Showing papers by "University College Dublin published in 2012"

2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design

Abstract: During the past decade, catheter ablation of atrial fibrillation (AF) has evolved rapidly from an investigational procedure to its current status as a commonly performed ablation procedure in many major hospitals throughout the world. Surgical ablation of AF, using either standard or minimally invasive techniques, is also performed in many major hospitals throughout the world. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society.1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons and the American College of Cardiology. Since the publication of the 2007 document, there has been much learned about AF ablation, and the indications for these procedures have changed. Therefore the purpose of this 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation, including definitions relevant to this topic. This statement summarizes the opinion of the Task Force members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF. This statement is not intended to recommend or promote catheter ablation of AF. Rather the ultimate judgment regarding care of a particular patient …

Gut microbiota composition correlates with diet and health in the elderly

Abstract: Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.

Biomolecular coronas provide the biological identity of nanosized materials

Abstract: The search for understanding the interactions of nanosized materials with living organisms is leading to the rapid development of key applications, including improved drug delivery by targeting nanoparticles, and resolution of the potential threat of nanotechnological devices to organisms and the environment. Unless they are specifically designed to avoid it, nanoparticles in contact with biological fluids are rapidly covered by a selected group of biomolecules to form a corona that interacts with biological systems. Here we review the basic concept of the nanoparticle corona and its structure and composition, and highlight how the properties of the corona may be linked to its biological impacts. We conclude with a critical assessment of the key problems that need to be resolved in the near future.

Fermi Large Area Telescope Second Source Catalog

Abstract: We present the second catalog of high-energy γ-ray sources detected by the Large Area Telescope (LAT), the primary science instrument on the Fermi Gamma-ray Space Telescope (Fermi), derived from data taken during the first 24 months of the science phase of the mission, which began on 2008 August 4. Source detection is based on the average flux over the 24 month period. The second Fermi-LAT catalog (2FGL) includes source location regions, defined in terms of elliptical fits to the 95% confidence regions and spectral fits in terms of power-law, exponentially cutoff power-law, or log-normal forms. Also included are flux measurements in five energy bands and light curves on monthly intervals for each source. Twelve sources in the catalog are modeled as spatially extended. We provide a detailed comparison of the results from this catalog with those from the first Fermi-LAT catalog (1FGL). Although the diffuse Galactic and isotropic models used in the 2FGL analysis are improved compared to the 1FGL catalog, we attach caution flags to 162 of the sources to indicate possible confusion with residual imperfections in the diffuse model. The 2FGL catalog contains 1873 sources detected and characterized in the 100 MeV to 100 GeV range of which we consider 127 as being firmly identified and 1171 as being reliably associated with counterparts of known or likely γ-ray-producing source classes.

Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells

Abstract: Nanoparticles enter cells through active processes, thanks to their capability of interacting with the cellular machinery. The protein layer (corona) that forms on their surface once nanoparticles are in contact with biological fluids, such as the cell serum, mediates the interactions with cells in situ. As a consequence of this, here we show that the same nanomaterial can lead to very different biological outcomes, when exposed to cells in the presence or absence of a preformed corona. In particular, silica nanoparticles exposed to cells in the absence of serum have a stronger adhesion to the cell membrane and higher internalization efficiency, in comparison to what is observed in medium containing serum, when a preformed corona is present on their surface. The different exposure conditions not only affect the uptake levels but also result in differences in the intracellular nanoparticle location and impact on cells. Interestingly, we also show that after only one hour of exposure, a corona of very different nature forms on the nanoparticles exposed to cells in the absence of serum. Evidence suggests that these different outcomes can all be connected to the different adhesion and surface properties in the two conditions.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

Global landscape of HIV-human protein complexes

Abstract: Human immunodeficiency virus (HIV) has a small genome and therefore relies heavily on the host cellular machinery to replicate. Identifying which host proteins and complexes come into physical contact with the viral proteins is crucial for a comprehensive understanding of how HIV rewires the host's cellular machinery during the course of infection. Here we report the use of affinity tagging and purification mass spectrometry to determine systematically the physical interactions of all 18 HIV-1 proteins and polyproteins with host proteins in two different human cell lines (HEK293 and Jurkat). Using a quantitative scoring system that we call MiST, we identified with high confidence 497 HIV-human protein-protein interactions involving 435 individual human proteins, with ∼40% of the interactions being identified in both cell types. We found that the host proteins hijacked by HIV, especially those found interacting in both cell types, are highly conserved across primates. We uncovered a number of host complexes targeted by viral proteins, including the finding that HIV protease cleaves eIF3d, a subunit of eukaryotic translation initiation factor 3. This host protein is one of eleven identified in this analysis that act to inhibit HIV replication. This data set facilitates a more comprehensive and detailed understanding of how the host machinery is manipulated during the course of HIV infection.

