Cell cycle specific radiosensitisation by the disulfiram and copper complex

The disulfiram and copper complex (DSF:Cu) has emerged as a potent radiosensitising anti-cancer agent. The ability of copper to stabilise DSF in a planar conformation and to inhibit DNA replication enzymes stimulated our investigation of the effect of DSF:Cu on cell cycle regulation. Flow cytometry and immunoblotting were used to assess the effect of DSF:Cu on cell cycle progression of the neuroblastoma cell line SK-N-BE(2c) and the glioma cell line UVW. Treatment with 0.1 and 0.3 μM DSF:Cu inhibited DNA synthesis in SK-N-BE(2c) and UVW cells, respectively. The increased potency of ionising radiation treatment induced by DSF:Cu and/or gemcitabine was determined by clonogenic assay. Treatment with 0.3 μM DSF:Cu resulted in greater radiation kill, exemplified by dose enhancement factor values of 2.64 and 2.84 in SKN-BE(2c) and UVW cells, respectively. Although DSF:Cu failed to sensitise S phase cells to irradiation, we observed that DSF:Cu radiosensitisation was potentiated by the S phase-specific cytotoxic drug gemcitabine. The efficacy of the combination treatment consisting of DSF:Cu, gemcitabine and ionising radiation was scheduledependent. Together, these results describe cell cycle specific radiosensitisation by DSF:Cu. The well-established toxicity profiles of DSF and gemcitabine should facilitate their evaluation as a combination treatment in patients undergoing radiotherapy

Identifying the Surfaces of Human Protein TPP1 and Telomerase RNA that Interact with One Another to Improve Enzyme Function and Association at the Telomere

Telomerase is a cellular reverse transcriptase that adds tracts of telomeric DNA to the ends of linear chromosomes as a means of solving the end replication problem, preventing nonhomologous end joining, and eliminating inappropriate DNA damage response. In humans, the G-rich telomeric repeats are bound in a sequence-specific manner by proteins belonging to the shelterin complex. Two of the proteins incorporated in the shelterin complex are POT1 and TPP1. POT1 binds to the single stranded telomeric overhang with high affinity and specificity, and TPP1 forms a complex with POT1 to increase POT1-DNA affinity. The POT1-TPP1 complex has been found to participate in a dual role at the chromosome end, both protecting the integrity of the telomere and engaging in telomerase stimulation. Oligonucleotide/oligosaccharide binding folds (OB domains) consist of a five-stranded closed beta barrel, and most OB-folds use this folded face for ligand binding or as an active site. The DNA-binding domain of POT1 is composed of two tandem N-terminal OB domains. Interestingly, the N-terminal OB-fold of TPP1 (TPP1-OB) is the domain implicated in the actual act of recruiting telomerase to the telomere via interaction with the telomerase RNA and/or TERT protein; this interaction could be direct or indirect. The goal of this work was to elucidate what surface of TPP1-OB is responsible for the recruitment interaction with telomerase, and then to examine what element, if any, in the telomerase RNA subunit is interacting with TPP1. Studying the mechanisms of telomerase access to the telomere is essential for understanding normal biological processes, like aging, as well as comprehending the mechanistic cause of diseases like aplastic anemia, dyskeratosis congenita, cancer, and idiopathic pulmonary fibrosis

You Can Get There From Here: Not Your Mother\u27s Book Club

In this presentation we discuss how we implemented a professional reading group with the staff of Ladd Library and Muskie Archives. The full reading lists can be found here: Ladd Looking Forward - A Reading Group - https://scarab.bates.edu/ils_scholarship/3 Ladd Looking Forward - the Next Generation - https://scarab.bates.edu/ils_scholarship/

Ladd Looking Forward - the Remix

This is the third installment and second year of our Ladd Looking Forward group. Based on community feedback we operated on a new format and schedule incorporating colleagues from IT services and other staff offices located in the library

An evaluation of the relationship between fire history and cultural activities on Star Island, Cass Lake, Minnesota

Faculty advisor: Dr. Kurt KipfmuellerThis research was supported by the Undergraduate Research Opportunities Program (UROP)

