5-deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2

Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure–activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy

'Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole

Subspecies of the protozoan parasite Trypanosoma brucei are the causative agents of Human African Trypanosomiasis (HAT), a debilitating neglected tropical disease prevalent across sub-Saharan Africa. HAT case numbers have steadily decreased since the start of the century, and sustainable elimination of one form of the disease is in sight. However, key to this is the development of novel drugs to combat the disease. Acoziborole is a recently developed benzoxaborole, currently in advanced clinical trials, for treatment of stage 1 and stage 2 HAT. Importantly, acoziborole is orally bioavailable, and curative with one dose. Recent studies have made significant progress in determining the molecular mode of action of acoziborole. However, less is known about the potential mechanisms leading to acoziborole resistance in trypanosomes. In this study, an in vitro-derived acoziborole-resistant cell line was generated and characterised. The Aco(R) line exhibited significant cross-resistance with the methyltransferase inhibitor sinefungin as well as hypersensitisation to known trypanocides. Interestingly, transcriptomics analysis of Aco(R) cells indicated the parasites had obtained a procyclic- or stumpy-like transcriptome profile, with upregulation of procyclin surface proteins as well as differential regulation of key metabolic genes known to be expressed in a life cycle-specific manner, even in the absence of major morphological changes. However, no changes were observed in transcripts encoding CPSF3, the recently identified protein target of acoziborole. The results suggest that generation of resistance to this novel compound in vitro can be accompanied by transcriptomic switches resembling a procyclic- or stumpy-type phenotype

Factors Facilitating Acceptable Mammography Services for Women with Disabilities

Prior research has described general barriers to breast cancer screening for women with disabilities (WWD). We explored specific accommodations described as necessary by WWD who have accessed screening services, and the presence of such accommodations in community based screening programs

Symmetries and Asymmetries of B -> K* mu+ mu- Decays in the Standard Model and Beyond

The rare decay B -> K* (-> K pi) mu+ mu- is regarded as one of the crucial channels for B physics as the polarization of the K* allows a precise angular reconstruction resulting in many observables that offer new important tests of the Standard Model and its extensions. These angular observables can be expressed in terms of CP-conserving and CP-violating quantities which we study in terms of the full form factors calculated from QCD sum rules on the light-cone, including QCD factorization corrections. We investigate all observables in the context of the Standard Model and various New Physics models, in particular the Littlest Higgs model with T-parity and various MSSM scenarios, identifying those observables with small to moderate dependence on hadronic quantities and large impact of New Physics. One important result of our studies is that new CP-violating phases will produce clean signals in CP-violating asymmetries. We also identify a number of correlations between various observables which will allow a clear distinction between different New Physics scenarios.Comment: 56 pages, 18 figures, 14 tables. v5: Missing factor in eqs. (3.31-32) and fig. 6 corrected. Minor misprints in eq. (2.10) and table A corrected. Conclusions unchange

HST Snaphot Study of Variable Stars in Globular Clusters: Inner Region of NGC 6441

[Abridged] We present the results of a Hubble Space Telescope snapshot program to survey the inner region of the globular cluster NGC 6441 for its variable stars. A total of 57 variable stars was found including 38 RR Lyrae stars, 6 Population II Cepheids, and 12 long period variables. Of the RR Lyrae stars observed in this survey, 26 are pulsating in the fundamental mode with a mean period of 0.753d and 12 are first-overtone mode pulsators with a mean period of 0.365d. These values match up very well with those found in ground-based surveys. Combining all the available data for NGC 6441, we find mean periods of 0.759d and 0.375d for the RRab and RRc stars, respectively. We also find that the RR Lyrae in this survey are located in the same regions of a period-amplitude diagram as those found in ground-based surveys. Although NGC 6441 is a metal-rich globular cluster, its RR Lyrae more closely resemble those in Oosterhoff type II globular clusters. However, even compared to typical Oosterhoff type II systems, the mean period of its RRab stars is unusually long. We also derived I-band period-luminosity relations for the RR Lyrae stars. Of the six Population II Cepheids, five are of W Virginis type and one is a BL Herculis variable stars. This makes NGC 6441, along with NGC 6388, the most metal-rich globular cluster known to contain these types of variable stars. Another variable, V118, may also be a Population II Cepheid given its long period and its separation in magnitude from the RR Lyrae stars. We argue that there does not appear to be a change in the period-luminosity relation slope between the BL Herculis and W Virginis stars, but that a change of slope does occur when the RV Tauri stars are added to the period-luminosity relation.Comment: 28 pages, including 9 figures and 8 tables, emulateapj5/apjfonts style. Accepted by the Astronomical Journal. Approximate publication date September 2003. We recommend the interested reader to download the preprint with full-resolution figures, which can be found at http://www.astro.puc.cl/~mcatelan/Pritzl.zi

