A distinct seismite horizon in Mid-Miocene Molasse sediments of southern Germany, genetically linked with the Ries impact event, exhibits dewatering structures and contains numerous sand spikes with tails systematically orientated away from the Ries crater. Sand spikes at Mount Signal, strikingly similar in shape to those found in Germany, have tails that point away from the nearby San Andreas Fault. Based on their structural and stratigraphic context, we interpret sand spikes as a new type of seismite and a promising tool to identify strong impact-induced or tectonic palaeo-earthquakes and their source regions in the geologic record.The effects of the size and position of an aluminum bipolar electrode (BPE) on the uniformity of formation of anodic porous alumina in an alternating current electric field were investigated. Anodized specimens were dyed, and the resistance was measured after the specimens were anodized again. Phenomena observed during film formation indicated that the BPEs had unique potential distributions that strongly depended on their length and width. The color variations and electrical resistance of the BPEs were symmetrical and varied from the centers of the BPEs to their ends. When multiple BPEs were processed at the same time, their position in the non-uniform electric field was demonstrated to be an important factor for controlling the uniformity of film formation. The best results were obtained when the BPE was placed at the center of the defined space.Sleep deficiencies and associated performance decrements are common among astronauts during spaceflight missions. Previously, sleep in space was analyzed with a focus on global measures while the intricate structure of sleep oscillations remains largely unexplored. This study extends previous findings by analyzing how spaceflight affects characteristics of sleep spindles and slow waves, two sleep oscillations associated with sleep quality and quantity, in four astronauts before, during and after two Space Shuttle missions. Analysis of these oscillations revealed significantly increased fast spindle density, elevated slow spindle frequency, and decreased slow wave amplitude in space compared to on Earth. These results reflect sleep characteristics during spaceflight on a finer electrophysiological scale and provide an opportunity for further research on sleep in space.We developed a SARS-CoV-2 spike subunit vaccine formulation containing dual TLR ligand liposome adjuvant. The vaccine-induced robust systemic neutralizing antibodies and completely protected mice from a lethal challenge. Two immunizations protected against lung injury and cleared the virus from lungs upon challenge. The adjuvanted vaccine also elicited systemic and local anti-Spike IgA which can be an important feature for a COVID-19 vaccine.Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.Communication between the soma and germline optimizes germ cell fate programs. Notch receptors are key determinants of germ cell fate but how somatic signals direct Notch-dependent germ cell behavior is undefined. Here we demonstrate that SDN-1 (syndecan-1), a somatic transmembrane proteoglycan, controls expression of the GLP-1 (germline proliferation-1) Notch receptor in the Caenorhabditis elegans germline. We find that SDN-1 control of a somatic TRP calcium channel governs calcium-dependent binding of an AP-2 transcription factor (APTF-2) to the glp-1 promoter. Hence, SDN-1 signaling promotes GLP-1 expression and mitotic germ cell fate. Together, these data reveal SDN-1 as a putative communication nexus between the germline and its somatic environment to control germ cell fate decisions.Physical and chemical stabilisation mechanisms are now known to play a critical role in controlling carbon (C) storage in mineral soils, leading to suggestions that climate warming-induced C losses may be lower than previously predicted. By analysing > 9,000 soil profiles, here we show that, overall, C storage declines strongly with mean annual temperature. selleckchem However, the reduction in C storage with temperature was more than three times greater in coarse-textured soils, with limited capacities for stabilising organic matter, than in fine-textured soils with greater stabilisation capacities. This pattern was observed independently in cool and warm regions, and after accounting for potentially confounding factors (plant productivity, precipitation, aridity, cation exchange capacity, and pH). The results could not, however, be represented by an established Earth system model (ESM). We conclude that warming will promote substantial soil C losses, but ESMs may not be predicting these losses accurately or which stocks are most vulnerable.Fundamental symmetry breaking and relativistic spin-orbit coupling give rise to fascinating phenomena in quantum materials. Of particular interest are the interfaces between ferromagnets and common s-wave superconductors, where the emergent spin-orbit fields support elusive spin-triplet superconductivity, crucial for superconducting spintronics and topologically-protected Majorana bound states. Here, we report the observation of large magnetoresistances at the interface between a quasi-two-dimensional van der Waals ferromagnet Fe0.29TaS2 and a conventional s-wave superconductor NbN, which provides the possible experimental evidence for the spin-triplet Andreev reflection and induced spin-triplet superconductivity at ferromagnet/superconductor interface arising from Rashba spin-orbit coupling. The temperature, voltage, and interfacial barrier dependences of the magnetoresistance further support the induced spin-triplet superconductivity and spin-triplet Andreev reflection. This discovery, together with the impressive advances in two-dimensional van der Waals ferromagnets, opens an important opportunity to design and probe superconducting interfaces with exotic properties.Determination of SARS-CoV-2 antibody responses in the context of pre-existing immunity to circulating human coronavirus (HCoV) is critical for understanding protective immunity. Here we perform a multifactorial analysis of SARS-CoV-2 and HCoV antibody responses in pre-pandemic (N = 825) and SARS-CoV-2-infected donors (N = 389) using a custom-designed multiplex ABCORA assay. ABCORA seroprofiling, when combined with computational modeling, enables accurate definition of SARS-CoV-2 seroconversion and prediction of neutralization activity, and reveals intriguing interrelations with HCoV immunity. Specifically, higher HCoV antibody levels in SARS-CoV-2-negative donors suggest that pre-existing HCoV immunity may provide protection against SARS-CoV-2 acquisition. In those infected, higher HCoV activity is associated with elevated SARS-CoV-2 responses, indicating cross-stimulation. Most importantly, HCoV immunity may impact disease severity, as patients with high HCoV reactivity are less likely to require hospitalization.