An Analysis of Anonymity in the Bitcoin System

Abstract: Anonymity in Bitcoin, a peer-to-peer electronic currency system, is a complicated issue. Within the system, users are identified by public-keys only. An attacker wishing to de-anonymize its users will attempt to construct the one-to-many mapping between users and public-keys and associate information external to the system with the users. Bitcoin tries to prevent this attack by storing the mapping of a user to his or her public-keys on that user's node only and by allowing each user to generate as many public-keys as required. In this chapter we consider the topological structure of two networks derived from Bitcoin's public transaction history. We show that the two networks have a non-trivial topological structure, provide complementary views of the Bitcoin system and have implications for anonymity. We combine these structures with external information and techniques such as context discovery and flow analysis to investigate an alleged theft of Bitcoins, which, at the time of the theft, had a market value of approximately half a million U.S. dollars.

Nanotechnologies in the food industry – Recent developments, risks and regulation

Abstract: Recent research has highlighted the potential for nanotechnologies’ use in wide ranging food applications, including improving supplements, novel food packaging, increasing the range of food textures, colours and tastes, increasing the efficiency of liquid filters, cooking oil catalysation and targeted crop pesticides. Because of these new developments it is likely that radical changes in the way food is perceived, stored, packaged, transported, monitored, consumed and processed will come about. Available literature suggests that many uncertainties remain about nanomaterials, including the potential for bioaccumulation and potential human health risks. While proposed applications of nanotechnologies are wide and varied, developments are met with some caution, while progress may be stifled by lack of governance and potential risks.

Characterization of the anisotropic mechanical properties of excised human skin

Abstract: The mechanical properties of skin are important for a number of applications including surgery, dermatology, impact biomechanics and forensic science. In this study, we have investigated the influence of location and orientation on the deformation characteristics of 56 samples of excised human skin. Uniaxial tensile tests were carried out at a strain rate of 0.012 s(-1) on skin from the back. Digital Image Correlation was used for 2D strain measurement and a histological examination of the dermis was also performed. The mean ultimate tensile strength (UTS) was 21.6±8.4 MPa, the mean failure strain 54%±17%, the mean initial slope 1.18±0.88 MPa, the mean elastic modulus 83.3±34.9 MPa and the mean strain energy was 3.6±1.6 MJ/m(3). A multivariate analysis of variance has shown that these mechanical properties of skin are dependent upon the orientation of the Langer lines (P<0.0001-P=0.046). The location of specimens on the back was also found to have a significant effect on the UTS (P=0.0002), the elastic modulus (P=0.001) and the strain energy (P=0.0052). The histological investigation concluded that there is a definite correlation between the orientation of the Langer lines and the preferred orientation of collagen fibres in the dermis (P<0.001). The data obtained in this study will provide essential information for those wishing to model the skin using a structural constitutive model.

Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population

Abstract: Nanoparticles are considered a primary vehicle for targeted therapies because they can pass biological barriers and enter and distribute within cells by energy-dependent pathways. So far, most studies have shown that nanoparticle properties, such as size and surface, can influence how cells internalize nanoparticles. Here, we show that uptake of nanoparticles by cells is also influenced by their cell cycle phase. Although cells in different phases of the cell cycle were found to internalize nanoparticles at similar rates, after 24 h the concentration of nanoparticles in the cells could be ranked according to the different phases: G2/M > S > G0/G1. Nanoparticles that are internalized by cells are not exported from cells but are split between daughter cells when the parent cell divides. Our results suggest that future studies on nanoparticle uptake should consider the cell cycle, because, in a cell population, the dose of internalized nanoparticles in each cell varies as the cell advances through the cell cycle.

