Improving binding affinity through cyclization

Cancer chemotherapy results in systematic damage as the drugs used are also toxic to benign tissue. Sensitizing a cancer cell to therapy by interfering with the DNA repair mechanisms would decrease overall toxicity, as the necessary dosage of chemotherapy drugs would be lowered. The Hartman lab developed a peptide (8.6) that binds with a KD of 1 μM to the C-terminal domain of breast cancer associated protein (BRCA1), blocking homologous recombination. The crystal structure of the peptide shows the tyrosine and threonine residues are close together, suggesting that by cyclizing these positions, the peptide may already be constrained into its bound conformation. A series of dibromomethylnaphthalene linkers of various length were synthesized and cyclized through alkylation of the cysteine residues on peptide 8.6. The binding of the cyclic peptides with the BRCA1 (BRCT)2 domain will be compared to peptide 8.6 through the use of fluorescence polarization.https://scholarscompass.vcu.edu/uresposters/1248/thumbnail.jp

Appraisal of the Karnofsky Performance Status and proposal of a simple algorithmic system for its evaluation

BACKGROUND: For over 60 years, the Karnofsky Performance Status (KPS) has proven itself a valuable tool with which to perform measurement of and comparison between the functional statuses of individual patients. In recent decades conditions for patients have changed, and so too has the KPS undergone several adjustments since its initial development. DISCUSSION: The most important works regarding the KPS tend to focus upon a variety of issues, including but not limited to reliability, validity and health-related quality of life. Also discussed is the question of what quantity the KPS may in fact be said to measure. The KPS is increasingly used as a prognostic factor in patient assessment. Thus, questions regarding if and how it affects survival are relevant. In this paper, we propose an algorithm which uses a minimum of two and a maximum of three questions to facilitate an adequate and efficient evaluation of the KPS. SUMMARY: This review honors the original intention of the discoverer and gives an overview of adaptations made in recent years. The proposed algorithm suggests specific updates with the goal of ensuring continued adequacy and expediency in the determination of the KPS

Discovery and characterization of two new stem rust resistance genes in Aegilops sharonensis

Stem rust is one of the most important diseases of wheat in the world. When single stem rust resistance (Sr) genes are deployed in wheat, they are often rapidly overcome by the pathogen. To this end, we initiated a search for novel sources of resistance in diverse wheat relatives and identified the wild goat grass species Aegilops sharonesis (Sharon goatgrass) as a substantial reservoir of resistance to wheat stem rust. The objectives of this study were to discover and map novel Sr genes in Ae. sharonensis and to explore the possibility of identifying new Sr genes by genome-wide association study (GWAS). We developed two biparental populations between resistant and susceptible accessions of Ae. sharonensis and performed QTL and linkage analysis. In an F6 recombinant inbred line and an F2 population, two genes were identified that mapped to the short arm of chromosome 1Ssh, designated as Sr-1644-1Sh, and the long arm of chromosome 5Ssh, designated as Sr-1644-5Sh. The gene Sr-1644-1Sh confers a high level of resistance to race TTKSK (one of the Ug99 lineage races), while the gene Sr-1644-5Sh conditions strong resistance to TRTTF, another widely virulent race found in Yemen. Additionally, GWAS was conducted on 125 diverse Ae. sharonensis accessions for stem rust resistance. The gene Sr-1644-1Sh was detected by GWAS, while Sr-1644-5Sh was not detected, indicating that the effectiveness of GWAS might be affected by marker density, population structure, low allele frequency and other factors

Telomere structure and maintenance gene variants and risk of five cancer types.

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/ijc.3028

The socialization of performance goals.

How are competitive goals transmitted over time? As most competence-relevant contexts (e.g., school) are hierarchy-relevant (e.g., teacher/students), supervisors’ performance-approach goals (desire to outperform others) should play a major role. We formulated a performance goals socialization hypothesis: The higher a supervisor’s performance-approach goals, the stronger the effects of time on followers’ performance-approach and -avoidance (desire not to be outperformed by others) goals. Study 1, involving coaches and their soccer players, showed that indeed a performance goals socialization phenomenon exists. Study 2, involving thesis supervisors and their Ph.D. students, showed its consequences: performance goals socialization reduced subordinates’ motivation and well-being over time. Study 3, involving video game team leaders and their players, showed its enabling condition: the stronger the subordinates’ identification to their team, the more pronounced the performance goals socialization. Study 4, involving schoolteachers and their pupils, showed its directional moderator: the higher the subordinates’ perceived self-competence, the higher the change in performance-approach goals over time, and the lower that in performance-avoidance goals. It is then crucial to consider social hierarchy when studying goal formation

Vocal Culture in the Age of Laryngoscopy

For several months beginning in 1884, readers of Life, Science, Health, the Atlantic Monthly and similar magazines would have encountered half-page advertisements for a newly patented medical device called the ‘ammoniaphone’ (Figure 2.1). Invented and promoted by a Scottish doctor named Carter Moffat and endorsed by the soprano Adelina Patti, British Prime Minister William Gladstone and the Princess of Wales, the ammoniaphone promised a miraculous transformation in the voices of its users. It was recommended for ‘vocalists, clergymen, public speakers, parliamentary men, readers, reciters, lecturers, leaders of psalmody, schoolmasters, amateurs, church choirs, barristers, and all persons who have to use their voices professionally, or who desire to greatly improve their speaking or singing tones’. Some estimates indicated that Moffat sold upwards of 30,000 units, yet the ammoniaphone was a flash in the pan as far as such things go, fading from public view after 1886

Opera and Hypnosis: Victor Maurel’s Experiments with Verdi’s Otello

One day in his private home on the avenue Bugeaud, in Paris’s sixteenth arrondissement, the famous baritone Victor Maurel hosted a meeting which combined music with hypnotism of a young woman

Unsound Seeds

With this image of a curtain hiding and at the same time heightening some terrible secret, Max Kalbeck began his review of the first Viennese performance of Richard Strauss’s Salome. Theodor W. Adorno picked up the image of the curtain in the context of Strauss’s fabled skill at composing non-musical events, when he identified the opening flourish of Strauss’s Salome as the swooshing sound of the rising curtain. If this is so, the succès de scandale of the opera was achieved, in more than one sense, as soon as the curtain rose at Dresden’s Semperoper on 10 December 1905. Critics of the premiere noted that the opera set ‘boundless wildness and degeneration to music’; it brought ‘high decadence’ onto the operatic stage; a ‘composition of hysteria’, reflecting the ‘disease of our time’, Salome is ‘hardly music any more’.The outrage did not end there

Science, Technology and Love in Late Eighteenth-Century Opera

It is a tale told by countless operas: young love, thwarted by an old man’s financially motivated marriage plans, triumphs in the end thanks to a deception that tricks the old man into blessing the young lovers’ union. Always a doddering fool, the old man is often also an enthusiast for knowledge. Such is the case, for instance, in Carlo Goldoni’s comic opera libretto Il mondo della luna (1750), in which Buonafede’s interest in the moon opens him to an elaborate hoax that has him believe he and his daughters have left Earth for the lunar world; and also in the Singspiel Die Luftbälle, oder der Liebhaber à la Montgolfier (1788), wherein the apothecary Wurm trades Sophie, the ward he intended to marry himself, for a technological innovation that will make him a pioneering aeronaut