The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model

<p>Abstract</p> <p>Background</p> <p>Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development.</p> <p>Results</p> <p>We find that cell turnover rate increases with decreasing androgen levels, which may increase the rate of mutation and malignant evolution. We model the evolution of a heterogeneous prostate cell population using a continuous state-transition model. Using this model we study selection for AR expression under different androgen levels and find that low androgen environments, caused either by low serum testosterone or by reduced 5<it>α</it>-reductase activity, select more strongly for elevated AR expression than do normal environments. High androgen actually slightly reduces selective pressure for AR upregulation. Moreover, our results suggest that an aberrant androgen environment may delay progression to a malignant phenotype, but result in a more dangerous cancer should one arise.</p> <p>Conclusions</p> <p>The model represents a useful initial framework for understanding the role of androgens in prostate cancer etiology, and it suggests that low androgen levels can increase selection for phenotypes resistant to hormonal therapy that may also be more aggressive. Moreover, clinical treatment with 5<it>α</it>-reductase inhibitors such as finasteride may increase the incidence of therapy resistant cancers.</p> <p>Reviewers</p> <p>This article was reviewed by Ariosto S. Silva (nominated by Marek Kimmel) and Marek Kimmel.</p

The Safety and Efficacy of Phage Therapy for Infections in Cardiac and Peripheral Vascular Surgery:A Systematic Review

New approaches to managing infections in cardiac and peripheral vascular surgery are required to reduce costs to patients and healthcare providers. Bacteriophage (phage) therapy is a promising antimicrobial approach that has been recommended for consideration in antibiotic refractory cases. We systematically reviewed the clinical evidence for phage therapy in vascular surgery to support the unlicensed use of phage therapy and inform future research. Three electronic databases were searched for articles that reported primary data about human phage therapy for infections in cardiac or peripheral vascular surgery. Fourteen reports were eligible for inclusion, representing 40 patients, among which an estimated 70.3% of patients (n = 26/37) achieved clinical resolution. A further 10.8% (n = 4/37) of patients showed improvement and 18.9% (n = 7/37) showed no improvement. Six of the twelve reports that commented on the safety of phage therapy did not report adverse effects. No adverse effects documented in the remaining six reports were directly linked to phages but reflected the presence of manufacturing contaminants or release of bacterial debris following bacterial lysis. The reports identified by this review suggest that appropriately purified phages represent a safe and efficacious treatment option for infections in cardiac and peripheral vascular surgery.</p

The Safety and Efficacy of Phage Therapy for Infections in Cardiac and Peripheral Vascular Surgery:A Systematic Review

New approaches to managing infections in cardiac and peripheral vascular surgery are required to reduce costs to patients and healthcare providers. Bacteriophage (phage) therapy is a promising antimicrobial approach that has been recommended for consideration in antibiotic refractory cases. We systematically reviewed the clinical evidence for phage therapy in vascular surgery to support the unlicensed use of phage therapy and inform future research. Three electronic databases were searched for articles that reported primary data about human phage therapy for infections in cardiac or peripheral vascular surgery. Fourteen reports were eligible for inclusion, representing 40 patients, among which an estimated 70.3% of patients (n = 26/37) achieved clinical resolution. A further 10.8% (n = 4/37) of patients showed improvement and 18.9% (n = 7/37) showed no improvement. Six of the twelve reports that commented on the safety of phage therapy did not report adverse effects. No adverse effects documented in the remaining six reports were directly linked to phages but reflected the presence of manufacturing contaminants or release of bacterial debris following bacterial lysis. The reports identified by this review suggest that appropriately purified phages represent a safe and efficacious treatment option for infections in cardiac and peripheral vascular surgery.</p

Assessing direct contributions of morphological awareness and prosodic sensitivity to children’s word reading and reading comprehension

We examined the independent contributions of prosodic sensitivity and morphological awareness to word reading, text reading accuracy, and reading comprehension. We did so in a longitudinal study of English-speaking children (N = 70). At 5 to 7 years of age, children completed the metalinguistic measures along with control measures of phonological awareness and vocabulary. Children completed the reading measures two years later. Morphological awareness, but not prosodic sensitivity made a significant independent contribution to word reading, text reading accuracy and reading comprehension. The effects of morphological awareness on reading comprehension remained after controls for word reading. These results suggest that morphological awareness needs to be considered seriously in models of reading development and that prosodic sensitivity might have primarily indirect relations to reading outcomes. Keywords: Morphological Awareness; Prosody; Word Reading; Reading Comprehension

Cell autonomous regulation of herpes and influenza virus infection by the circadian clock.

Viruses are intracellular pathogens that hijack host cell machinery and resources to replicate. Rather than being constant, host physiology is rhythmic, undergoing circadian (∼24 h) oscillations in many virus-relevant pathways, but whether daily rhythms impact on viral replication is unknown. We find that the time of day of host infection regulates virus progression in live mice and individual cells. Furthermore, we demonstrate that herpes and influenza A virus infections are enhanced when host circadian rhythms are abolished by disrupting the key clock gene transcription factor Bmal1. Intracellular trafficking, biosynthetic processes, protein synthesis, and chromatin assembly all contribute to circadian regulation of virus infection. Moreover, herpesviruses differentially target components of the molecular circadian clockwork. Our work demonstrates that viruses exploit the clockwork for their own gain and that the clock represents a novel target for modulating viral replication that extends beyond any single family of these ubiquitous pathogens.A.B.R. acknowledges funding from the Wellcome Trust (083643/Z/07/Z, 100333/Z/12/Z and 100574/Z/12/Z), the European Research Council (ERC Starting Grant No. 281348, MetaCLOCK), the EMBO Young Investigators Programme, the Lister Institute of Preventative Medicine and the Medical Research Council (MRC_MC_UU_12012/5). A.D.N acknowledges funding from the People Programme (Marie Curie Actions) of the European Union Seventh Framework Programme (FP7/2007-2013; REA grant agreement 627630). We thank L. Ansel-Bollepalli for assistance with animal breeding, I. Robinson for assistance with pilot animal experiments, A. Snijders and H. Flynn (Francis Crick Institute Proteomics Core) for help with proteomics work, Cambridge NIHR BRC Cell Phenotyping Hub for flow cytometry assistance, A. Miyawaki (RIKEN Brain Science Institute, Japan) for Fucci2 lentiviral vectors, and H. Coleman, J. May and M. Jain for helpful discussions. We thank Prof J. Bass (Northwestern University, USA) for Bmal-/- mouse embryonic fibroblasts used in preliminary experiments, and N. Heaton and P. Palese (Icahn School of Medicine at Mount Sinai, USA) for PB2::Gaussia luciferase IAV (PR8 PB2::GLUC).This is the author accepted manuscript. The final version is available from the National Academy of Sciences via http://dx.doi.org/10.1073/pnas.160189511

Large-scale, high-density (up to 512 channels) recording of local circuits in behaving animals

Monitoring representative fractions of neurons from multiple brain circuits in behaving animals is necessary for understanding neuronal computation. Here we describe a system that allows high channel count recordings from a small volume of neuronal tissue using a lightweight signal multiplexing head-stage that permits free behavior of small rodents. The system integrates multi-shank, high-density recording silicon probes, ultra-flexible interconnects and a miniaturized microdrive. These improvements allowed for simultaneous recordings of local field potentials and unit activity from hundreds of sites without confining free movements of the animal. The advantages of large-scale recordings are illustrated by determining the electro-anatomical boundaries of layers and regions in the hippocampus and neocortex and constructing a circuit diagram of functional connections among neurons in real anatomical space. These methods will allow the investigation of circuit operations and behavior-dependent inter-regional interactions for testing hypotheses of neural networks and brain function

Constraining the Chemical Signatures and the Outburst Mechanism of the Class 0 Protostar HOPS 383

We present observations toward HOPS 383, the first known outbursting Class 0 protostar located within the Orion molecular cloud using ALMA, VLA, and SMA. The SMA observations reveal envelope scale continuum and molecular line emission surrounding HOPS 383 at 0.85 mm, 1.1 mm, and 1.3 mm. The images show that HCO$^+$ and H$^{13}$CO$^+$ peaks on or near the continuum, while N$_2$H$^+$ is reduced at the same position. This reflects the underlying chemistry where CO evaporating close to the protostar destroys N$_2$H$^+$ while forming HCO$^+$. We also observe the molecular outflow traced by $^{12}$CO ($J = 2 \rightarrow 1$) and ($J = 3 \rightarrow 2$). A disk is resolved in the ALMA 0.87 mm dust continuum, orthogonal to the outflow direction, with an apparent radius of $\sim$62 AU. Radiative transfer modeling of the continuum gives disk masses of 0.02 M$_{\odot}$ when fit to the ALMA visibilities. The models including VLA 8 mm data indicate that the disk mass could be up to a factor of 10 larger due to lower dust opacity at longer wavelengths. The disk temperature and surface density profiles from the modeling, and an assumed protostar mass of 0.5 M$_{\odot}$ suggest that the Toomre $Q$ parameter $< 1$ before the outburst, making gravitational instability a viable mechanism to explain outbursts at an early age if the disk is sufficiently massive.Comment: Accepted by Ap