On the Stability and Structural Dynamics of Metal Nanowires

This article presents a brief review of the nanoscale free-electron model, which provides a continuum description of metal nanostructures. It is argued that surface and quantum-size effects are the two dominant factors in the energetics of metal nanowires, and that much of the phenomenology of nanowire stability and structural dynamics can be understood based on the interplay of these two competing factors. A linear stability analysis reveals that metal nanocylinders with certain magic conductance values G=1, 3, 6, 12, 17, 23, 34, 42, 51, 67, 78, 96, ... times the conductance quantum are exceptionally stable. A nonlinear dynamical simulation of nanowire structural evolution reveals a universal equilibrium shape consisting of a magic cylinder suspended between unduloidal contacts. The lifetimes of these metastable structures are also computed.Comment: 8 pages, 6 figure

Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients

Cell killing and resistance in pre-operative breast cancer chemotherapy

<p>Abstract</p> <p>Background</p> <p>Despite the recent development of technologies giving detailed images of tumours <it>in vivo</it>, direct or indirect ways to measure how many cells are actually killed by a treatment or are resistant to it are still beyond our reach.</p> <p>Methods</p> <p>We designed a simple model of tumour progression during treatment, based on descriptions of the key phenomena of proliferation, quiescence, cell killing and resistance, and giving as output the macroscopically measurable tumour volume and growth fraction. The model was applied to a database of the time course of volumes of breast cancer in patients undergoing pre-operative chemotherapy, for which the initial estimate of proliferating cells by the measure of the percentage of Ki67-positive cells was available.</p> <p>Results</p> <p>The analysis recognises different patterns of response to treatment. In one subgroup of patients the fitting implied drug resistance. In another subgroup there was a shift to higher sensitivity during the therapy. In the subgroup of patients where killing of cycling cells had the highest score, the drugs showed variable efficacy against quiescent cells.</p> <p>Conclusion</p> <p>The approach was feasible, providing items of information not otherwise available. Additional data, particularly sequential Ki67 measures, could be added to the system, potentially reducing uncertainty in estimates of parameter values.</p

CLOTU: An online pipeline for processing and clustering of 454 amplicon reads into OTUs followed by taxonomic annotation

<p>Abstract</p> <p>Background</p> <p>The implementation of high throughput sequencing for exploring biodiversity poses high demands on bioinformatics applications for automated data processing. Here we introduce <smcaps>CLOTU</smcaps>, an online and open access pipeline for processing 454 amplicon reads. C<smcaps>LOTU</smcaps> has been constructed to be highly user-friendly and flexible, since different types of analyses are needed for different datasets.</p> <p>Results</p> <p>In <smcaps>CLOTU</smcaps>, the user can filter out low quality sequences, trim tags, primers, adaptors, perform clustering of sequence reads, and run <smcaps>BLAST</smcaps> against NCBInr or a customized database in a high performance computing environment. The resulting data may be browsed in a user-friendly manner and easily forwarded to downstream analyses. Although <smcaps>CLOTU</smcaps> is specifically designed for analyzing 454 amplicon reads, other types of DNA sequence data can also be processed. A fungal ITS sequence dataset generated by 454 sequencing of environmental samples is used to demonstrate the utility of <smcaps>CLOTU</smcaps>.</p> <p>Conclusions</p> <p>C<smcaps>LOTU</smcaps> is a flexible and easy to use bioinformatics pipeline that includes different options for filtering, trimming, clustering and taxonomic annotation of high throughput sequence reads. Some of these options are not included in comparable pipelines. C<smcaps>LOTU</smcaps> is implemented in a Linux computer cluster and is freely accessible to academic users through the Bioportal web-based bioinformatics service (<url>http://www.bioportal.uio.no</url>).</p

Enzyme sequestration as a tuning point in controlling response dynamics of signalling networks

Signalling networks result from combinatorial interactions among many enzymes and scaffolding proteins. These complex systems generate response dynamics that are often essential for correct decision-making in cells. Uncovering biochemical design principles that underpin such response dynamics is a prerequisite to understand evolved signalling networks and to design synthetic ones. Here, we use in silico evolution to explore the possible biochemical design space for signalling networks displaying ultrasensitive and adaptive response dynamics. By running evolutionary simulations mimicking different biochemical scenarios, we find that enzyme sequestration emerges as a key mechanism for enabling such dynamics. Inspired by these findings, and to test the role of sequestration, we design a generic, minimalist model of a signalling cycle, featuring two enzymes and a single scaffolding protein. We show that this simple system is capable of displaying both ultrasensitive and adaptive response dynamics. Furthermore, we find that tuning the concentration or kinetics of the sequestering protein can shift system dynamics between these two response types. These empirical results suggest that enzyme sequestration through scaffolding proteins is exploited by evolution to generate diverse response dynamics in signalling networks and could provide an engineering point in synthetic biology applications

Enzymatic capacities of metabolic fuel use in cuttlefish (Sepia officinalis) and responses to food deprivation: insight into the metabolic organization and starvation survival strategy of cephalopods

