Mapping the magic numbers in binary Lennard-Jones clusters

Using a global optimization approach that directly searches for the composition of greatest stability, we have been able to find the particularly stable structures for binary Lennard-Jones clusters with up to 100 atoms for a range of Lennard-Jones parameters. In particular, we have shown that just having atoms of different size leads to a remarkable stabilization of polytetrahedral structures, including both polyicosahedral clusters and at larger sizes structures with disclination lines.Comment: 5 pages, 5 figure

Flow Resistance Dynamics in Step-pool Channels: 2. Partitioning Between Grain, Spill, and Woody Debris Resistance

In step-pool stream channels, flow resistance is created primarily by bed sediments, spill over step-pool bed forms, and large woody debris (LWD). In order to measure resistance partitioning between grains, steps, and LWD in step-pool channels we completed laboratory flume runs in which total resistance was measured with and without grains and steps, with various LWD configurations, and at multiple slopes and discharges. Tests of additive approaches to resistance partitioning found that partitioning estimates are highly sensitive to the order in which components are calculated and that such approaches inflate the values of difficult-to-measure components that are calculated by subtraction from measured components. This effect is especially significant where interactions between roughness features create synergistic increases in resistance such that total resistance measured for combinations of resistance components greatly exceeds the sum of those components measured separately. LWD contributes large proportions of total resistance by creating form drag on individual pieces and by increasing the spill resistance effect of steps. The combined effect of LWD and spill over steps was found to dominate total resistance, whereas grain roughness on step treads was a small component of total resistance. The relative contributions of grain, spill, and woody debris resistance were strongly influenced by discharge and to a lesser extent by LWD density. Grain resistance values based on published formulas and debris resistance values calculated using a cylinder drag approach typically underestimated analogous flume-derived values, further illustrating sources of error in partitioning methods and the importance of accounting for interaction effects between resistance components

Biological Consequences of Tightly Bent DNA: The Other Life of a Macromolecular Celebrity

The mechanical properties of DNA play a critical role in many biological functions. For example, DNA packing in viruses involves confining the viral genome in a volume (the viral capsid) with dimensions that are comparable to the DNA persistence length. Similarly, eukaryotic DNA is packed in DNA-protein complexes (nucleosomes) in which DNA is tightly bent around protein spools. DNA is also tightly bent by many proteins that regulate transcription, resulting in a variation in gene expression that is amenable to quantitative analysis. In these cases, DNA loops are formed with lengths that are comparable to or smaller than the DNA persistence length. The aim of this review is to describe the physical forces associated with tightly bent DNA in all of these settings and to explore the biological consequences of such bending, as increasingly accessible by single-molecule techniques.Comment: 24 pages, 9 figure

Factors associated with screening or treatment initiation among male United States veterans at risk for osteoporosis fracture

Male osteoporosis continues to be under-recognized and undertreated in men. An understanding of which factors cue clinicians about osteoporosis risk in men, and which do not, is needed to identify areas for improvement. This study sought to measure the association of a provider\u27s recognition of osteoporosis with patient information constructs that are available at the time of each encounter. Using clinical and administrative data from the Veterans Health Administration system, we used a stepwise procedure to construct prognostic models for a combined outcome of osteoporosis diagnosis, treatment, or a bone mineral density (BMD) test order using time-varying covariates and Cox regression. We ran separate models for patients with at least one primary care visit and patients with only secondary care visits in the pre-index period. Some of the strongest predictors of clinical osteoporosis identification were history of gonadotropin-releasing hormone (GnRH) agonist exposure, fragility fractures, and diagnosis of rheumatoid arthritis. Other characteristics associated with a higher likelihood of having osteoporosis risk recognized were underweight or normal body mass index, cancer, fall history, and thyroid disease. Medication exposures associated with osteoporosis risk recognition included opioids, glucocorticoids, and antidepressants. Several known clinical risk factors for fracture were not correlated with osteoporosis risk including smoking and alcohol abuse. Results suggest that clinicians are relying on some, but not all, clinical risk factors when assessing osteoporosis risk