Genomic instability at the locus of sterol C24-methyltransferase promotes amphotericin B resistance in Leishmania parasites

Amphotericin B is an increasingly important tool in efforts to reduce the global disease burden posed by Leishmania parasites. With few other chemotherapeutic options available for the treatment of leishmaniasis, the potential for emergent resistance to this drug is a considerable threat. Here we characterised four novel amphotericin B-resistant Leishmania mexicana lines. All lines exhibited altered sterol biosynthesis, and hypersensitivity to pentamidine. Whole genome sequencing demonstrated resistance-associated mutation of the sterol biosynthesis gene sterol C5-desaturase in one line. However, in three out of four lines, RNA-seq revealed loss of expression of sterol C24-methyltransferase (SMT) responsible for drug resistance and altered sterol biosynthesis. Additional loss of the miltefosine transporter was associated with one of those lines. SMT is encoded by two tandem gene copies, which we found to have very different expression levels. In all cases, reduced overall expression was associated with loss of the 3' untranslated region of the dominant gene copy, resulting from structural variations at this locus. Local regions of sequence homology, between the gene copies themselves, and also due to the presence of SIDER1 retrotransposon elements that promote multi-gene amplification, correlate to these structural variations. Moreover, in at least one case loss of SMT expression was not associated with loss of virulence in primary macrophages or in vivo. Whilst such repeat sequence-mediated instability is known in Leishmania genomes, its presence associated with resistance to a major antileishmanial drug, with no evidence of associated fitness costs, is a significant concern

Bovine Genome Database: integrated tools for genome annotation and discovery

The Bovine Genome Database (BGD; http://BovineGenome.org) strives to improve annotation of the bovine genome and to integrate the genome sequence with other genomics data. BGD includes GBrowse genome browsers, the Apollo Annotation Editor, a quantitative trait loci (QTL) viewer, BLAST databases and gene pages. Genome browsers, available for both scaffold and chromosome coordinate systems, display the bovine Official Gene Set (OGS), RefSeq and Ensembl gene models, non-coding RNA, repeats, pseudogenes, single-nucleotide polymorphism, markers, QTL and alignments to complementary DNAs, ESTs and protein homologs. The Bovine QTL viewer is connected to the BGD Chromosome GBrowse, allowing for the identification of candidate genes underlying QTL. The Apollo Annotation Editor connects directly to the BGD Chado database to provide researchers with remote access to gene evidence in a graphical interface that allows editing and creating new gene models. Researchers may upload their annotations to the BGD server for review and integration into the subsequent release of the OGS. Gene pages display information for individual OGS gene models, including gene structure, transcript variants, functional descriptions, gene symbols, Gene Ontology terms, annotator comments and links to National Center for Biotechnology Information and Ensembl. Each gene page is linked to a wiki page to allow input from the research community

Non-Nuclear Testing of Fission Technologies at NASA MSFC

Highly realistic non-nuclear testing can be used to investigate and resolve potential issues with space nuclear power and propulsion systems. Non-nuclear testing is particularly useful for systems designed with fuels and materials operating within their demonstrated nuclear performance envelope. Non-nuclear testing also provides an excellent way for screening potential advanced fuels and materials prior to nuclear testing, and for investigating innovative geometries and operating regimes. Non-nuclear testing allows thermal hydraulic, heat transfer, structural, integration, safety, operational, performance, and other potential issues to be investigated and resolved with a greater degree of flexibility and at reduced cost and schedule compared to nuclear testing. The primary limit of non-nuclear testing is that nuclear characteristics and potential nuclear issues cannot be directly investigated. However, non-nuclear testing can be used to augment the potential benefit from any nuclear testing that may be required for space nuclear system design and development. This paper describes previous and ongoing non-nuclear testing related to space nuclear systems at NASA s Marshall Space Flight Center (MSFC)

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [F-18]GE-180 and effect of docosahexaenoic acid

Centre for Trauma Sciences, funded by the Barts & The London Charity, GE Healthcare Ltd, the Experimental Medicine Awards from the Blizard Institute and the Imaging Centre at the Barts Cancer Institute