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The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

The first part of the dissertation describes the total synthesis of the lepadiformine alkaloids A, B, and C. The key bond forming reactions involve a one-pot nitrile anion double alkylation and reductive decyanation/cyclization. The double alkylation was exploited to stereoselectively form the cyclohexyl C ring using an achiral aminonitrile and chiral dibromide electrophile. The reductive cyclization was utilized in the diastereoselective construction of the spiropyrrolidine motif. The spirocyclization proceeded by a double SEinv sequence to provide the spiropyrrolidine with overall retention of stereochemistry at the nitrile bearing carbon. The second portion details the extension of the double alkylation/reductive cyclization approach to the synthesis of various spirocyclic heterocycles. Simple achiral spirocycles of various ring sizes were explored. The construction of chiral substrates was also investigated to determine the diastereoselectivity concerning the double alkylation as well as the reductive cyclization. The diastereoselectivity for the double alkylation was low to moderate. The reductive cyclization proceeded with high diastereoselectivity for six membered nitrile bearing ring systems. The final chapter tells of the initial findings concerning two separate projects both involving reductive lithiation. The first details the reductive decyanation of decalin and hydrindane substrates that contain a nitrile at the ring junction carbon. The second involves the reductive lithiation and cyclization of tertiary organolithiums onto a pendent fluoride electrophile.

Started in 1997, Chemidex is a recognized market leader in raw material product information retrieval and sales-lead generation for the coatings market and global chemical industry. The Chemidex Cybrary is a knowledge-based service that speeds formulators' product development while simultaneously enhancing chemical suppliers' sales efforts. The company's service web enables the sales cycle and invention process to speed information delivery and reduce the time-to-market for new products.

A manure may be defined to be any fertilizing compound or simple ingredient added to a soil of which it is naturally deficient; and as all cultivated lands should contain the earths, silica, carbonate of lime, clay, magnesia, decomposing organic matter, and certain saline substances, it is evident that in cases where any one of these is contained in the land in insufficient quantities for the supply of vegetables, then the addition of that substance, either in its simple or compoand form, constitutes the great art of manuring.

Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunitiesPI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.

Jian Yang and colleagues present a method, GREML-LDMS, to estimate heritability for complex human traits using whole-genome sequencing data or imputation with the 1000 Genomes Project reference panel. Using the heritability estimates from GREML-LDMS, they find that there is negligible missing heritability for human height and BMI. We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60–70% for height and 30–40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

Widespread uptake of vaccines is necessary to achieve herd immunity. However, uptake rates have varied across U.S. states during the first six months of the COVID-19 vaccination program. Misbeliefs may play an important role in vaccine hesitancy, and there is a need to understand relationships between misinformation, beliefs, behaviors, and health outcomes. Here we investigate the extent to which COVID-19 vaccination rates and vaccine hesitancy are associated with levels of online misinformation about vaccines. We also look for evidence of directionality from online misinformation to vaccine hesitancy. We find a negative relationship between misinformation and vaccination uptake rates. Online misinformation is also correlated with vaccine hesitancy rates taken from survey data. Associations between vaccine outcomes and misinformation remain significant when accounting for political as well as demographic and socioeconomic factors. While vaccine hesitancy is strongly associated with Republican vote share, we observe that the effect of online misinformation on hesitancy is strongest across Democratic rather than Republican counties. Granger causality analysis shows evidence for a directional relationship from online misinformation to vaccine hesitancy. Our results support a need for interventions that address misbeliefs, allowing individuals to make better-informed health decisions.

Genomic rearrangements, encompassing mutational changes in the genome such as insertions, deletions or inversions, are essential for genetic diversity. These rearrangements are typically orchestrated by enzymes that are involved in fundamental DNA repair processes, such as homologous recombination, or in the transposition of foreign genetic material by viruses and mobile genetic elements 1 , 2 . Here we report that IS110 insertion sequences, a family of minimal and autonomous mobile genetic elements, express a structured non-coding RNA that binds specifically to their encoded recombinase. This bridge RNA contains two internal loops encoding nucleotide stretches that base-pair with the target DNA and the donor DNA, which is the IS110 element itself. We demonstrate that the target-binding and donor-binding loops can be independently reprogrammed to direct sequence-specific recombination between two DNA molecules. This modularity enables the insertion of DNA into genomic target sites, as well as programmable DNA excision and inversion. The IS110 bridge recombination system expands the diversity of nucleic-acid-guided systems beyond CRISPR and RNA interference, offering a unified mechanism for the three fundamental DNA rearrangements—insertion, excision and inversion—that are required for genome design. A bispecific non-coding RNA expressed by the IS110 family of mobile genetic elements forms the basis of a programmable genome-editing system that enables the insertion, excision or inversion of specific target DNA sequences.

The role of EGFR in lung cancer is well described with numerous activating mutations that result in phosphorylation and tyrosine kinase inhibitors that target EGFR. While the role of the EGFR kinase in non-small cell lung cancer (NSCLC) is appreciated, control of EGFR signaling pathways through dephosphorylation by phosphatases is not as clear. Through whole genome sequencing we have uncovered conserved V483M Ptprh mutations in PyMT induced tumors. Profiling the downstream events of Ptprh mutant tumors revealed AKT activation, suggesting a key target of PTPRH was EGFR tyrosine 1197. Given the role of EGFR in lung cancer, we explored TCGA data which revealed that a subset of PTPRH mutant tumors shared gene expression profiles with EGFR mutant tumors, but that EGFR mutations and PTPRH mutations were mutually exclusive. Generation of a PTPRH knockout NSCLC cell line resulted in Y1197 phosphorylation of EGFR, and a rescue with expression of wild type PTPRH returned EGFR phosphorylation to parental line values while rescue with catalytically dead PTPRH did not. A dose response curve illustrated that two human NSCLC lines with naturally occurring PTPRH mutations responded to EGFR tyrosine kinase inhibition. Osimertinib treatment of these tumors resulted in a reduction of tumor volume relative to vehicle controls. PTPRH mutation resulted in nuclear pEGFR as seen in immunohistochemistry, suggesting that there may also be a role for EGFR as a transcriptional co-factor. Together these data suggest mutations in PTPRH in NSCLC is inhibitory to PTPRH function, resulting in aberrant EGFR activity and ultimately may result in clinically actionable alterations using existing therapies.