Catalysis by electrons and holes: formal potential scales and preparative organic electrochemistry

The present review surveys current chemical understanding of catalysis by addition and removal of an electron. As an overarching theme of this type of catalysis, we introduce the role of redox scales in oxidation and reduction reactions as a direct analogue of pK_a scales in acid/base catalysis. Each scale is helpful in determining the type of reactivity to be expected. In addition, we describe several means of generating electrons and holes via chemical reactions, plasmonic resonance, radiolytic, photochemical and electrochemical methods. We specifically draw parallels between the now well-established fields of photoredox catalysis and chemical opportunities made available by electrochemical methods. We highlight accessible potential ranges for a series of electrochemical solvents and provide a discussion on experimental design, pitfalls and some remaining challenges in preparative organic electrochemistry

Spot the difference: Comparing results of analyses from real patient data and synthetic derivatives

BACKGROUND: Synthetic data may provide a solution to researchers who wish to generate and share data in support of precision healthcare. Recent advances in data synthesis enable the creation and analysis of synthetic derivatives as if they were the original data; this process has significant advantages over data deidentification. OBJECTIVES: To assess a big-data platform with data-synthesizing capabilities (MDClone Ltd., Beer Sheva, Israel) for its ability to produce data that can be used for research purposes while obviating privacy and confidentiality concerns. METHODS: We explored three use cases and tested the robustness of synthetic data by comparing the results of analyses using synthetic derivatives to analyses using the original data using traditional statistics, machine learning approaches, and spatial representations of the data. We designed these use cases with the purpose of conducting analyses at the observation level (Use Case 1), patient cohorts (Use Case 2), and population-level data (Use Case 3). RESULTS: For each use case, the results of the analyses were sufficiently statistically similar ( DISCUSSION AND CONCLUSION: This article presents the results of each use case and outlines key considerations for the use of synthetic data, examining their role in clinical research for faster insights and improved data sharing in support of precision healthcare

Using comparative genomics to reorder the human genome sequence into a virtual sheep genome

Using BAC-end sequences, a sparse marker map and the sequences of the human, dog and cow genomes, an accurate and detailed sub-gene level map of the sheep genome has been constructed

Multi-frequency study of DEM L299 in the Large Magellanic Cloud

We have studied the HII region DEM L299 in the Large Magellanic Cloud to understand its physical characteristics and morphology in different wavelengths. We performed a spectral analysis of archived XMM-Newton EPIC data and studied the morphology of DEM L299 in X-ray, optical, and radio wavelengths. We used H alpha, [SII], and [OIII] data from the Magellanic Cloud Emission Line Survey and radio 21 cm line data from the Australia Telescope Compact Array (ATCA) and the Parkes telescope, and radio continuum data from ATCA and the Molonglo Synthesis Telescope. Our morphological studies imply that, in addition to the supernova remnant SNR B0543-68.9 reported in previous studies, a superbubble also overlaps the SNR in projection. The position of the SNR is clearly defined through the [SII]/H alpha flux ratio image. Moreover, the optical images show a shell-like structure that is located farther to the north and is filled with diffuse X-ray emission, which again indicates the superbubble. Radio 21 cm line data show a shell around both objects. Radio continuum data show diffuse emission at the position of DEM L299, which appears clearly distinguished from the HII region N 164 that lies south-west of it. We determined the spectral index of SNR B0543-68.9 to be alpha=-0.34, which indicates the dominance of thermal emission and therefore a rather mature SNR. We determined the basic properties of the diffuse X-ray emission for the SNR, the superbubble, and a possible blowout region of the bubble, as suggested by the optical and X-ray data. We obtained an age of 8.9 (3.5-18.1) kyr for the SNR and a temperature of 0.64 (0.44-1.37) keV for the hot gas inside the SNR, and a temperature of the hot gas inside the superbubble of 0.74 (0.44-1.1) keV. We conclude that DEM L299 consists of a superposition of SNR B0543-68.9 and a superbubble, which we identified based on optical data.Comment: Accepted for publication in Astronomy and Astrophysics. 17 pages, 16 figure