Food limitation is a common challenge for animals. Cephalopods are sensitive to starvation because of high metabolic rates and growth rates related to their "live fast, die young" life history. We investigated how enzymatic capacities of key metabolic pathways are modulated during starvation in the common cuttlefish (Sepia officinalis) to gain insight into the metabolic organization of cephalopods and their strategies for coping with food limitation. In particular, lipids have traditionally been considered unimportant fuels in cephalopods, yet, puzzlingly, many species (including cuttlefish) mobilize the lipid stores in their digestive gland during starvation. Using a comprehensive multi-tissue assay of enzymatic capacities for energy metabolism, we show that, during long-term starvation (12 days), glycolytic capacity for glucose use is decreased in cuttlefish tissues, while capacities for use of lipid-based fuels (fatty acids and ketone bodies) and amino acid fuels are retained or increased. Specifically, the capacity to use the ketone body acetoacetate as fuel is widespread across tissues and gill has a previously unrecognized capacity for fatty acid catabolism, albeit at low rates. The capacity for de novo glucose synthesis (gluconeogenesis), important for glucose homeostasis, likely is restricted to the digestive gland, contrary to previous reports of widespread gluconeogenesis among cephalopod tissues. Short-term starvation (3-5 days) had few effects on enzymatic capacities. Similar to vertebrates, lipid-based fuels, putatively mobilized from fat stores in the digestive gland, appear to be important energy sources for cephalopods, especially during starvation when glycolytic capacity is decreased perhaps to conserve available glucose

Finding the Needles in the Metagenome Haystack

In the collective genomes (the metagenome) of the microorganisms inhabiting the Earth’s diverse environments is written the history of life on this planet. New molecular tools developed and used for the past 15 years by microbial ecologists are facilitating the extraction, cloning, screening, and sequencing of these genomes. This approach allows microbial ecologists to access and study the full range of microbial diversity, regardless of our ability to culture organisms, and provides an unprecedented access to the breadth of natural products that these genomes encode. However, there is no way that the mere collection of sequences, no matter how expansive, can provide full coverage of the complex world of microbial metagenomes within the foreseeable future. Furthermore, although it is possible to fish out highly informative and useful genes from the sea of gene diversity in the environment, this can be a highly tedious and inefficient procedure. Microbial ecologists must be clever in their pursuit of ecologically relevant, valuable, and niche-defining genomic information within the vast haystack of microbial diversity. In this report, we seek to describe advances and prospects that will help microbial ecologists glean more knowledge from investigations into metagenomes. These include technological advances in sequencing and cloning methodologies, as well as improvements in annotation and comparative sequence analysis. More significant, however, will be ways to focus in on various subsets of the metagenome that may be of particular relevance, either by limiting the target community under study or improving the focus or speed of screening procedures. Lastly, given the cost and infrastructure necessary for large metagenome projects, and the almost inexhaustible amount of data they can produce, trends toward broader use of metagenome data across the research community coupled with the needed investment in bioinformatics infrastructure devoted to metagenomics will no doubt further increase the value of metagenomic studies in various environments

Evaluating the Fidelity of De Novo Short Read Metagenomic Assembly Using Simulated Data

A frequent step in metagenomic data analysis comprises the assembly of the sequenced reads. Many assembly tools have been published in the last years targeting data coming from next-generation sequencing (NGS) technologies but these assemblers have not been designed for or tested in multi-genome scenarios that characterize metagenomic studies. Here we provide a critical assessment of current de novo short reads assembly tools in multi-genome scenarios using complex simulated metagenomic data. With this approach we tested the fidelity of different assemblers in metagenomic studies demonstrating that even under the simplest compositions the number of chimeric contigs involving different species is noticeable. We further showed that the assembly process reduces the accuracy of the functional classification of the metagenomic data and that these errors can be overcome raising the coverage of the studied metagenome. The results presented here highlight the particular difficulties that de novo genome assemblers face in multi-genome scenarios demonstrating that these difficulties, that often compromise the functional classification of the analyzed data, can be overcome with a high sequencing effort

Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses

Hard ticks subvert the immune responses of their vertebrate hosts in order to feed for much longer periods than other blood-feeding ectoparasites; this may be one reason why they transmit perhaps the greatest diversity of pathogens of any arthropod vector. Tick-induced immunomodulation is mediated by salivary components, some of which neutralise elements of innate immunity or inhibit the development of adaptive immunity. As dendritic cells (DC) trigger and help to regulate adaptive immunity, they are an ideal target for immunomodulation. However, previously described immunoactive components of tick saliva are either highly promiscuous in their cellular and molecular targets or have limited effects on DC. Here we address the question of whether the largest and globally most important group of ticks (the ixodid metastriates) produce salivary molecules that specifically modulate DC activity. We used chromatography to isolate a salivary gland protein (Japanin) from Rhipicephalus appendiculatus ticks. Japanin was cloned, and recombinant protein was produced in a baculoviral expression system. We found that Japanin specifically reprogrammes DC responses to a wide variety of stimuli in vitro, radically altering their expression of co-stimulatory and co-inhibitory transmembrane molecules (measured by flow cytometry) and their secretion of pro-inflammatory, anti-inflammatory and T cell polarising cytokines (assessed by Luminex multiplex assays); it also inhibits the differentiation of DC from monocytes. Sequence alignments and enzymatic deglycosylation revealed Japanin to be a 17.7 kDa, N-glycosylated lipocalin. Using molecular cloning and database searches, we have identified a group of homologous proteins in R. appendiculatus and related species, three of which we have expressed and shown to possess DC-modulatory activity. All data were obtained using DC generated from at least four human blood donors, with rigorous statistical analysis. Our results suggest a previously unknown mechanism for parasite-induced subversion of adaptive immunity, one which may also facilitate pathogen transmission