Chan–Lam amination of secondary and tertiary benzylic boronic esters

We report a Chan–Lam coupling reaction of benzylic and allylic boronic esters with primary and secondary anilines to form valuable alkyl amine products. Both secondary and tertiary boronic esters can be used as coupling partners, with mono-alkylation of the aniline occurring selectively. This is a rare example of a transition-metal-mediated transformation of a tertiary alkylboron reagent. Initial investigation into the reaction mechanism suggests that transmetalation from B to Cu occurs through a single-electron, rather than a two-electron process

Alternative boronic acids in the detection of Mycolactone A/B using the thin layer chromatography (f-TLC) method for diagnosis of Buruli ulcer

Background Mycobacterium ulcerans is the causative agent of Buruli ulcer. The pathology of M. ulcerans disease has been attributed to the secretion of a potent macrolide cytotoxin known as mycolactone which plays an important role in the virulence of the disease. Mycolactone is a biomarker for the diagnosis of BU that can be detected using the fluorescent-thin layer chromatography (f-TLC) technique. The technique relies on the chemical derivatization of mycolactone A/B with 2-naphthylboronic acid (BA) which acts as a fluorogenic chemosensor. However, background interferences due to co-extracted human tissue lipids, especially with clinical samples coupled with the subjectivity of the method call for an investigation to find an alternative to BA. Methods Twenty-six commercially available arylboronic acids were initially screened as alternatives to BA using the f-TLC experiment. UV–vis measurements were also conducted to determine the absorption maximum spectra of mycolactone A/B and myco-boronic acid adducts followed by an investigation of the fluorescence-enhancing ability of the boronate ester formation between mycolactone A/B and our three most promising boronic acids (BA15, BA18, and BA21). LC–MS technique was employed to confirm the adduct formation between mycolactone and boronic acids. Furthermore, a comparative study was conducted between BA18 and BA using 6 Polymerase Chain Reaction (PCR) confirmed BU patient samples. Results Three of the boronic acids (BA15, BA18, and BA21) produced fluorescent band intensities superior to BA. Complexation studies conducted on thin layer chromatography (TLC) using 0.1 M solution of the three boronic acids and various volumes of 10 ng/µL of synthetic mycolactone ranging from 1 µL – 9 µL corresponding to 10 ng – 90 ng gave similar results with myco-BA18 adduct emerging with the most visibly intense fluorescence bands. UV–vis absorption maxima (λmax) for the free mycolactone A/B was observed at 362 nm, and the values for the adducts myco-BA15, myco-BA18, and myco-BA21 were at 272 nm, 270 nm, and 286 nm respectively. The comparable experimental λmax of 362 nm for mycolactone A/B to the calculated Woodward-Fieser value of 367 nm for the fatty acid side chain of mycolactone A/B demonstrate that even though 2 cyclic boronates were formed, only the boronate of the southern side chain with the chromophore was excited by irradiation at 365 nm. Fluorescence experiments have demonstrated that coupling BA18 to mycolactone A/B along the 1,3-diols remarkably enhanced the fluorescence intensity at 537 nm. High-Resolution Mass Spectrometer (HR-MS) was used to confirm the formation of the myco-BA15 adduct. Finally, f-TLC analysis of patient samples with BA18 gave improved BA18-adduct intensities compared to the original BA-adduct. Conclusion Twenty-six commercially available boronic acids were investigated as alternatives to BA, used in the f-TLC analysis for the diagnosis of BU. Three (3) of them BA15, BA18, and BA21 gave superior fluorescence band intensity profiles. They gave profiles that were easier to interpret after the myco-boronic acid adduct formation and in experiments with clinical samples from patients with BA18 the best. BA18, therefore, has been identified as a potential alternative to BA and could provide a solution to the challenge of background interference of co-extracted human tissue lipids from clinical samples currently associated with the use of BA

Synthesis of boronic ester γ‐lactam building blocks

Saturated heterocycles are found widely in biologically active compounds such as medicinal drugs and agrochemicals. However, boronic acid‐derived building blocks for these structures have limited availability, particularly in comparison to heteroaromatic boronic acids. We report the preparation of boronic ester γ‐lactams through a Cu‐catalysed conjugate borylation‐cyclisation protocol. Using a chiral catalyst, this can be performed in high enantioselectivity. Exploration of the further transformations of these reagents suggest that the boronic esters have much potential as chemical building blocks

Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development

The Unitary Gas and its Symmetry Properties

The physics of atomic quantum gases is currently taking advantage of a powerful tool, the possibility to fully adjust the interaction strength between atoms using a magnetically controlled Feshbach resonance. For fermions with two internal states, formally two opposite spin states, this allows to prepare long lived strongly interacting three-dimensional gases and to study the BEC-BCS crossover. Of particular interest along the BEC-BCS crossover is the so-called unitary gas, where the atomic interaction potential between the opposite spin states has virtually an infinite scattering length and a zero range. This unitary gas is the main subject of the present chapter: It has fascinating symmetry properties, from a simple scaling invariance, to a more subtle dynamical symmetry in an isotropic harmonic trap, which is linked to a separability of the N-body problem in hyperspherical coordinates. Other analytical results, valid over the whole BEC-BCS crossover, are presented, establishing a connection between three recently measured quantities, the tail of the momentum distribution, the short range part of the pair distribution function and the mean number of closed channel molecules.Comment: 63 pages, 8 figures. Contribution to the Springer Lecture Notes in Physics "BEC-BCS Crossover and the Unitary Fermi gas" edited by Wilhelm Zwerger. Revised version correcting a few typo

Planck Early Results. VII. The Early Release Compact Source Catalogue

A brief description of the methodology of construction, contents and usage of the Planck Early Release Compact Source Catalogue (ERCSC), including the Early Cold Cores (ECC) and the Early Sunyaev-Zeldovich (ESZ) cluster catalogue is provided. The catalogue is based on data that consist of mapping the entire sky once and 60% of the sky a second time by Planck, thereby comprising the first high sensitivity radio/submillimetre observations of the entire sky. Four source detection algorithms were run as part of the ERCSC pipeline. A Monte-Carlo algorithm based on the injection and extraction of artificial sources into the Planck maps was implemented to select reliable sources among all extracted candidates such that the cumulative reliability of the catalogue is ≥90%. There is no requirement on completeness for the ERCSC. As a result of the Monte-Carlo assessment of reliability of sources from the different techniques, an implementation of the PowellSnakes source extraction technique was used at the five frequencies between 30 and 143 GHz while the SExtractor technique was used between 217 and 857GHz. The 10σ photometric flux density limit of the catalogue at |b| > 30◦ is 0.49, 1.0, 0.67, 0.5, 0.33, 0.28, 0.25, 0.47 and 0.82 Jy at each of the nine frequencies between 30 and 857 GHz. Sources which are up to a factor of ∼2 fainter than this limit, and which are present in “clean” regions of the Galaxy where the sky background due to emission from the interstellar medium is low, are included in the ERCSC if they meet the high reliability criterion. The Planck ERCSC sources have known associations to stars with dust shells, stellar cores, radio galaxies, blazars, infrared luminous galaxies and Galactic interstellar medium features. A significant fraction of unclassified sources are also present in the catalogs. In addition, two early release catalogs that contain 915 cold molecular cloud core candidates and 189 SZ cluster candidates that have been generated using multifrequency algorithms are presented. The entire source list, with more than 15000 unique sources, is ripe for follow-up characterisation with Herschel, ATCA, VLA, SOFIA, ALMA and other ground-based observing facilities

Helicity of the W Boson in Lepton+Jets ttbar Events

We examine properties of ttbar candidates events in lepton+jets final states to establish the helicities of the W bosons in t->W+b decays. Our analysis is based on a direct calculation of a probability that each event corresponds to a ttbar final state, as a function of the helicity of the W boson. We use the 125 events/pb sample of data collected by the DO experiment during Run I of the Fermilab Tevatron collider at sqrt{s}=1.8 TeV, and obtain a longitudinal helicity fraction of F_0=0.56+/-0.31, which is consistent with the prediction of F_0=0.70 from the standard model

Hard Single Diffraction in pbarp Collisions at root-s = 630 and 1800 GeV

Using the D0 detector, we have studied events produced in proton-antiproton collisions that contain large forward regions with very little energy deposition (``rapidity gaps'') and concurrent jet production at center-of-mass energies of root-s = 630 and 1800 Gev. The fractions of forward and central jet events associated with such rapidity gaps are measured and compared to predictions from Monte Carlo models. For hard diffractive candidate events, we use the calorimeter to extract the fractional momentum loss of the scattered protons.Comment: 11 pages 4 figures. submitted to PR

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease