Iterative in Situ Click Chemistry Assembles a Branched Capture Agent and Allosteric Inhibitor for Akt1

We describe the use of iterative in situ click chemistry to design an Akt-specific branched peptide triligand that is a drop-in replacement for monoclonal antibodies in multiple biochemical assays. Each peptide module in the branched structure makes unique contributions to affinity and/or specificity resulting in a 200 nM affinity ligand that efficiently immunoprecipitates Akt from cancer cell lysates and labels Akt in fixed cells. Our use of a small molecule to preinhibit Akt prior to screening resulted in low micromolar inhibitory potency and an allosteric mode of inhibition, which is evidenced through a series of competitive enzyme kinetic assays. To demonstrate the efficiency and selectivity of the protein-templated in situ click reaction, we developed a novel QPCR-based methodology that enabled a quantitative assessment of its yield. These results point to the potential for iterative in situ click chemistry to generate potent, synthetically accessible antibody replacements with novel inhibitory properties

The Journal of the Friends' Historical Society vol. 3 No. 3

1. Notices. 2. Notes and Queries. 3. Letter from William Penn. 4. David Lloyd II. 5. Friends on the Atlantic. 6. King's Briefs the Forerunners of Mutual Insurance Societies. 7. Whitefield's Estimate of Quakerism. 8. Earlham College Library, Richmond, Ind. 9. Editors' Notes. 10. Large Gatherings of Friends. 11. Meeting Records I. 12. Friends in Current Literature. 13. A Quotation in the London Y.M. Epistle. 14. List of Officers for 1906-7. 15. Accounts and Balance Sheet for 1905

Discovery of new Milky Way star cluster candidates in the 2MASS point source catalog III. Follow-up observations of cluster candidates in the Galactic Center region

This paper is part of a project to search the inner Milky Way for hidden massive clusters and to address the question of whether our Galaxy still forms clusters similar to the progenitors of the present-day globular clusters. We report high angular resolution deep near-infrared imaging of 21 cluster candidates selected from the catalogues of Bica et al. (2003) and Dutra et al.(2003) in a region around the Galactic Center. These catalogues were created from visual inspection of the 2MASS images. Seven objects appear to be genuine clusters, and for these objects we present estimates of extinction, distance and in some cases age and mass. Our estimated masses range from 1200 to 5500 solar masses. These clusters are thus significantly smaller than any Galactic globular cluster, and indicate that the formation of massive young clusters such as Arches and Quintuplet is not common in the present-day Milky Way. The remaining 14 objects are either not clusters or cannot be classified based on our data.Comment: 8 pages, 19 figures, accepted for publication in A&

Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis

Esophageal squamous cell carcinoma (ESCC) is endemic in regions of sub-Saharan Africa (SSA), where it is the third most common cancer. Here, we describe whole-exome tumor/normal sequencing and RNA transcriptomic analysis of 59 patients with ESCC in Malawi. We observed similar genetic aberrations as reported in Asian and North American cohorts, including mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1, and FBXW7. Analyses for nonhuman sequences did not reveal evidence for infection with HPV or other occult pathogens. Mutational signature analysis revealed common signatures associated with aging, cytidine deaminase activity (APOBEC), and a third signature of unknown origin, but signatures of inhaled tobacco use, aflatoxin and mismatch repair were notably absent. Based on RNA expression analysis, ESCC could be divided into 3 distinct subtypes, which were distinguished by their expression of cell cycle and neural transcripts. This study demonstrates discrete subtypes of ESCC in SSA, and suggests that the endemic nature of this disease reflects exposure to a carcinogen other than tobacco and oncogenic viruses

High-resolution FUSE and HST ultraviolet spectroscopy of the white dwarf central star of Sh 2-216

LS V +4621 is the DAO-type central star of the planetary nebula Sh 2-216. We perform a comprehensive spectral analysis of high-resolution, high-S/N ultraviolet observations obtained with FUSE and STIS aboard the HST as well as the optical spectrum of LS V +4621 by means of state-of-the-art NLTE model-atmosphere techniques in order to compare its photospheric properties to theoretical predictions from stellar evolution theory as well as from diffusion calculations. From the N IV - NV, O IV - O VI, Si IV - Si V, and Fe V - Fe VII ionization equilibria, we determined an effective temperature of 95 +/- 2 kK with high precision. The surface gravity is log g = 6.9 +/- 0.2. An unexplained discrepancy appears between the spectroscopic distance d = 224 +46/-58 pc and the parallax distance d = 129 +6/-5 pc of LS V +4621. For the first time, we have identified Mg IV and Ar VI absorption lines in the spectrum of a hydrogen-rich central star and determined the Mg and Ar abundances as well as the individual abundances of iron-group elements (Cr, Mn, Fe, Co, and Ni). With the realistic treatment of metal opacities up to the iron group in the model-atmosphere calculations, the so-called Balmer-line problem (found in models that neglect metal-line blanketing) vanishes. Spectral analysis by means of NLTE model atmospheres has presently arrived at a high level of sophistication, which is now hampered largely by the lack of reliable atomic data and accurate line-broadening tables. Strong efforts should be made to improve upon this situation.Comment: 13 pages, 20 figure

Pre-Main Sequence stars in the star forming complex Sh 2-284

Located at the galactic anticenter, Sh 2-284 is a HII region which harbors several young open clusters; Dolidze 25, a rare metal poor (Z~0.004) young cluster, is one of these. Given its association with Sh 2-284, it is reasonable to assume the low metallicity for the whole HII region. Sh~2-284 is expected to host a significant population of Pre-Main Sequence (PMS) stars of both low and intermediate mass stars (Herbig Ae stars). We aim at characterizing these stars by means of a spectroscopic and photometric survey conducted with VIMOS@VLT and complemented with additional optical and infrared observations. In this survey we selected and characterized 23 PMS objects. We derived the effective temperature, the spectral energy distribution and luminosity of these objects; using theoretical PMS evolutionary tracks, with the appropriate metallicity, we estimated the mass and the age of the studied objects. We also estimated a distance of 4 Kpc for Sh 2-284 by using spectroscopic parallax of 3 OB stars. From the age determination we concluded that triggered star formation is in act in this region. Our results show that a significant fraction of the young stellar objects (YSOs) may have preserved their disk/envelopes, in contrast with what is found in other recent studies of low-metallicity star forming regions in the Galaxy. Finally, among the 23 bona fide PMS stars, we identified 8 stars which are good candidates to pulsators of the delta Scuti type.Comment: accepted for publication in MNRA

Far infrared mapping of three Galactic star forming regions : W3(OH), S 209 & S 187

Three Galactic star forming regions associated with W3(OH), S209 and S187 have been simultaneously mapped in two trans-IRAS far infrared (FIR) bands centered at ~ 140 and 200 micron using the TIFR 100 cm balloon borne FIR telescope. These maps show extended FIR emission with structures. The HIRES processed IRAS maps of these regions at 12, 25, 60 & 100 micron have also been presented for comparison. Point-like sources have been extracted from the longest waveband TIFR maps and searched for associations in the other five bands. The diffuse emission from these regions have been quantified, which turns out to be a significant fraction of the total emission. The spatial distribution of cold dust (T < 30 K) for two of these sources (W3(OH) & S209), has been determined reliably from the maps in TIFR bands. The dust temperature and optical depth maps show complex morphology. In general the dust around S209 has been found to be warmer than that in W3(OH) region.Comment: Accepted for publication in Journal of Astrophysics and Astronomy (20 pages including 8 figures & 3 tables

Production of two highly abundant 2-methyl-branched fatty acids by blooms of the globally significant marine cyanobacteria Trichodesmium erythraeum

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Gosselin, K. M., Nelson, R. K., Spivak, A. C., Sylva, S. P., Van Mooy, B. A. S., Aeppli, C., Sharpless, C. M., O’Neil, G. W., Arrington, E. C., Reddy, C. M., & Valentine, D. L. Production of two highly abundant 2-methyl-branched fatty acids by blooms of the globally significant marine cyanobacteria Trichodesmium erythraeum. ACS Omega, 6(35), (2021): 22803–22810, https://doi.org/10.1021/acsomega.1c03196.The bloom-forming cyanobacteria Trichodesmium contribute up to 30% to the total fixed nitrogen in the global oceans and thereby drive substantial productivity. On an expedition in the Gulf of Mexico, we observed and sampled surface slicks, some of which included dense blooms of Trichodesmium erythraeum. These bloom samples contained abundant and atypical free fatty acids, identified here as 2-methyldecanoic acid and 2-methyldodecanoic acid. The high abundance and unusual branching pattern of these compounds suggest that they may play a specific role in this globally important organism.This work was funded with grants from the National Science Foundation grants OCE-1333148, OCE-1333162, and OCE-1756254 and the Woods Hole Oceanographic Institution (IR&D). GCxGC analysis made possible by WHOI’s Investment in Science Fund

Iterative in situ click chemistry creates antibody-like protein-capture agents

Iterative in situ click chemistry (see scheme for the tertiary ligand screen) and the one-bead-one-compound method for the creation of a peptide library enable the fragment-based assembly of selective high-affinity protein-capture agents. The resulting ligands are water-soluble and stable chemically, biochemically, and thermally. They can be produced in gram quantities through copper (I)-catalyzed cycloaddition