Usability Test Results for a Discovery Tool in an Academic Library

Discovery tools are emerging in libraries. These tools offer library patrons the ability to concurrently search the library catalog and journal articles. While vendors rush to provide feature-rich interfaces and access to as much content as possible, librarians wonder about the usefulness of these tools to library patrons. In order to learn about both the utility and usability of EBSCO Discovery Service, James Madison University conducted a usability test with eight students and two faculty members. The test consisted of nine tasks focused on common patron requests or related to the utility of specific discovery tool features. Software recorded participants’ actions and time on task, human observers judged the success of each task, and a post-survey questionnaire gathered qualitative feedback and comments from the participants. Overall, participants were successful at most tasks, but specific usability problems suggested some interface changes for both EBSCO Discovery Service and JMU’s customizations of the tool. The study also raised several questions for libraries above and beyond any specific discovery tool interface, including the scope and purpose of a discovery tool versus other library systems, working with the large result sets made possible by discovery tools, and navigation between the tool and other library services and resources. This article will be of interest to those who are investigating discovery tools, selecting products, integrating discovery tools into a library web presence, or performing evaluations of similar systems

Stratigraphy, Radiocarbon Dating and Culture History of Charlie Lake Cave, British Columbia

Three seasons of fieldwork at Charlie Lake Cave, British Columbia, have revealed a sequence of stratified deposits that spans the Late Pleistocene and entire Holocene. Analyses of sediments, radiocarbon dates, faunal remains, and artifacts show that the site was first occupied by people at about 10 500 B.P., when local environments were more open than today. By 9500 B.P., boreal forest had moved into the area, and human use of the site was minimal until about 7000 B.P., when a brief occupation of the site probably included a human burial. Use of the site intensified after about 4500 B.P., possibly because the cave became more accessible. The site was used both as a residential base camp and as a more temporary hunting station or lookout.   Article Summary by Jonathan C. Driver, May 2015   After we had completed our excavations in 1991 we decided that we should focus on writing up what we had excavated, and not undertake further excavations at the site. This paper was written to summarize our state of knowledge about the archaeological remains at the site, and focused on describing the stone tools, the overall stratigraphy, and the dating. The stratigraphic summary replaced earlier work based on the 1983 excavations, and we were able to refine our dating of the site as a result of more radiocarbon dates. The different cultural periods were based mainly on the work done by Martin Handly for his M.A. thesis at Trent University. The long list of authors reflects the need for a team approach to archaeological work, and include the project directors (Knut Fladmark and Jon Driver), stone tool analysis and development of the cultural sequence (Martin Handly), animal bone analysis (Randall Preston and Jon Driver), sediment analysis (Greg Sullivan and Knut Fladmark), and radiocarbon dating (Erle Nelson). The most important aspect of the site is that it preserves a very rare record of humanly made artifacts dating from the end of the last ice age (at least 10,500 BC) to very recent times. The many layers at the site allow us to separate the different cultural periods. Good preservation of bone allowed us to submit radiocarbon dates that provide approximate ages for the various cultures that used the site. The artifacts that exhibit the most change through time are projectile points – the sharp stone tips for spears, darts and arrows. In much of western Canada it is difficult to date archaeological sites, because many of them are found in shallow soils where radiocarbon dating is difficult for two reasons. First, animal bone is often not preserved due to the acidic nature of the soils. Second, although charcoal is often found, it cannot be reliably associated with human activity, because natural forest fires also produce charcoal. As a result, archaeologists look at the style of the projectile points to assign approximate ages. Tse’K’wa provides an opportunity to link artifacts of different styles to radiocarbon dates in a site with many distinct layers. So Tse’K’wa is a foundation for understanding the sequence of different cultures in the region. The article also discusses the possible early presence of microblade technology. Microblades are the most efficient way of producing a cutting edge when the base technology is chipped stone. A small piece of high-quality raw material (known as the core) is shaped in such a way that numerous parallel-sided slivers of stone can be removed. These “microblades” can then be hafted in wood or antler to form knives or arrow barbs. The concept is rather like our utility knives that have replaceable blades. This technology allows people to carry small quantities of high quality stone with them, ensuring that they always have a sharp blade available. Not all archaeologists agree that the early microblade core from Tse’K’wa is part of this technology, because it doesn’t conform to the classic methods of core manufacture. However, we argue that evidence for the removal of microblades is very obvious, and the lack of classic core preparation is because of the tabular nature of the raw material. The paper also introduces some information about animal bones, including the raven burials, evidence for environmental change, and the presence of collared lemming. These topics were subsequently explored in more detail in other papers

in silico verification and parallel reaction monitoring prevalidation of potential prostate cancer biomarkers

Purpose: Targeted proteomics of potential biomarkers is often challenging. Hence, we developed an intermediate workflow to streamline potential urinary biomarkers of prostate cancer (PCa). Materials & methods: Using previously discovered potential PCa biomarkers; we selected proteotypic peptides for targeted validation. Preliminary in silico immunohistochemical and single reaction monitoring (SRM) verification was performed. Successful PTPs were then prevalidated using parallel reaction monitoring (PRM) and reconfirmed in 15 publicly available databases. Results: Stringency-based targetable potential biomarkers were shortlisted following in silico screening. PRM reveals top 12 potential biomarkers including the top ranking seven in silico verification-based biomarkers. Database reconfirmation showed differential expression between PCa and benign/normal prostatic urine samples. Conclusion: The pragmatic penultimate screening step, described herein, would immensely improve targeted proteomics validation of ..

