Our vulnerable high streets – death by permitted development?

Ben Clifford, Adam Dennett, Bin Chi and Daniel Slade outline some of the key findings of research on the likely impacts of the latest expansion of permitted development rights

Spirality: A Novel Way to Measure Spiral Arm Pitch Angle

We present the MATLAB code Spirality, a novel method for measuring spiral arm pitch angles by fitting galaxy images to spiral templates of known pitch. Computation time is typically on the order of 2 minutes per galaxy, assuming at least 8 GB of working memory. We tested the code using 117 synthetic spiral images with known pitches, varying both the spiral properties and the input parameters. The code yielded correct results for all synthetic spirals with galaxy-like properties. We also compared the code's results to two-dimensional Fast Fourier Transform (2DFFT) measurements for the sample of nearby galaxies defined by DMS PPak. Spirality's error bars overlapped 2DFFT's error bars for 26 of the 30 galaxies. The two methods' agreement correlates strongly with galaxy radius in pixels and also with i-band magnitude, but not with redshift, a result that is consistent with at least some galaxies' spiral structure being fully formed by z=1.2, beyond which there are few galaxies in our sample. The Spirality code package also includes GenSpiral, which produces FITS images of synthetic spirals, and SpiralArmCount, which uses a one-dimensional Fast Fourier Transform to count the spiral arms of a galaxy after its pitch is determined. The code package is freely available online; see Comments for URL.Comment: 19 pages, 9 figures, 3 tables. The code package is available at http://dafix.uark.edu/~doug/SpiralityCode

Major Depression among methamphetamine users entering drug treatment programs

Objective: To determine the prevalence of major depression among people entering treatment for methamphetamine use. Design, setting and participants: The study was a cross-sectional survey involving 41 specialised drug and alcohol treatment agencies in Brisbane and Sydney. Services provided by these agencies included residential rehabilitation, detoxification and counselling. Participants were 400 people entering treatment for methamphetamine use who were recruited from participating treatment agencies between January 2006 and November 2007. Participants underwent a structured, face-to-face, 1.5-hour interview. Assessment instruments included the Composite International Diagnostic Interview and the Short Form 12. Main outcome measure: Diagnosis of a major depressive episode in the year prior to the study. Results: The prevalence of major depression in the year prior to the study was 40% (95% CI, 35%-44%). A noteworthy post-hoc observation was that a further 44% of participants met the symptom criteria for major depression but were excluded from a diagnosis because their symptoms were better accounted for by psychoactive substance use. Both major depression and these latter cases of "substance-induced depression" were associated with severe symptoms of depression, high levels of disability and suicidal ideation. Conclusion: Most people entering treatment programs for methamphetamine use have levels of depression that require clinical management. Making a diagnosis of major depression in the context of heavy methamphetamine use is problematic because of substance-induced symptoms of depression

Neutral Evolution as Diffusion in phenotype space: reproduction with mutation but without selection

The process of `Evolutionary Diffusion', i.e. reproduction with local mutation but without selection in a biological population, resembles standard Diffusion in many ways. However, Evolutionary Diffusion allows the formation of local peaks with a characteristic width that undergo drift, even in the infinite population limit. We analytically calculate the mean peak width and the effective random walk step size, and obtain the distribution of the peak width which has a power law tail. We find that independent local mutations act as a diffusion of interacting particles with increased stepsize.Comment: 4 pages, 2 figures. Paper now representative of published articl

Implementing the time-to-event continual reassessment method in the presence of partial orders in a phase I head and neck cancer trial

BackgroundIn this article we describe the methodology of the time-to-event continual reassessment method in the presence of partial orders (PO-TITE-CRM) and the process of implementing this trial design into a phase I trial in head and neck cancer called ADePT-DDR. The ADePT-DDR trial aims to find the maximum tolerated dose of an ATR inhibitor given in conjunction with radiotherapy in patients with head and neck squamous cell carcinoma.MethodsThe PO-TITE-CRM is a phase I trial design that builds upon the time-to-event continual reassessment method (TITE-CRM) to allow for the presence of partial ordering of doses. Partial orders occur in the case where the monotonicity assumption does not hold and the ordering of doses in terms of toxicity is not fully known.ResultsWe arrived at a parameterisation of the design which performed well over a range of scenarios. Results from simulations were used iteratively to determine the best parameterisation of the design and we present the final set of simulations. We provide details on the methodology as well as insight into how it is applied to the trial.ConclusionsWhilst being a very efficient design we highlight some of the difficulties and challenges that come with implementing such a design. As the issue of partial ordering may become more frequent due to the increasing investigations of combination therapies we believe this account will be beneficial to those wishing to implement a design with partial orders.Trial registrationADePT-DDR was added to the European Clinical Trials Database (EudraCT number: 2020-001034-35) on 2020-08-07