The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction.

Abstract: Lysosomal storage diseases (LSDs) are a family of disorders that result from inherited gene mutations that perturb lysosomal homeostasis. LSDs mainly stem from deficiencies in lysosomal enzymes, but also in some non-enzymatic lysosomal proteins, which lead to abnormal storage of macromolecular substrates. Valuable insights into lysosome functions have emerged from research into these diseases. In addition to primary lysosomal dysfunction, cellular pathways associated with other membrane-bound organelles are perturbed in these disorders. Through selective examples, we illustrate why the term “cellular storage disorders” may be a more appropriate description of these diseases and discuss therapies that can alleviate storage and restore normal cellular function.

Measuring energy poverty: Focusing on what matters

Abstract: The provision of modern energy services is recognised as a critical foundation for sustainable development, and is central to the everyday lives of people. Effective policies to dramatically expand modern energy access need to be grounded in a robust information-base. Metrics that can be used for comparative purposes and to track progress towards targets therefore represent an essential support tool. This paper reviews the relevant literature, and discusses the adequacy and applicability of existing instruments to measure energy poverty. Drawing on those insights, it proposes a new composite index to measure energy poverty. Both the associated methodology and initial results for several African countries are discussed. Whereas most existing indicators and composite indices focus on assessing the access to energy, or the degree of development related to energy, our new index – the Multidimensional Energy Poverty Index (MEPI) – focuses on the deprivation of access to modern energy services. It captures both the incidence and intensity of energy poverty, and provides a new tool to support policy-making.

Optimal Charging of Electric Vehicles in Low-Voltage Distribution Systems

Abstract: Advances in the development of electric vehicles, along with policy incentives, will see a wider uptake of this technology in the transport sector in future years. However, the widespread adoption of electric vehicles could lead to adverse effects on the power system, especially for existing distribution networks. These effects would include excessive voltage drops and overloading of network components, which occur mainly during periods of simultaneous charging of large numbers of electric vehicles. This paper demonstrates how controlling the rate at which electric vehicles charge can lead to better utilization of existing networks. A technique based on linear programming is employed, which determines the optimal charging rate for each electric vehicle in order to maximize the total power that can be delivered to the vehicles while operating within network limits. The technique is tested on a section of residential distribution network. Results show that, by controlling the charging rate of individual vehicles, high penetrations can be accommodated on existing residential networks with little or no need for upgrading network infrastructure.

Evaluation of Power System Flexibility

Abstract: As the penetration of variable renewable generation increases in power systems worldwide, planning for the effects of variability will become more important. Traditional capacity adequacy planning techniques have been supplemented with integration studies, which have been carried out in power systems with high targets for renewable generation. These have highlighted the increased variability that a system may experience in the future. As system generation planning techniques evolve with the challenge of integrating variable generation, the flexibility of a system to manage periods of high variability needs to be assessed. The insufficient ramping resource expectation (IRRE) metric is proposed to measure power system flexibility for use in long-term planning, and is derived from traditional generation adequacy metrics. Compared to existing generation adequacy metrics, flexibility assessment is more data intensive. A flexibility metric can identify the time intervals over which a system is most likely to face a shortage of flexible resources, and can measure the relative impact of changing operational policies and the addition of flexible resources. The flexibility of a test system with increasing penetrations of variable generation is assessed. The results highlight the time horizons of increased and decreased risk associated with the integration of VG.

European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies

Abstract: Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-infl ammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extraarticular manifestations of PsA. Five overarching principles and a research agenda were defi ned. Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design

Abstract: This is a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). This is endorsed by the governing bodies of the ACC Foundation, the AHA, the ECAS, the EHRA, the STS, the APHRS, and the HRS.

