Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents

DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1 – DNA covalent complex. This complex can be trapped by a group of anticancer agents interacting with the DNA bases and the enzyme at the cleavage site, preventing further topoisomerase activity. Here we have identified novel Top1 inhibitors as potential anticancer agents by using a combination of structure- and ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristics of derivatives of the alkaloid camptothecin (CPT), which represent potent antitumour agents and the main group of Top1 inhibitors. The models generated were used for in silico screening of the National Cancer Institute (NCI, USA) compound database, leading to the identification of a set of structurally diverse molecules. The strategy is validated by the observation that amongst these molecules are several known Top1 inhibitors and agents cytotoxic against human tumour cell lines. The potential of the untested hits to inhibit Top1 activity was further evaluated by docking into the binding site of a Top1 – DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability, 7 compounds have been tested in vitro for their Top1 inhibitory activity, 5 of which display mild to moderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the identification of structurally novel Top1 inhibitors worthy of further investigation as potential anticancer agents

Anti-idiotypic antibody Ab2/3H6 mimicking gp41: a potential HIV-1 vaccine?

Meeting abstract from 22nd European Society for Animal Cell Technology(ESACT) Meeting on Cell Based Technologies Vienna, Austria. 15-18 May 2011(VLID)90658

Infection of malaria (Anopheles gambiae s.s.) and filariasis (Culex quinquefasciatus) vectors with the entomopathogenic fungus Metarhizium anisopliae

BACKGROUND: Current intra-domiciliary vector control depends on the application of residual insecticides and/or repellents. Although biological control agents have been developed against aquatic mosquito stages, none are available for adults. Following successful use of an entomopathogenic fungus against tsetse flies (Diptera: Glossinidae) we investigated the potency of this fungus as a biological control agent for adult malaria and filariasis vector mosquitoes. METHODS: In the laboratory, both sexes of Anopheles gambiae sensu stricto and Culex quinquefasciatus were passively contaminated with dry conidia of Metarhizium anisopliae. Pathogenicity of this fungus for An. gambiae was further tested for varying exposure times and different doses of oil-formulated conidia. RESULTS: Comparison of Gompertz survival curves and LT(50 )values for treated and untreated specimens showed that, for both species, infected mosquitoes died significantly earlier (p < 0.0001) than uninfected control groups. No differences in LT(50 )values were found for different exposure times (24, 48 hrs or continuous exposure) of An. gambiae to dry conidia. Exposure to oil-formulated conidia (doses ranging from 1.6 × 10(7 )to 1.6 × 10(10 )conidia/m(2)) gave LT(50 )values of 9.69 ± 1.24 (lowest dose) to 5.89 ± 0.35 days (highest dose), with infection percentages ranging from 4.4–83.7%. CONCLUSION: Our study marks the first to use an entomopathogenic fungus against adult Afrotropical disease vectors. Given its high pathogenicity for both adult Anopheles and Culex mosquitoes we recommend development of novel targeted indoor application methods for the control of endophagic host-seeking females

Tax Incentives for Cross-Border Giving in an Era of Philanthropic Globalization

The 21st century has ushered in an era of philanthropic globalization marked by a significant rise in international charitable giving. At the same time, cross-border philanthropy has raised legitimate fiscal and regulatory concerns for government. To understand how donor countries have responded to this changed global philanthropic landscape, we use comparative tax methodology to develop a spectrum of approaches to the tax treatment of cross-border giving and apply tax policy criteria to critically evaluate the divergent approaches of Australia and the Netherlands, located at opposing ends of the spectrum. Findings from the comparative analysis reveal that in the current global environment for philanthropy there is a strong case to be made for allowing tax deductible donations to cross borders

Struggling to Breathe: COVID-19, Protest, and the LIS Response

The purpose of this article is to provide a follow up to “Libraries on the Frontlines: Neutrality and Social Justice,” which was published in 2017. It addresses institutional responses to protests and uprising in the spring and summer of 2020 after the deaths of Ahmaud Arbery, Breonna Taylor, and George Floyd—all of which occurred in the context of the global COVID-19 pandemic. The article expands the previous call for libraries to take a stand for Black Lives. We describe the events of 2020 (a global pandemic, multiple murders of unarmed Black people, and the consequent global protests) and responses from within library and information science, from our perspectives as women of color faculty and library professionals. We comment on how libraries are responding to current events, as well as the possibilities for panethnic solidarity. We also consider specifically how libraries and other institutions are responding to the racial uprisings through statements on social media and call for concrete action to ensure that their organizations and information practices are actively antiracist. In so doing, we update the claims and expand the appeals we made in 2017—that Black Lives Matter and that librarianship must not remain neutral

Orienteering with One Endomorphism

In supersingular isogeny-based cryptography, the path-finding problem reduces to the endomorphism ring problem. Can path-finding be reduced to knowing just one endomorphism? It is known that a small endomorphism enables polynomial-time path-finding and endomorphism ring computation (Love-Boneh [36]). An endomorphism gives an explicit orientation of a supersingular elliptic curve. In this paper, we use the volcano structure of the oriented supersingular isogeny graph to take ascending/descending/horizontal steps on the graph and deduce path-finding algorithms to an initial curve. Each altitude of the volcano corresponds to a unique quadratic order, called the primitive order. We introduce a new hard problem of computing the primitive order given an arbitrary endomorphism on the curve, and we also provide a sub-exponential quantum algorithm for solving it. In concurrent work (Wesolowski [54]), it was shown that the endomorphism ring problem in the presence of one endomorphism with known primitive order reduces to a vectorization problem, implying path-finding algorithms. Our path-finding algorithms are more general in the sense that we don't assume the knowledge of the primitive order associated with the endomorphism.Comment: 40 pages, 1 figure; 3rd revision implements small corrections and expositional improvement

Libraries on the Frontlines: Neutrality and Social Justice

Purpose This article examines libraries’ responsibility to engage with and support communities of color as they challenge systemic racism, engage in the political process, and exercise their right to free speech. Many libraries have ignored the Black Lives Matter movement, citing the need to maintain neutrality. Despite extensive scholarship questioning the validity of this concept, the framing of library neutrality as nonpartisanship continues. This article examines librarianship’s engagement with, and disengagement from Black communities through the lens of the Black Lives Matter movement. It also explores the implications of education, engagement, and activism for people of color and libraries today. Design/methodology/approach The authors have engaged the topic from a critical race perspective as a practice in exercising voice - telling stories, presenting counterstories, and practicing advocacy (Ladson-Billings, 1998). Findings The assertion that libraries have been socially and politically neutral organizations is ahistorical. When libraries decide not to address issues relevant to people of color, they are not embodying neutrality; they are actively electing not to support the information and service needs of a service population. In order for libraries to live up to their core values, they must engage actively with communities, especially when those communities are in crisis. Originality/value As a service field, librarianship has an ethos, values, and history that parallel those of many other service fields. This paper has implications for developing understanding of questions about equitable service provision