Genetic Reporter System for Positioning of Proteins at the Bacterial Pole

Spatial organization within bacteria is fundamental to many cellular processes, although the basic mechanisms underlying localization of proteins to specific sites within bacteria are poorly understood. The study of protein positioning has been limited by a paucity of methods that allow rapid large-scale screening for mutants in which protein positioning is altered. We developed a genetic reporter system for protein localization to the pole within the bacterial cytoplasm that allows saturation screening for mutants in Escherichia coli in which protein localization is altered. Utilizing this system, we identify proteins required for proper positioning of the Shigella autotransporter IcsA. Autotransporters, widely distributed bacterial virulence proteins, are secreted at the bacterial pole. We show that the conserved cell division protein FtsQ is required for localization of IcsA and other autotransporters to the pole. We demonstrate further that this system can be applied to the study of proteins other than autotransporters that display polar positioning within bacterial cells.Molecular and Cellular Biolog

Acute Ozone-Induced Differential Gene Expression Profiles in Rat Lung

Ozone (O(3)) is an oxidant gas that can directly induce lung injury. Knowledge of the initial molecular events of the acute O(3) response would be useful in developing biomarkers of exposure or response. Toward this goal, we exposed rats to toxic concentrations of O(3) (2 and 5 ppm) for 2 hr and the molecular changes were assessed in lung tissue 2 hr postexposure using a rat cDNA expression array containing 588 characterized genes. Gene array analysis indicated differential expression in almost equal numbers of genes for the two exposure groups: 62 at 2 ppm and 57 at 5 ppm. Most of these genes were common to both exposure groups, suggesting common roles in the initial toxicity response. However, we also identified the induction of nine genes specific to 2-ppm (thyroid hormone-β receptor c-erb-A-β and glutathione reductase) or 5-ppm exposure groups (c-jun, induced nitric oxide synthase, macrophage inflammatory protein-2, and heat shock protein 27). Injury markers in bronchoalveolar lavage fluid (BALF) were used to assess immediate toxicity and inflammation in rats similarly exposed. At 2 ppm, injury was marked by significant increases in BALF total protein, N-acetylglucosaminidase, and lavageable ciliated cells. Because infiltration of neutrophils was observed only at the higher 5 ppm concentration, the distinctive genes suggested a potential amplification role for inflammation in the gene profile. Although the specific gene interactions remain unclear, this is the first report indicating a dose-dependent direct and immediate induction of gene expression that may be separate from those genes involved in inflammation after acute O(3) exposure

Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2

Protein arginine deiminases (PADs) are calcium-dependent enzymes that mediate the post-translational conversion of arginine into citrulline. Dysregulated PAD activity is associated with numerous autoimmune disorders and cancers. In breast cancer, PAD2 citrullinates histone H3R26 and activates the transcription of estrogen receptor target genes. However, PAD2 lacks a canonical nuclear localization sequence, and it is unclear how this enzyme is transported into the nucleus. Here, we show for the first time that PAD2 translocates into the nucleus in response to calcium signaling. Using BioID2, a proximity-dependent biotinylation method for identifying interacting proteins, we found that PAD2 preferentially associates with ANXA5 in the cytoplasm. Binding of calcium to PAD2 weakens this cytoplasmic interaction, which generates a pool of calcium-bound PAD2 that can interact with Ran. We hypothesize that this latter interaction promotes the translocation of PAD2 into the nucleus. These findings highlight a critical role for ANXA5 in regulating PAD2 and identify an unusual mechanism whereby proteins translocate between the cytosol and nucleus

Chromatin Modifying Agents in the In Vitro Production of Bovine Embryos

The low efficiency observed in cloning by nuclear transfer is related to an aberrant gene expression following errors in epigenetic reprogramming. Recent studies have focused on further understanding of the modifications that take place in the chromatin of embryos during the preimplantation period, through the use of chromatin modifying agents. The goal of these studies is to identify the factors involved in nuclear reprogramming and to adjust in vitro manipulations in order to better mimic in vivo conditions. Therefore, proper knowledge of epigenetic reprogramming is necessary to prevent possible epigenetic errors and to improve efficiency and the use of in vitro fertilization and cloning technologies in cattle and other species