ELM—the database of eukaryotic linear motifs

Abstract: Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instances

The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization

Abstract: Both the basal body and the microtubule-based axoneme it nucleates have evolutionarily conserved subdomains crucial for cilium biogenesis, function and maintenance. Here, we focus on two conspicuous but underappreciated regions of these structures that make membrane connections. One is the basal body distal end, which includes transition fibres of largely undefined composition that link to the base of the ciliary membrane. Transition fibres seem to serve as docking sites for intraflagellar transport particles, which move proteins within the ciliary compartment and are required for cilium biogenesis and sustained function. The other is the proximal-most region of the axoneme, termed the transition zone, which is characterized by Y-shaped linkers that span from the axoneme to the ciliary necklace on the membrane surface. The transition zone comprises a growing number of ciliopathy proteins that function as modular components of a ciliary gate. This gate, which forms early during ciliogenesis, might function in part by regulating intraflagellar transport. Together with a recently described septin ring diffusion barrier at the ciliary base, the transition fibres and transition zone deserve attention for their varied roles in forming functional ciliary compartments.

Demonstration of Blind Quantum Computing

Abstract: Quantum computers, besides offering substantial computational speedups, are also expected to preserve the privacy of a computation. We present an experimental demonstration of blind quantum computing in which the input, computation, and output all remain unknown to the computer. We exploit the conceptual framework of measurement-based quantum computation that enables a client to delegate a computation to a quantum server. Various blind delegated computations, including one- and two-qubit gates and the Deutsch and Grover quantum algorithms, are demonstrated. The client only needs to be able to prepare and transmit individual photonic qubits. Our demonstration is crucial for unconditionally secure quantum cloud computing and might become a key ingredient for real-life applications, especially when considering the challenges of making powerful quantum computers widely available.

Small-molecule conversion of toxic oligomers to nontoxic β-sheet–rich amyloid fibrils

Abstract: Several lines of evidence indicate that prefibrillar assemblies of amyloid-β (Aβ) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Aβ fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aβ peptides and stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Aβ oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Aβ oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.

Clinicopathological significance of psychotic experiences in non-psychotic young people: evidence from four population-based studies

Abstract: Background Epidemiological research has shown that hallucinations and delusions, the classic symptoms of psychosis, are far more prevalent in the population than actual psychotic disorder. These symptoms are especially prevalent in childhood and adolescence. Longitudinal research has demonstrated that psychotic symptoms in adolescence increase the risk of psychotic disorder in adulthood. There has been a lack of research, however, on the immediate clinicopathological significance of psychotic symptoms in adolescence. Aims To investigate the relationship between psychotic symptoms and non-psychotic psychopathology in community samples of adolescents in terms of prevalence, co-occurring disorders, comorbid (multiple) psychopathology and variation across early v. middle adolescence. Method Data from four population studies were used: two early adolescence studies (ages 11–13 years) and two mid-adolescence studies (ages 13–16 years). Studies 1 and 2 involved school-based surveys of 2243 children aged 11–16 years for psychotic symptoms and for emotional and behavioural symptoms of psychopathology. Studies 3 and 4 involved in-depth diagnostic interview assessments of psychotic symptoms and lifetime psychiatric disorders in community samples of 423 children aged 11–15 years. Results Younger adolescents had a higher prevalence (21–23%) of psychotic symptoms than older adolescents (7%). In both age groups the majority of adolescents who reported psychotic symptoms had at least one diagnosable non-psychotic psychiatric disorder, although associations with psychopathology increased with age: nearly 80% of the mid-adolescence sample who reported psychotic symptoms had at least one diagnosis, compared with 57% of the early adolescence sample. Adolescents who reported psychotic symptoms were at particularly high risk of having multiple co-occurring diagnoses. Conclusions Psychotic symptoms are important risk markers for a wide range of non-psychotic psychopathological disorders, in particular for severe psychopathology characterised by multiple co-occurring diagnoses. These symptoms should be carefully assessed in all patients.

Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance.

Abstract: In the present paper, we describe multiple levels of cross-talk between the PI3K (phosphoinositide 3-kinase)/Akt and Ras/MAPK (mitogen-activated protein kinase) signalling pathways. Experimental data and computer simulations demonstrate that cross-talk is context-dependent and that both pathways can activate or inhibit each other. Positive influence of the PI3K pathway on the MAPK pathway is most effective at sufficiently low doses of growth factors, whereas negative influence of the MAPK pathway on the PI3K pathway is mostly pronounced at high doses of growth factors. Pathway cross-talk endows a cell with emerging capabilities for processing and decoding signals from multiple receptors activated by different combinations of extracellular cues.

Psychiatry beyond the current paradigm.