Selection Signatures in Worldwide Sheep Populations

The diversity of populations in domestic species offers great opportunities to study genome response to selection. The recently published Sheep HapMap dataset is a great example of characterization of the world wide genetic diversity in sheep. In this study, we re-analyzed the Sheep HapMap dataset to identify selection signatures in worldwide sheep populations. Compared to previous analyses, we made use of statistical methods that (i) take account of the hierarchical structure of sheep populations, (ii) make use of linkage disequilibrium information and (iii) focus specifically on either recent or older selection signatures. We show that this allows pinpointing several new selection signatures in the sheep genome and distinguishing those related to modern breeding objectives and to earlier post-domestication constraints. The newly identified regions, together with the ones previously identified, reveal the extensive genome response to selection on morphology, color and adaptation to new environments

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep

Stefan Hiendleder is a member of the International Sheep Genomics ConsortiumIn sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.Michael P. Heaton, Theodore S. Kalbfleisch, Dustin T. Petrik, Barry Simpson, James W. Kijas, Michael L. Clawson, Carol G. Chitko-McKown, Gregory P. Harhay, Kreg A. Leymaster, the International Sheep Genomics Consortiu

Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities Towards EGFR Mutants

Unstable atropisomerism is innate in many common scaffolds in drug discovery, commonly existing as freely rotating aryl-aryl bonds. Such compounds can access the majority of dihedral conformations around the bond axis, however most small-molecules bind their target within a narrow range of these available conformations. The remaining accessible conformations can interact with other proteins leading to compound promiscuity. Herein, we leverage atropisomerism to restrict the accessible low energy dihedral conformations available to a promiscuous kinase inhibitor and achieve highly selective and potent inhibitors of the oncogenic target RET kinase. We then evaluate our lead inhibitor against kinases that were predicted to bind compounds in a similar conformational window to RET, discovering a potent inhibitor of drug resistant EGFR mutants including L858R/T790M/C797S EGFR. Leveraging atropisomerism to restrict accessible conformational space should be a generally applicable strategy due to the prevalence of unstable atropisomerism in drug discovery.</p

A Practical Lewis Base Catalyzed Electrophilic Chlorination of Arenes and Heterocycles

A mild phosphine sulfide catalyzed electrophilic halogenation of arenes and heterocycles that utilizes inexpensive and readily available <i>N</i>-halosuccinimides is disclosed. This methodology is shown to efficiently chlorinate diverse aromatics, including simple arenes such as anthracene, and heterocycles such as indoles, pyrrolopyrimidines, and imidazoles. Arenes with Lewis acidic moieties also proved amenable, underscoring the mild nature of this chemistry. Lewis base catalysis was also found to improve several diverse aromatic brominations and iodinations

The Catalyst-Controlled Regiodivergent Chlorination of Phenols

Different catalysts are demonstrated to overcome or augment a substrate’s innate regioselectivity. Nagasawa’s bis-thiourea catalyst was found to overcome the innate <i>para</i>-selectivity of electrophilic phenol chlorination, yielding <i>ortho</i>-chlorinated phenols that are not readily obtainable via canonical electrophilic chlorinations. Conversely, a phosphine sulfide derived from 2,2′-Bis­(diphenyl­phosphino)-1,1′-binaphthyl (BINAP) was found to enhance the innate <i>para</i>-preference of phenol chlorination

Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones

We report a cinchona alkaloid catalyzed addition of thiophenol into rapidly interconverting aryl-naphthoquinones, resulting in stable biaryl atropisomers upon reductive methylation. An array of thiophenols and naphthoquinone substrates were evaluated, and we observed selectivities up to 98.5:1.5 e.r. Control of the quinone redox properties allowed us to study the stereochemical stabilities of each oxidation state of the substrates. The resulting enantioenriched products can also be moved on via an S_NAr-like reaction sequence to arrive at stable derivatives with excellent enantioretention