Role of vascular smooth muscle cell clonality in atherosclerosis

Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. While many cell types contribute to the growing atherosclerotic plaque, the vascular smooth muscle cell (SMC) is a major contributor due in part to its remarkable plasticity and ability to undergo phenotype switching in response to injury. SMCs can migrate into the fibrous cap, presumably stabilizing the plaque, or accumulate within the lesional core, possibly accelerating vascular inflammation. How SMCs expand and react to disease stimuli has been a controversial topic for many decades. While early studies relying on X-chromosome inactivation were inconclusive due to low resolution and sensitivity, recent advances in multi-color lineage tracing models have revitalized the concept that SMCs likely expand in an oligoclonal fashion during atherogenesis. Current efforts are focused on determining whether all SMCs have equal capacity for clonal expansion or if a “stem-like” progenitor cell may exist, and to understand how constituents of the clone decide which phenotype they will ultimately adopt as the disease progresses. Mechanistic studies are also beginning to dissect the processes which confer cells with their overall survival advantage, test whether these properties are attributable to intrinsic features of the expanding clone, and define the role of cross-talk between proliferating SMCs and other plaque constituents such as neighboring macrophages. In this review, we aim to summarize the historical perspectives on SMC clonality, highlight unanswered questions, and identify translational issues which may need to be considered as therapeutics directed against SMC clonality are developed as a novel approach to targeting atherosclerosis

Predicting the Effects of Restoring Tidal Connectivity on the Vegetation of Fresh and Oligohaline Wetlands: Clarence River Floodplain, Northern NSW

Tidal wetlands are decreasing in number and extent worldwide due to the effects of drains and tidal barriers. These disrupt salinity gradients, reduce the depth, duration and frequency of inundation, prevent exchange of organic and inorganic materials, and interrupt movement of aquatic biota and propagules. Common effects include reductions in bird and fish populations, invasion by terrestrial and freshwater macrophytes, sediment subsidence caused by peat degradation, and activation of acid sulfate soils leading to land degradation and water quality problems. Active management of floodgates has been proposed to restore tidal exchange to waterways and wetlands of the Clarence River floodplain, on the north coast of New South Wales, Australia. Predicting the potential effects of tidal restoration on macrophyte communities is of high priority, particularly for wetlands in the fresher half of the estuarine salinity gradient. The vegetation at these sites provides important foraging and nesting habitat for rare waterbirds and a valuable pasture resource. Our ability to predict the effects of increased tidal connectivity on macrophyte communities in these wetlands is limited. Previous research in Australia has focused on saltmarsh species found in saline habitats and few data are available on the salinity and inundation tolerance ranges of macrophytes found further upstream. Existing models for predicting the effects of tidal restoration on macrophyte community composition are generally inapplicable to these communities because of the need for reference data, either from natural tidal wetlands located nearby or from surveys carried out at rehabilitation sites prior to drainage and tidal restriction. Neither of these are available for wetlands on the Clarence River floodplain. An extensive survey was used to determine distributions of macrophyte species in floodgate-affected wetlands along the Clarence River floodplain, and to relate these distributions to environmental variables, including salinity, relative elevation, acidity, water management and grazing intensity. Strong significant correlations were found between community composition and both site salinity and water depth, indicating the potential value of these variables as predictors of species occurrence

SafeSpot:An innovative app and mental health support package for Scottish schools - a qualitative analysis as part of a mixed methods study

Aims: The aim of the study was to investigate teachers’ and pupils’ perceptions about the effect of the SafeSpot mental health curriculum on the well‐being of young people and on their knowledge of mental health conditions. This trial intends to determine the acceptability and benefits of web and mobile technology in delivering emotional well‐being in schools, through use of the SafeSpot programme. Background: With 10% of young people aged 5 to 16 diagnosed with a mental disorder, there is pressure for schools to address their pupils’ emotional well‐being. However, many educators report that their schools have insufficient provisions and feel inadequately equipped to support pupils’ mental health. Methods: This qualitative analysis was embedded within a randomly allocated stepped‐wedge design, conducted in six West of Scotland secondary schools. A total of 2320 pupils (aged 11 to 14 years) and 90 teachers were included. Young people’s understanding of health‐seeking, and teacher’s confidence in delivering and accessing well‐being information was assessed qualitatively. Results: Qualitative analysis revealed themes highlighting the beneficial nature of SafeSpot, including pupil engagement, content of tutorials, perceived impact of SafeSpot and level of training provided for teachers. Conclusions: Web technology could potentially offer a more structured way for staff to support their pupils’ mental health, whilst reducing stigma. SafeSpot was perceived, by pupils and teachers, to be engaging