Abstract: What makes a good psychiatrist? What particular skills are needed to practice a ‘medicine of the mind’? Although it is impossible to answer such questions fully we believe that there is mounting evidence that good practice in psychiatry primarily involves engagement with the non-technical dimensions of our work such as relationships, meanings and values. Psychiatry has thus far been guided by a technological paradigm that, although not ignoring these aspects of our work, has kept them as secondary concerns. The dominance of this paradigm can be seen in the importance we have attached to classification systems, causal models of understanding mental distress and the framing of psychiatric care as a series of discrete interventions that can be analysed and measured independent of context. 1 In recent years this Journal has published a series of editorials arguing that the profession should adopt an even more technological and biomedical identity, and that psychiatrists should focus on their mastery of technology to allow progress in the development of brain research, genetics, pharmacology and neuroradiology. 2–4 These resonate with calls in North

The transcriptional landscape and small RNAs of Salmonella enterica serovar Typhimurium

Abstract: More than 50 y of research have provided great insight into the physiology, metabolism, and molecular biology of Salmonella enterica serovar Typhimurium (S. Typhimurium), but important gaps in our knowledge remain. It is clear that a precise choreography of gene expression is required for Salmonella infection, but basic genetic information such as the global locations of transcription start sites (TSSs) has been lacking. We combined three RNA-sequencing techniques and two sequencing platforms to generate a robust picture of transcription in S. Typhimurium. Differential RNA sequencing identified 1,873 TSSs on the chromosome of S. Typhimurium SL1344 and 13% of these TSSs initiated antisense transcripts. Unique findings include the TSSs of the virulence regulators phoP, slyA, and invF. Chromatin immunoprecipitation revealed that RNA polymerase was bound to 70% of the TSSs, and two-thirds of these TSSs were associated with σ(70) (including phoP, slyA, and invF) from which we identified the -10 and -35 motifs of σ(70)-dependent S. Typhimurium gene promoters. Overall, we corrected the location of important genes and discovered 18 times more promoters than identified previously. S. Typhimurium expresses 140 small regulatory RNAs (sRNAs) at early stationary phase, including 60 newly identified sRNAs. Almost half of the experimentally verified sRNAs were found to be unique to the Salmonella genus, and <20% were found throughout the Enterobacteriaceae. This description of the transcriptional map of SL1344 advances our understanding of S. Typhimurium, arguably the most important bacterial infection model.

Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.

Abstract: Background Hormone-refractory prostate cancer remains hindered by inevitable progression of resistance to first-line treatment with docetaxel. Recent studies suggest that phenotypic changes associated with cancer may be transferred from cell-to-cell via microvesicles/exosomes. Here we aimed to investigate phenotypic changes associated with docetaxel-resistance in order to help determine the complexity of this problem and to assess the relevance of secreted exosomes in prostate cancer. Methodology/Principal Findings Docetaxel-resistant variants of DU145 and 22Rv1 were established and characterised in terms of cross-resistance, morphology, proliferation, motility, invasion, anoikis, colony formation, exosomes secretion their and functional relevance. Preliminary analysis of exosomes from relevant serum specimens was also performed. Acquired docetaxel-resistance conferred cross-resistance to doxorubicin and induced alterations in motility, invasion, proliferation and anchorage-independent growth. Exosomes expelled from DU145 and 22Rv1 docetaxel-resistant variants (DU145RD and 22Rv1RD) conferred docetaxel-resistance to DU145, 22Rv1 and LNCap cells, which may be partly due to exosomal MDR-1/P-gp transfer. Exosomes from prostate cancer patients’ sera induced increased cell proliferation and invasion, compared to exosomes from age-matched controls. Furthermore, exosomes from sera of patients undergoing a course of docetaxel treatment compared to matched exosomes from the same patients prior to commencing docetaxel treatment, when applied to both DU145 and 22Rv1 cells, showed a correlation between cellular response to docetaxel and patients’ response to treatment with docetaxel. Conclusions/Significance Our studies indicate the complex and multifaceted nature of docetaxel-resistance in prostate cancer. Furthermore, our in vitro observations and preliminary clinical studies indicate that exosomes may play an important role in prostate cancer, in cell-cell communication, and thus may offer potential as vehicles containing predictive biomarkers and new therapeutic targets.