Bone morphogenetic protein 7 sensitizes O6-methylguanine methyltransferase expressing-glioblastoma stem cells to clinically relevant dose of temozolomide.

BackgroundTemozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 μM).MethodsMGMT-expressing GSC cultures are resistant to TMZ, and IC50 (half maximal inhibitory concentration) is estimated at around 500 μM. Clonogenic GSC surviving 500 μM TMZ (GSC-500 μM TMZ), were isolated. Molecular signatures were identified via comparative analysis of expression microarray against parental GSC (GSC-parental). The recombinant protein of top downregulated signature was used as a single agent or in combination with TMZ, for evaluating therapeutic effects of treatment of GSC.ResultsThe molecular signatures characterized an activation of protective stress responses in GSC-500 μM TMZ, mainly including biotransformation/detoxification of xenobiotics, blocked endoplasmic reticulum stress-mediated apoptosis, epithelial-to-mesenchymal transition (EMT), and inhibited growth/differentiation. Bone morphogenetic protein 7 (BMP7) was identified as the top down-regulated gene in GSC-500 μM TMZ. Although augmenting BMP7 signaling in GSC by exogenous BMP7 treatment did not effectively stop GSC growth, it markedly sensitized both GSC-500 μM TMZ and GSC-parental to 35 μM TMZ treatment, leading to loss of self-renewal and migration capacity. BMP7 treatment induced senescence of GSC cultures and suppressed mRNA expression of CD133, MGMT, and ATP-binding cassette drug efflux transporters (ABCB1, ABCG2), as well as reconfigured transcriptional profiles in GSC by downregulating genes associated with EMT/migration/invasion, stemness, inflammation/immune response, and cell proliferation/tumorigenesis. BMP7 treatment significantly prolonged survival time of animals intracranially inoculated with GSC when compared to those untreated or treated with TMZ alone (p = 0.0017), whereas combination of two agents further extended animal survival compared to BMP7 alone (p = 0.0489).ConclusionsThese data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT

Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients.

Glioblastoma stem cells (GSC) co-exhibiting a tumor-initiating capacity and a radio-chemoresistant phenotype, are a compelling cell model for explaining tumor recurrence. We have previously characterized patient-derived, treatment-resistant GSC clones (TRGC) that survived radiochemotherapy. Compared to glucose-dependent, treatment-sensitive GSC clones (TSGC), TRGC exhibited reduced glucose dependence that favor the fatty acid oxidation pathway as their energy source. Using comparative genome-wide transcriptome analysis, a series of defense signatures associated with TRGC survival were identified and verified by siRNA-based gene knockdown experiments that led to loss of cell integrity. In this study, we investigate the prognostic value of defense signatures in glioblastoma (GBM) patients using gene expression analysis with Probeset Analyzer (131 GBM) and The Cancer Genome Atlas (TCGA) data, and protein expression with a tissue microarray (50 GBM), yielding the first TRGC-derived prognostic biomarkers for GBM patients. Ribosomal protein S11 (RPS11), RPS20, individually and together, consistently predicted poor survival of newly diagnosed primary GBM tumors when overexpressed at the RNA or protein level [RPS11: Hazard Ratio (HR) = 11.5, p<0.001; RPS20: HR = 4.5, p = 0.03; RPS11+RPS20: HR = 17.99, p = 0.001]. The prognostic significance of RPS11 and RPS20 was further supported by whole tissue section RPS11 immunostaining (27 GBM; HR = 4.05, p = 0.01) and TCGA gene expression data (578 primary GBM; RPS11: HR = 1.19, p = 0.06; RPS20: HR = 1.25, p = 0.02; RPS11+RPS20: HR = 1.43, p = 0.01). Moreover, tumors that exhibited unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) or wild-type isocitrate dehydrogenase 1 (IDH1) were associated with higher RPS11 expression levels [corr (IDH1, RPS11) = 0.64, p = 0.03); [corr (MGMT, RPS11) = 0.52, p = 0.04]. These data indicate that increased expression of RPS11 and RPS20 predicts shorter patient survival. The study also suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers